阅读说明：本技术 制成-可实现目标pk曲线的口服药物剂型及其设计和制备方法 (Oral pharmaceutical dosage form capable of achieving target PK profile, design and preparation method thereof ) 是由 邓飞黄 刘昕 郑愉 程洁 成森平 李霄凌 于 2020-07-08 设计创作，主要内容包括：本发明在一些方面涉及设计口服药物剂型的方法,所述口服药物剂型经配制和配置为具有目标药代动力学(PK)曲线。在其他方面,本发明涉及具有目标药代动力学曲线的口服药物剂型,及该口服药物剂型的制备方法,诸如三维打印。(The present invention relates in some aspects to methods of designing an oral pharmaceutical dosage form formulated and configured to have a target Pharmacokinetic (PK) profile. In other aspects, the invention relates to oral pharmaceutical dosage forms having a target pharmacokinetic profile, and methods of making the oral pharmaceutical dosage forms, such as three-dimensional printing.)

1. A method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject,

wherein the oral pharmaceutical dosage form comprises a dosage unit comprising:

a first modified release (MR1) portion, the MR1 portion comprising the drug; and

a second modified release (MR2) portion, the MR2 portion comprising the drug,

the method comprises the following steps:

(a) obtaining a MR1 PK profile in a subject of a MR1 precursor dosage form, said MR1 precursor dosage form comprising said MR1 moiety;

(b) obtaining a MR2 PK profile in a subject of a MR2 precursor dosage form, said MR2 precursor dosage form comprising said MR2 moiety; and

(c) determining the relative amount of the drug in the MR1 and MR2 portions from the MR1 PK profiles and MR2 PK profiles such that the MR1 portion and the MR2 portion when combined together make the oral pharmaceutical dosage form having a composite target PK profile in an individual.

2. A method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject,

wherein the oral pharmaceutical dosage form comprises a dosage unit comprising:

a first modified release (MR1) portion, the MR1 portion comprising the drug; and

a second modified release (MR2) portion, the MR2 portion comprising the drug,

the method comprises the following steps:

determining the relative amounts of said drug in said MR1 and MR2 portions based on the MR1 PK profile in a subject of a MR1 precursor dosage form comprising said MR1 portion and the MR2 PK profile in a subject of a MR2 precursor dosage form comprising said MR2 portion, such that said MR1 portion and said MR2 portion, when combined together, produce said oral pharmaceutical dosage form having a composite target PK profile in a subject.

3. The method of claim 2, further comprising obtaining a MR2 PK profile in a subject of said MR2 precursor dosage form, said MR2 precursor dosage form comprising said MR2 moiety.

4. The method of claim 2 or 3, further comprising a MR1 PK profile of the MR1 precursor dosage form in a subject, the MR1 precursor dosage form comprising the MR1 moiety.

5. The method of any one of claims 1-4, wherein the individual is a human.

6. The method of any one of claims 1-4, wherein the individual is selected from the group consisting of a dog, a rodent, a ferret, a pig, a guinea pig, a rabbit, and a non-human primate.

7. The method of any one of claims 1-6, wherein the drug has linear pharmacokinetics.

8. The method of any one of claims 1-7, wherein the MR1 portion is an MR1 layer.

9. The method of any one of claims 1-8, wherein the MR2 portion is an MR2 layer.

10. The method of any one of claims 1-9, wherein the MR1 portion is an Immediate Release (IR) portion, the IR portion having an immediate release profile.

11. The method according to any one of claims 1-10, wherein the MR2 portion is a sustained release (ER) portion, the ER portion having a sustained release profile.

12. The method of any one of claims 1-9, wherein the MR1 fraction is a first sustained release (ER) fraction having a sustained release profile, and wherein the MR2 fraction is a second sustained release (ER) fraction having a sustained release profile.

13. The method according to any one of claims 1-12, wherein the MR1 portion and the MR2 portion are stacked on top of each other.

14. The method according to any one of claims 1-12, wherein the MR1 portion and the MR2 portion are placed side-by-side with each other.

15. The method according to claim 13 or 14, wherein the MR1 fraction and the MR2 fraction are partially surrounded by a shell, and wherein the shell has a slower dissolution rate than the ER fraction.

16. The method of claim 15, wherein the shell is non-erodable.

17. The method of claim 15 or 16, wherein the MR1 portion has an upper surface and a lower surface, wherein the MR2 portion has an upper surface and a lower surface, and wherein the shell is in direct contact with the MR1 portion and the MR2 portion, and leaves one surface of the MR1 portion and/or one surface of the MR2 portion exposed.

18. The method of claim 17, wherein the MR1 portion is stacked over the MR2 portion, and wherein the shell leaves only an upper surface of the MR1 portion exposed.

19. The method of claim 18, wherein a lower surface of the MR1 portion is in direct contact with an upper surface of the MR2 portion.

20. The method of claim 18 or 19, wherein the dosage unit further comprises a third modified release (MR3) portion, wherein the MR3 portion is an IR portion having an immediate release profile.

21. The method of claim 20, wherein the MR3 portion has an upper surface and a lower surface, wherein the MR2 portion is stacked over the MR3 portion, and wherein the shell leaves only the upper surface of the MR1 portion exposed.

22. The method of claim 21, wherein a lower surface of the MR2 portion is in direct contact with an upper surface of the MR3 portion.

23. The method of claim 17, wherein the MR2 portion is stacked over the MR1 portion, and wherein the shell leaves only an upper surface of the MR2 portion exposed.

24. The method of claim 23, wherein a lower surface of the MR2 portion is in direct contact with an upper surface of the MR1 portion.

25. The method of claim 17, wherein the MR1 portion is stacked over the MR2 portion, and wherein the shell leaves exposed an upper surface of the MR1 portion and a lower surface of the MR2 portion.

26. The method of claim 25, wherein a lower surface of the MR1 portion is in direct contact with an upper surface of the MR2 portion.

27. The method of claim 25, wherein the shell is between the MR1 portion and the MR2 portion.

28. The method of claim 25, wherein said dosage unit further comprises an intermediate portion, wherein said intermediate portion is between said MR1 portion and said MR2 portion.

29. The method of claim 17, wherein the MR1 and MR2 portions are placed side-by-side with each other, wherein the shell leaves exposed the upper surfaces of the MR1 and MR2 portions.

30. The method of claim 29, wherein the MR1 portion has side surfaces, wherein the MR2 portion has side surfaces, and wherein the side surfaces of the MR1 portion are in direct contact with the side surfaces of the MR2 portion.

31. The method of claim 29, wherein the shell separates the MR1 portion from the MR2 portion.

32. The method of claim 29, wherein said dosage unit further comprises an intermediate portion, wherein said intermediate portion is between said MR1 portion and said MR2 portion.

33. The method of any one of claims 1-32, wherein the oral pharmaceutical dosage form comprises two dosage units.

34. The method of claim 33, wherein the two dosage units are the same.

35. A method as in claim 33, wherein the two dosage units are different.

36. The method of any one of claims 33-35, wherein the two dosage units are stacked back-to-back.

37. A method according to claim 36, wherein the two dosage units are separated by the shell.

38. A method according to claim 36, wherein the two dosage units are separated by an intermediate portion.

39. The method of any one of claims 1-38, wherein at least 80% of the MR1 partially erodes within about 60 minutes after administration of the oral pharmaceutical dosage form to the subject.

40. The method of claim 29, wherein the MR1 portion comprises an erodable material.

41. The method of any one of claims 1-40, wherein said MR2 portion comprises an erodible material, and wherein the drug contained in said MR2 portion is released from said oral pharmaceutical dosage form over a period of at least about 5 hours.

42. The method of any one of claims 1-41, wherein the composite target PK profile has an area under the curve (AUC) and a Cc within an acceptable threshold of a reference PK profile for the drug_maxAnd (4) determining.

43. The method of claim 42, wherein the composite target PK profile is further based on having a t within an acceptable threshold of a reference PK profile for the drug_maxAnd (4) determining.

44. The method according to any one of claims 1-43, wherein said method comprises selecting one or more parameters for said MR2 fraction to obtain a target release profile of drug from said MR2 fraction.

45. The method of claim 44, wherein the one or more parameters are selected from the group consisting of: thickness, surface area, matrix erosion rate, and drug concentration in MR2 section.

46. The method of any one of claims 1-45, further comprising determining the MR1 PK profile and the MR2 PK profile and correcting for the relative amounts of drug in the MR1 and the MR2 fractions.

47. The method of any one of claims 1-46, further comprising determining a composite PK profile for the oral pharmaceutical dosage form.

48. The method of claim 47, further comprising correcting the relative amount of drug in the MR1 fraction based on a comparison of the composite PK profile to the composite target PK profile.

49. The method of any one of claims 1-48, further comprising forming the oral pharmaceutical dosage form.

50. The method of claim 49, wherein the oral pharmaceutical dosage form is made by three-dimensional printing.

51. The method of claim 50, wherein the three-dimensional printing is by Fused Deposition Modeling (FDM).

52. The method of claim 50, wherein the three-dimensional printing is performed by Melt Extrusion Deposition (MED).

53. A method of three-dimensional printing of an oral pharmaceutical dosage form designed according to any of claims 1-52.

54. An oral pharmaceutical dosage form made by the method of claim 53.

55. An oral pharmaceutical dosage form comprising a fixed amount of a drug formulated and configured to have a composite target Pharmacokinetic (PK) profile, the oral pharmaceutical dosage form having two dosage units stacked back-to-back, wherein each dosage unit comprises:

an Immediate Release (IR) portion comprising a drug, the IR portion having an immediate release profile;

an Extended Release (ER) portion comprising a drug, the ER portion having an extended release profile; and

the shell is provided with a plurality of grooves,

wherein the IR portion has an upper surface and a lower surface, wherein the ER portion has an upper surface and a lower surface, wherein the shell partially surrounds the IR portion and the ER portion, and wherein the shell is in direct contact with the IR portion and the ER portion and leaves one surface of the IR portion and/or one surface of the ER portion exposed.

56. The oral pharmaceutical dosage form of claim 55, wherein the drug has linear pharmacokinetics.

57. The oral pharmaceutical dosage form of claim 55 or 56, wherein the shell is non-erodable.

58. The oral pharmaceutical dosage form of any one of claims 55-57, wherein the IR and ER portions are stacked on top of one another.

59. The oral pharmaceutical dosage form of any one of claims 55-57, wherein the IR and ER moieties are positioned side-by-side one another.

60. The oral pharmaceutical dosage form of claim 58, wherein, in at least one of the dosage units, the IR portion is stacked over the ER portion, and wherein the shell leaves only an upper surface of the IR portion exposed.

61. The oral pharmaceutical dosage form of claim 60, wherein the lower surface of the IR is in direct contact with the upper surface of the ER moiety.

62. The oral pharmaceutical dosage form of claim 60 or 61, wherein the dosage form unit further comprises a second IR portion, wherein the second IR portion has an upper surface and a lower surface, wherein the ER portion is stacked over the second IR portion, and wherein the shell leaves only the upper surface of the IR portion exposed.

63. The oral pharmaceutical dosage form of claim 62, wherein a lower surface of the ER moiety is in direct contact with an upper surface of the second IR moiety.

64. The oral pharmaceutical dosage form of claim 58, wherein, in at least one of the dosage units, the ER portion is stacked over the IR portion, and wherein the shell leaves only an upper surface of the ER portion exposed.

65. The oral pharmaceutical dosage form of claim 64, wherein a lower surface of the ER is in direct contact with an upper surface of the IR moiety.

66. The oral pharmaceutical dosage form according to claim 59, wherein, in at least one of the dosage units, the IR portion and the ER portion are positioned alongside one another, and wherein the shell leaves exposed an upper surface of the IR portion and the ER portion.

67. The oral pharmaceutical dosage form of any one of claims 55-66, wherein the two dosage units are identical.

68. The oral pharmaceutical dosage form of any one of claims 55-66, wherein the two dosage units are different.

69. The oral pharmaceutical dosage form of any one of claims 55-68, wherein substantially all of the IR portion erodes within at least about 20 minutes after administration of the oral pharmaceutical dosage form to a subject.

70. The oral pharmaceutical dosage form of claim 69, wherein the IR portion comprises an erodable material.

71. The oral pharmaceutical dosage form of any one of claims 55-70, wherein the ER portion comprises an erodable material, and wherein the drug contained in the ER portion is released from the oral pharmaceutical dosage form over a period of at least about 6 hours.

Technical Field

The present disclosure, in some aspects, relates to methods of designing an oral pharmaceutical dosage form formulated and configured to have a target pharmacokinetic profile. In other aspects, the disclosure relates to oral pharmaceutical dosage forms having a target pharmacokinetic profile, and methods of making the oral pharmaceutical dosage forms, such as three-dimensional printing.

Background

Increasingly, understanding the mechanisms of drugs and agents is underscoring the importance of the accuracy of drug delivery in vivo to ensure optimal delivery in terms of location, time and amount to achieve a target pharmacokinetic profile for optimal use, efficacy and safety of the drugs, drug candidates and agents. Certain drugs and agents may require, for example, complex release profiles and/or dosing schedules in order to achieve a target pharmacokinetic profile. However, this need often runs counter to manufacturing limitations and ensures proper use and patient compliance by simplifying administration (e.g., once daily, oral dosage form or delivery system). Furthermore, even based on assays such as in vitro release profile assays, the design of a pharmaceutical dosage form capable of achieving a target pharmacokinetic profile in a subject may not be readily available.

All references, including patent applications and publications, cited herein are hereby incorporated by reference in their entirety.

Disclosure of Invention

In some aspects, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: a first modified release (MR1) portion, the MR1 portion comprising the drug; and a second modified release (MR2) portion, the MR2 portion comprising the drug, the method comprising: (a) obtaining a MR1 PK profile in a subject of a MR1 precursor dosage form, said MR1 precursor dosage form comprising said MR1 moiety;

(b) obtaining a MR2 PK profile in a subject of a MR2 precursor dosage form, said MR2 precursor dosage form comprising said MR2 moiety; and (c) determining the relative amount of said drug in said MR1 and MR2 fractions according to said MR1 PK profile and MR2 PK profile, such that said MR1 fraction and said MR2 fraction when combined together make said oral pharmaceutical dosage form having a composite target PK profile in a subject.

In another aspect, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: a first modified release (MR1) portion, the MR1 portion comprising the drug; and a second modified release (MR2) portion, the MR2 portion comprising the drug, the method comprising: determining the relative amounts of said drug in said MR1 and MR2 portions based on the MR1 PK profile in a subject of a MR1 precursor dosage form comprising said MR1 portion and the MR2 PK profile in a subject of a MR2 precursor dosage form comprising said MR2 portion, such that said MR1 portion and said MR2 portion, when combined together, produce said oral pharmaceutical dosage form having a composite target PK profile in a subject.

In some embodiments, the method further comprises obtaining a MR2 PK profile in a subject of said MR2 precursor dosage form, said MR2 precursor dosage form comprising said MR2 moiety.

In some embodiments, the method further comprises obtaining a MR1 PK profile in a subject of said MR1 precursor dosage form, said MR1 precursor dosage form comprising said MR1 moiety.

In some embodiments, the individual is a human. In some embodiments, the individual is selected from the group consisting of dogs, rodents, ferrets, pigs, guinea pigs, rabbits, and non-human primates.

In some embodiments, the drug has linear pharmacokinetics.

In some embodiments, the MR1 portion is an MR1 layer. In some embodiments, the MR2 portion is an MR2 layer.

In some embodiments, the MR1 portion is an Immediate Release (IR) portion, the IR portion having an immediate release profile. In some embodiments, the MR2 portion is a sustained release (ER) portion, the ER portion having a sustained release profile.

In some embodiments, the MR1 portion is a first sustained release (ER) portion having a sustained release profile, and the MR2 portion is a second sustained release (ER) portion having a sustained release profile.

In some embodiments, the MR1 portion and the MR2 portion are stacked on top of each other. In some embodiments, the MR1 portion and the MR2 portion are placed side-by-side with each other.

In some embodiments, the MR1 portion and the MR2 portion are partially surrounded by a shell, and wherein the shell has a slower dissolution rate than the ER portion. In some embodiments, the shell is not erodible.

In some embodiments, the MR1 portion has an upper surface and a lower surface, wherein the MR2 portion has an upper surface and a lower surface, and wherein the shell is in direct contact with the MR1 portion and the MR2 portion, and leaves one surface of the MR1 portion and/or one surface of the MR2 portion exposed.

In some embodiments, the MR1 portion is stacked over the MR2 portion, and wherein the shell leaves only an upper surface of the MR1 portion exposed. In some embodiments, the lower surface of the MR1 portion is in direct contact with the upper surface of the MR2 portion.

In some embodiments, the dosage unit further comprises a third modified release (MR3) portion. In some embodiments, the MR3 portion is an IR portion having an immediate release profile. In some embodiments, the MR3 portion is an ER portion having a sustained release profile. In some embodiments, the MR3 portion has an upper surface and a lower surface, wherein the MR2 portion is stacked over the MR3 portion, and wherein the shell leaves only the upper surface of the MR1 portion exposed. In some embodiments, the lower surface of the MR2 portion is in direct contact with the upper surface of the MR3 portion.

In some embodiments, the MR2 portion is stacked over the MR1 portion, and wherein the shell leaves only an upper surface of the MR2 portion exposed. In some embodiments, the lower surface of the MR2 portion is in direct contact with the upper surface of the MR1 portion.

In some embodiments, the MR1 portion is stacked over the MR2 portion, and wherein the shell leaves exposed an upper surface of the MR1 portion and a lower surface of the MR2 portion. In some embodiments, the lower surface of the MR1 portion is in direct contact with the upper surface of the MR2 portion. In some embodiments, the shell is between the MR1 portion and the MR2 portion. In some embodiments, the dosage unit further comprises an intermediate portion, wherein the intermediate portion is between the MR1 portion and the MR2 portion.

In some embodiments, the MR1 portion and the MR2 portion are placed alongside each other, with the shell leaving the upper surfaces of the MR1 portion and the MR2 portion exposed. In some embodiments, the MR1 portion has side surfaces, wherein the MR2 portion has side surfaces, and wherein the side surfaces of the MR1 portion are in direct contact with the side surfaces of the MR2 portion. In some embodiments, the shell separates the MR1 portion from the MR2 portion. In some embodiments, the dosage unit further comprises an intermediate portion, wherein the intermediate portion is between the MR1 portion and the MR2 portion.

In some embodiments, the oral pharmaceutical dosage form comprises two dosage units. In some embodiments, the two dosage units are the same. In some embodiments, the two dosage units are different. In some embodiments, the two dosage units are stacked back-to-back. In some embodiments, the two dosage units are separated by the shell. In some embodiments, the two dosage units are separated by an intermediate portion.

In some embodiments, at least 80% of the MR1 partially erodes within about 60 minutes after administration of the oral pharmaceutical dosage form to the subject. In some embodiments, the MR1 portion includes an erodable material.

In some embodiments, the MR2 portion comprises an erodible material, and wherein the drug contained in the MR2 portion is released from the oral pharmaceutical dosage form over a period of at least about 5 hours.

In some embodiments, the composite target PK profile has an area under the curve (AUC) and C within an acceptable threshold of a reference PK profile for the drug_maxAnd (4) determining. In some embodiments, the composite target PK profile is further based on t having within an acceptable threshold of a reference PK profile for the drug_maxAnd (4) determining.

In some embodiments, the method comprises selecting one or more parameters for the MR2 moiety to obtain a target release profile of drug from the MR2 moiety. In some embodiments, the one or more parameters are selected from the group consisting of: thickness, surface area, matrix erosion rate, and drug concentration in MR2 section.

In some embodiments, the method further comprises determining the MR1 PK profile and the MR2 PK profile, and correcting the relative amounts of drug in the MR1 and the MR2 fractions.

In some embodiments, the method further comprises determining a composite PK profile for the oral pharmaceutical dosage form. In some embodiments, the method further comprises correcting the relative amount of drug in the MR1 fraction based on a comparison of the composite PK profile to the composite target PK profile.

In some embodiments, the method further comprises preparing the oral pharmaceutical dosage form. In some embodiments, the oral pharmaceutical dosage form is prepared by three-dimensional printing. In some embodiments, the three-dimensional printing is by Fused Deposition Modeling (FDM). In some embodiments, the three-dimensional printing is performed by Melt Extrusion Deposition (MED).

In another aspect, the present invention provides a method of three-dimensional printing of an oral pharmaceutical dosage form designed according to any of the methods described herein.

In another aspect, the present invention provides an oral pharmaceutical dosage form prepared by the method described herein.

In another aspect, the present invention provides an oral pharmaceutical dosage form comprising a fixed amount of a drug formulated and configured to have a composite target Pharmacokinetic (PK) profile, the oral pharmaceutical dosage form having two dosage units stacked back-to-back, wherein each dosage unit comprises: a first modified release (MR1) portion, the MR1 portion comprising the drug; a second modified release (MR2) portion, the MR2 portion comprising the drug; and a shell, wherein the MR1 portion has an upper surface and a lower surface, wherein the MR2 portion has an upper surface and a lower surface, wherein the shell partially surrounds the MR1 portion and the MR2 portion, and wherein the shell is in direct contact with the MR1 portion and the MR2 portion, and leaves one surface of the MR1 portion and/or one surface of the MR2 portion exposed. In some embodiments, the MR1 portion is an IR portion having an immediate release profile and the MR2 portion is an Extended Release (ER) portion having an extended release profile. In some embodiments, the MR1 portion is a first ER portion having a sustained release profile and the MR2 portion is a second sustained release (ER) portion comprising the drug, the second ER portion having a sustained release profile. In some embodiments, the drug has linear pharmacokinetics. In some embodiments, the shell is not erodible. In some embodiments, the MR1 portion and the MR2 portion are stacked on top of each other. In some embodiments, the MR1 portion and the MR2 portion are placed side-by-side with each other. In some embodiments, at least in one of the dosage units, the MR1 portion is stacked over the MR2 portion, and wherein the shell leaves only the upper surface of the MR1 portion exposed. In some embodiments, the lower surface of the MR1 portion is in direct contact with the upper surface of the MR2 portion. In some embodiments, the dosage unit further comprises a third modified release (MR3) portion. In some embodiments, the MR3 portion is an IR portion. In some embodiments, the MR3 portion is an ER portion. In some embodiments, the MR3 portion is an IR portion, wherein the MR3 portion has an upper surface and a lower surface, wherein the MR2 portion is stacked over the MR3 portion, and wherein the shell leaves only the upper surface of the MR1 portion exposed. In some embodiments, the lower surface of the MR2 portion is in direct contact with the upper surface of the MR3 portion. In some embodiments, at least in one of the dosage units, the MR2 portion is stacked over the MR1 portion, and wherein the shell leaves only the upper surface of the MR2 portion exposed. In some embodiments, the lower surface of the MR2 portion is in direct contact with the upper surface of the MR1 portion. In some embodiments, at least in one of the dosage units, the MR1 portion and the MR2 portion are placed side-by-side with each other, and wherein the shell leaves exposed the upper surfaces of the MR1 portion and the MR2 portion. In some embodiments, the two dosage units are the same. In some embodiments, the two dosage units are different. In some embodiments, substantially all of the MR1 portion erodes within at least about 20 minutes after administration of the oral pharmaceutical dosage form to a subject. In some embodiments, the MR1 portion includes an erodable material. In some embodiments, the MR2 portion comprises an erodible material, and wherein the drug contained in the MR2 portion is released from the oral pharmaceutical dosage form over a period of at least about 6 hours.

In another aspect, the present invention provides an oral pharmaceutical dosage form comprising a fixed amount of a drug formulated and configured to have a composite target Pharmacokinetic (PK) profile, the oral pharmaceutical dosage form having two dosage units stacked back-to-back, wherein each dosage unit comprises: an Immediate Release (IR) portion comprising a drug, the IR portion having an immediate release profile; an Extended Release (ER) portion comprising a drug, the ER portion having an extended release profile; and a shell, wherein the IR portion has an upper surface and a lower surface, wherein the ER portion has an upper surface and a lower surface, wherein the shell partially surrounds the IR portion and the ER portion, and wherein the shell is in direct contact with the IR portion and the ER portion and leaves one surface of the IR portion and/or one surface of the ER portion exposed. In some embodiments, the drug has linear pharmacokinetics. In some embodiments, the shell is not erodible. In some embodiments, the IR and ER portions are stacked on top of each other. In some embodiments, the IR and ER moieties are placed side-by-side to each other. In some embodiments, at least in one of the dosage units, the IR portion is stacked over the ER portion, and wherein the shell leaves only an upper surface of the IR portion exposed. In some embodiments, the lower surface of the IR is in direct contact with the upper surface of the ER portion. In some embodiments, the dosage unit further comprises a second IR portion, wherein the second IR portion has an upper surface and a lower surface, wherein the ER portion is stacked over the second IR portion, and wherein the shell leaves only the upper surface of the IR portion exposed. In some embodiments, the lower surface of the ER is in direct contact with the upper surface of the second IR moiety. In some embodiments, at least in one of the dosage units, the ER portion is stacked over the IR portion, and wherein the shell leaves only an upper surface of the ER portion exposed. In some embodiments, the lower surface of the ER is in direct contact with the upper surface of the IR moiety. In some embodiments, at least in one of the dosage units, the IR portion and the ER portion are positioned alongside each other, and wherein the shell leaves an upper surface of the IR portion and the ER portion exposed. In some embodiments, the two dosage units are the same. In some embodiments, the two dosage units are different. In some embodiments, substantially all of the IR portion erodes within at least about 20 minutes after administration of the oral pharmaceutical dosage form to a subject. In some embodiments, the IR portion comprises an erodable material. In some embodiments, the ER portion comprises an erodable material, and wherein the drug contained in the ER portion is released from the oral pharmaceutical dosage form over a period of at least about 6 hours.

It will also be understood by those of ordinary skill in the art that changes in form and details of the embodiments described herein may be made without departing from the scope of the present invention. Furthermore, although advantages, aspects, and objects have been described with reference to various embodiments, the scope of the invention should not be limited by reference to such advantages, aspects, and objects.

Drawings

Exemplary dosage units and oral pharmaceutical dosage forms are shown in fig. 1A-1J.

Fig. 2A-2E show deconstructed cross-sectional views of exemplary dosage units and oral pharmaceutical dosage forms.

FIG. 3 is a representation of dosage form source design by 3D printingAn exemplary workflow diagram of (a).

Fig. 4A-4E show schematic diagrams of exemplary oral pharmaceutical dosage forms, which include an Extended Release (ER) portion, an Immediate Release (IR) portion, and a shell. Fig. 4A is an exploded view of an oral pharmaceutical dosage form to show its individual components. Fig. 4B depicts an assembled oral pharmaceutical dosage form. Fig. 4C is a schematic diagram showing spatial aspects of an oral drug dosage form. Fig. 4D shows the composition of components of an oral pharmaceutical dosage form. Fig. 4E is a cross-sectional view of an oral pharmaceutical dosage form.

Figure 5 shows the in vivo pharmacokinetic profiles of the IR precursor dosage form and the IR reference pharmaceutical dosage form.

Figure 6 shows the in vivo pharmacokinetic profile of the ER precursor dosage form.

Figure 7 shows theoretical simulated PK profiles for oral drug dosage forms with different IR: ER drug ratios compared to PK profiles for the specific drug.

Figure 8 shows the in vivo pharmacokinetic profiles of a complete oral drug dosage form containing 100mg drug, an IR reference drug dosage form containing 50mg drug, and an ER reference drug dosage form containing 100mg drug.

Figure 9 shows the in vitro dissolution of a complete oral pharmaceutical dosage form containing 100mg drug and an ER reference pharmaceutical dosage form containing 100mg drug.

Figure 10 shows the in vivo pharmacokinetic profile of the optimized oral pharmaceutical dosage form.

FIG. 11 shows the in vivo pharmacokinetic profiles of an ER prodrug dosage form containing 100mg drug and an ER reference drug dosage form containing 100mg drug.

Figure 12 shows the in vivo pharmacokinetic profiles of the optimized 3D printed oral drug dosage form (100mg drug), the theoretical prediction of the 3D printed oral drug dosage form (100mg drug), the ER reference drug dosage form (100mg drug) and the IR reference drug dosage form (50mg drug).

Fig. 13A shows an exploded view of an oral drug dosage form 1400, which includes an ER portion (including drug 1405), an IR portion (including drug 1410), and a shell 1415. Fig. 13B shows PK profiles for IR precursor dosage forms and ER precursor dosage forms of oral drug dosage forms. Fig. 13C shows theoretical simulated PK profiles for oral drug dosage forms with different IR to ER drug ratios. Figure 13D shows the in vivo PK profile for an oral drug dosage form with an IR to ER drug ratio of 1:1 versus the theoretical simulated PK profile for an oral drug dosage form with an IR to ER drug ratio of 1: 1.

Detailed Description

The present invention provides a novel method of designing an oral pharmaceutical dosage form having a fixed amount of drug, the oral pharmaceutical dosage form comprising dosage units comprising: a first modified release (MR1) portion (such as an Immediate Release (IR) portion), the MR1 portion comprising the drug; and a second modified release (MR2) portion (such as an Extended Release (ER) portion), the MR2 portion comprising the drug, designed to meet a composite target PK profile in a subject based on the MR1 PK profile of a MR1 precursor dosage form comprising the MR1 portion and the MR2 PK profile of a MR2 precursor dosage form comprising the MR2 portion. As demonstrated herein, the inventors have discovered that based on PK data, such as MR1 PK profiles and/or MR2 PK profiles of precursor dosage forms, such oral pharmaceutical dosage forms can be designed by determining the relative amounts of drug in the MR1 portion (such as the IR portion) and the MR2 portion (such as the ER portion) of the dosage unit, such that the MR1 portion and the MR2 portion when combined together form the oral pharmaceutical dosage form, a composite target PK profile is obtained. In some aspects, the methods described herein may be applied to design an oral pharmaceutical dosage form having a fixed amount of drug and a composite target PK profile in a subject, wherein the oral pharmaceutical dosage form comprises a dosage unit comprising more than one ER portion and/or more than one IR portion. In some aspects, an oral pharmaceutical dosage form can be designed to be bioequivalent to a reference pharmaceutical dosage form or reference administration regimen using the methods described herein. Oral pharmaceutical dosage forms designed using the methods described herein can be readily printed using three-dimensional printing (3D) techniques or manufacturing techniques including 3D printing techniques. Such pharmaceutical dosage forms can be designed, for example, to improve efficacy, reduce toxicity and improve patient compliance by, for example, designing oral pharmaceutical dosage forms for once-a-day dosing regimens that are bioequivalent to regimens involving administration of the pharmaceutical dosage form two or more times per day. Further provided herein are novel oral pharmaceutical dosage forms, such as those produced by the methods described herein.

Provided herein are dosage form origins in design via 3D printingBy designing an oral pharmaceutical dosage form (including dosage forms having complex geometries) with a target pharmacokinetic profile.By means of a multipart design, provision is made for the production to haveA customizable and easily optimized method of 3D printing solid pharmaceutical dosage forms of a target PK profile, and thus can be used to efficiently and effectively design and manufacture drug delivery systems. As described herein, the inventionThe method can be used to design a modified release dosage form having a predetermined in vivo release profile. This innovative approach provides means for example to predictably and expeditiously develop preclinical and clinical trial prescriptions. The method described herein isExamples of the manner.

Although most of the present application discusses oral pharmaceutical dosage forms, one of ordinary skill in the art will readily appreciate that the present invention is also applicable to and directed to other oral dosage forms configured and formulated to provide a target PK profile for any compound, such as dosage forms that include an agent (e.g., oral agent dosage forms).

It will also be understood by those of ordinary skill in the art that changes in form and details of the embodiments described herein may be made without departing from the scope of the present invention. Furthermore, although advantages, aspects, and objects have been described with reference to various embodiments, the scope of the invention should not be limited by reference to such advantages, aspects, and objects.

Definition of

For the purpose of interpreting this specification, the following definitions will apply and where appropriate, terms used in the singular will also include the plural and vice versa. In the event that any of the definitions set forth below conflict with any document incorporated by reference, the proposed definition controls.

As used herein, unless otherwise specified, "rate of release" or "release rate" of a drug refers to the amount of drug released from a dosage form per unit time, e.g., milligrams of drug released per hour (mg/hour) or the percentage of the total drug dose released per hour. The drug release rate of a dosage form is typically measured as the in vitro release rate of the drug, e.g., the amount of drug released from the dosage form per unit time measured under suitable conditions and in a suitable fluid.

The "zero order release profile" characterizes the release profile of a dosage form that releases a constant amount of drug per unit time. The pseudo zero order release profile is a profile that approximates a zero order release profile. If the release rate of the dissolution profile remains constant (or relatively constant within 10% of the mean) over a time interval of 0. ltoreq. a < t. ltoreq.b, the dissolution profile shows a zero-order or pseudo-zero-order release profile. Any curve follows the equation: (M (t)/M_r)＝k(t-a)ⁿ0. ltoreq. n.ltoreq.1.1 has the following release rate equation: (1/M) (dM/dt) ═ kn (t-a)^n-1。

The "first order release profile" characterizes the release profile of a dosage form that releases a certain percentage of the drug load per unit time. The pseudo first order release profile is a profile that approximates the first order release profile. If the release rate of the dissolution profile is a continuous single decreasing function of time, the dissolution profile shows a first order or pseudo-first order release profile over a time interval 0. ltoreq. a < t. ltoreq.b. Specifically, the dissolution profile shows a first order profile, as long as its release rate is proportional to the remaining, undisolved amount of drug, as shown in the following equation: (M (t)/MT) ═ 1-exp (-kt). As shown in the Fickian or anomalous Fickian diffusion controlled release equation, the dissolution profile shows a pseudo first order profile as the drug release rate decreases over time: (MW/M)_T)＝ktⁿ,0.3≤n≤0.7。

The maximum plasma drug concentration during administration is called C_maxAnd C is_minRefers to the minimum plasma drug concentration at the end of the dosing interval; c_aveRefers to the average concentration during the dosing interval. "volatility" is defined as the quotient (C)_max-C_min)/C_ave。

One skilled in the art will appreciate that the plasma drug concentration obtained in an individual subject will vary due to patient-to-patient variability in many parameters that affect drug absorption, distribution, metabolism, and excretion. Thus, when drug plasma concentrations are listed, the values listed are averages calculated based on values obtained from a group of test subjects, unless otherwise specified.

The term "bioavailability" refers to the degree (and sometimes rate) at which an active moiety (drug or metabolite) enters the systemic circulation and thus can enter the site of action.

"AUC" is the area under the plasma concentration-time curve and is considered to be the most reliable indicator of bioavailability. It is proportional to the total amount of drug in its original form that reaches the systemic circulation.

As used herein, "treatment" (therapy) or "treatment" (therapy) is a method for obtaining beneficial or targeted results, including clinical results. For purposes of the present invention, beneficial or targeted clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, reducing the dosage of one or more other drugs required to treat the disease, and/or improving the quality of life.

As used herein, the term "individual" refers to a mammal, including but not limited to a human, bovine, equine, feline, canine, rodent, rat, mouse, canine, or primate. In some embodiments, the individual is a human.

As used herein, the terms "comprising," "having," "containing," and "including" and other similar forms, as well as grammatical equivalents thereof, are intended to be equivalent in meaning and the open end of any one of these terms does not indicate an exhaustive list of the item or items, nor does it indicate limitation to the listed item or items. For example, an article "comprising" components A, B and C can consist of (i.e., contain only) component A, B and C, or can contain not only component A, B and C, but one or more other components. Likewise, it is intended and understood that the disclosure of "including" and its equivalents, as well as grammatical equivalents thereof, includes embodiments that "consist essentially of … …" or "consist of … …".

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that range is encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

Reference herein to a "value or parameter of" about "includes (and describes) variations that are directed to that value or parameter itself. For example, a description referring to "about X" includes a description of "X".

As used herein, including in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

Method for designing oral pharmaceutical dosage forms

In some aspects, the present invention provides methods of designing an oral pharmaceutical dosage form described herein having a fixed amount of a drug and having a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises at least one drug unit comprising a MR1 portion, such as an IR portion or an ER portion, and a MR2 portion, such as an IR portion or an ER portion, the MR1 portion comprising the drug, the MR2 portion comprising the drug. The IR portion has an immediate release profile; and a sustained release (ER) portion, the ER portion comprising the drug, the ER portion having a sustained release profile. In some embodiments, the oral pharmaceutical dosage form comprises a dosage unit comprising: a first ER portion comprising the drug, the first ER portion having a sustained release profile; and a second ER portion comprising the drug, the second ER portion having a sustained release profile. In some embodiments, the dosage unit further comprises another component, such as another commissioning portion, e.g. an IR portion (such as an IR layer) or an ER portion (such as an ER layer), an intermediate portion or a shell.

For the sake of brevity, in many of the embodiments disclosed herein, dosage forms comprising an IR portion (as part of MR1) and an ER portion (as part of MR2) are described to illustrate the present invention. The present disclosure should not be construed as limiting the description herein and such teachings are also applicable to other configurations in which MR1 portion and/or MR2 portion are different debug portions.

FIG. 3 provides the description hereinExemplary schematic of the approach. Specifically, in some embodiments, the method comprises: modular PK analysis of precursor dosage forms, such as IR precursor dosage forms and ER precursor dosage forms; based on theoretical simulations of modular PK analysis, for one or more combination oral pharmaceutical dosage forms having a drug ratio of IR moiety to ER moiety (IR: ER drug ratio); and subsequent steps such as 3D printing of oral pharmaceutical dosage forms and in vivo and/or in vitro testing.

In some embodiments, the method comprises: determining the relative amounts of said drug in said MR1 and MR2 portions based on the MR1 PK profile in a subject of a MR1 precursor dosage form comprising said MR1 portion and the MR2 PK profile in a subject of a MR2 precursor dosage form comprising said MR2 portion, such that said MR1 portion and said MR2 portion, when combined together, produce said oral pharmaceutical dosage form having a composite target PK profile in a subject. In some embodiments, the method comprises: (a) obtaining a MR1 PK profile in a subject of a MR1 precursor dosage form, said MR1 precursor dosage form comprising said MR1 moiety; (b) obtaining a MR2 PK profile in a subject of a MR2 precursor dosage form, said MR2 precursor dosage form comprising said MR2 moiety; and (c) determining the relative amount of said drug in said MR1 and MR2 fractions from said MR1 PK profile and said MR2 PK profile, such that said MR1 fraction and said MR2 fraction when combined together make said oral pharmaceutical dosage form having a composite target PK profile in an individual. In some embodiments, the drug has linear pharmacokinetics.

In some embodiments, the method comprises: determining the relative amounts of the drug in the IR moiety and the ER moiety based on an IR PK profile in the subject for an IR precursor dosage form comprising the IR moiety and an ER PK profile in the subject for an ER precursor dosage form comprising the ER moiety, such that the IR moiety and the ER moiety, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the method comprises: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER moiety; and (c) determining the relative amount of the drug in the IR portion and the ER portion from the IR PK profile and the ER PK profile, such that the IR portion and the ER portion when combined together form the oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the drug has linear pharmacokinetics.

In other aspects, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) portion comprising the drug, the IR portion having an immediate release profile; and a sustained release (ER) portion comprising the drug, the ER portion having a sustained release profile, wherein the IR portion and the ER portion are stacked on top of each other, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER moiety; and (c) determining the relative amount of the drug in the IR portion and the ER portion from the IR PK profile and the ER PK profile, such that the IR portion and the ER portion when combined together form the oral pharmaceutical dosage form having a composite target PK profile in the subject.

In other aspects, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: a first sustained release (ER) portion comprising the drug, the first ER portion having a sustained release profile; and a second sustained release (ER) portion comprising the drug, the second ER portion having a sustained release profile, wherein the first ER portion and the second ER portion are stacked on top of each other, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining a first ER PK profile in a subject for a first ER precursor dosage form comprising the first ER moiety; (b) obtaining a second ER PK profile in the subject for a second ER precursor dosage form comprising the second ER moiety; and (c) determining the relative amount of the drug in the first and second ER portions based on the first and second ER PK profiles, such that the first ER portion and the second ER portion, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject.

In other aspects, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in humans, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) portion comprising the drug, the IR portion having an immediate release profile; and a sustained release (ER) portion comprising the drug, the ER portion having a sustained release profile, wherein the IR portion and the ER portion are stacked on top of each other, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining an IR PK profile in a human for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a human for an ER precursor dosage form comprising said ER moiety; and (c) determining the relative amount of the drug in the IR portion and the ER portion from the IR PK profile and the ER PK profile such that the IR portion and the ER portion when combined together form the oral pharmaceutical dosage form having a composite target PK profile in humans.

In other aspects, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) portion comprising the drug, the IR portion having an immediate release profile; and a sustained release (ER) portion comprising the drug, the ER portion having a sustained release profile, wherein the IR portion and the ER portion are stacked on top of each other, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER moiety; and (c) determining the relative amount of the drug in the IR portion and the ER portion from the IR PK profile and the ER PK profile such that the IR portion and the ER portion when combined together make the oral pharmaceutical dosage form having a composite target PK profile in the subject, wherein the oral pharmaceutical dosage form has a composite target PK profile in the subject from 0 hours to about 24 hours.

In other aspects, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: comprising said medicamentAn Immediate Release (IR) portion, the IR portion having an immediate release profile; and an Extended Release (ER) portion comprising the drug, the ER portion having an extended release profile, wherein the IR portion and the ER portion are stacked on top of each other, and wherein the composite target PK profile has an area under the curve (AUC), C, according to an acceptable threshold of a reference PK profile for the drug_maxAnd t_maxDetermining, the method comprises: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER moiety; and (c) determining the relative amount of the drug in the IR portion and the ER portion from the IR PK profile and the ER PK profile, such that the IR portion and the ER portion when combined together form the oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the drug has linear pharmacokinetics.

In other aspects, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) portion comprising the drug, the IR portion having an immediate release profile; and a sustained release (ER) portion comprising the drug, the ER portion having a sustained release profile, wherein the IR portion and the ER portion are positioned side-by-side, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER moiety; and (c) determining the relative amount of the drug in the IR portion and the ER portion from the IR PK profile and the ER PK profile, such that the IR portion and the ER portion when combined together form the oral pharmaceutical dosage form having a composite target PK profile in the subject.

In other aspects, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: a first sustained release (ER) portion comprising the drug, the first ER portion having a sustained release profile; and a second sustained release (ER) portion comprising the drug, the second ER portion having a sustained release profile, wherein the first ER portion and the second ER portion are positioned side-by-side, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining a first ER PK profile in a subject for a first ER precursor dosage form comprising the first ER moiety; (b) obtaining a second ER PK profile in the subject for a second ER precursor dosage form comprising the second ER moiety; and (c) determining the relative amount of the drug in the first and second ER portions based on the first and second ER PK profiles, such that the first ER portion and the second ER portion, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject.

In other aspects, the present invention provides a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in humans, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) portion comprising the drug, the IR portion having an immediate release profile; and a sustained release (ER) portion comprising the drug, the ER portion having a sustained release profile, wherein the IR portion and the ER portion are positioned side-by-side, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining an IR PK profile in a human for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a human for an ER precursor dosage form comprising said ER moiety; and (c) determining the relative amount of the drug in the IR portion and the ER portion from the IR PK profile and the ER PK profile such that the IR portion and the ER portion when combined together form the oral pharmaceutical dosage form having a composite target PK profile in humans.

In other aspects, the present application provides a method of determining the relative amount of a drug in an Immediate Release (IR) portion and a sustained release (ER) portion of an oral pharmaceutical dosage form having a fixed amount of drug and having a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an IR portion comprising the drug, the IR portion having an immediate release profile; and an ER portion comprising the drug, the ER portion having a sustained release profile, the method comprising: determining the relative amounts of the drug in the IR moiety and the ER moiety based on an IR PK profile in the subject for an IR precursor dosage form comprising the IR moiety and an ER PK profile in the subject for an ER precursor dosage form comprising the ER moiety, such that the IR moiety and the ER moiety, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the drug has linear pharmacokinetics.

In other aspects, the present application provides a method of determining the relative amount of a drug in an Immediate Release (IR) portion and a sustained release (ER) portion of an oral pharmaceutical dosage form having a fixed amount of drug and having a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an IR portion comprising the drug, the IR portion having an immediate release profile; and an ER portion comprising the drug, the ER portion having a sustained release profile, wherein the IR and the ER portion are stacked on top of each other, the method comprising: determining the relative amounts of the drug in the IR moiety and the ER moiety based on an IR PK profile in the subject for an IR precursor dosage form comprising the IR moiety and an ER PK profile in the subject for an ER precursor dosage form comprising the ER moiety, such that the IR moiety and the ER moiety, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the drug has linear pharmacokinetics.

In other aspects, the present application provides a method of determining the relative amount of a drug in an Immediate Release (IR) portion and a sustained release (ER) portion of an oral pharmaceutical dosage form having a fixed amount of drug and having a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an IR portion comprising the drug, the IR portion having an immediate release profile; and an ER portion comprising said drug, said ER portion having a sustained release profile, wherein said IR and said ER portions are positioned side-by-side, said method comprising: determining the relative amounts of the drug in the IR moiety and the ER moiety based on an IR PK profile in the subject for an IR precursor dosage form comprising the IR moiety and an ER PK profile in the subject for an ER precursor dosage form comprising the ER moiety, such that the IR moiety and the ER moiety, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the drug has linear pharmacokinetics.

In other aspects, the present application provides a method of making an oral pharmaceutical dosage form having a fixed amount of a drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an IR portion comprising the drug, the IR portion having an immediate release profile; and an ER portion comprising the drug, the ER portion having a sustained release profile, the method comprising: determining the relative amounts of the drug in the IR moiety and the ER moiety based on an IR PK profile in the subject for an IR precursor dosage form comprising the IR moiety and an ER PK profile in the subject for an ER precursor dosage form comprising the ER moiety, such that the IR moiety and the ER moiety, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the drug has linear pharmacokinetics.

In some aspects, the methods disclosed herein further comprise forming the oral pharmaceutical dosage form, such as by three-dimensional printing or a manufacturing technique comprising a 3D printing technique, such as 3D printing in combination with another method, e.g., injection molding in combination with 3D printing.

In some embodiments, the MR1 PK profile in the subject for the MR1 precursor dosage form comprising the MR1 moiety and/or the MR2 PK profile in the subject for the MR2 precursor dosage form comprising the MR2 moiety is determined prior to determining the relative amounts of drug in the MR1 moiety and the MR2 moiety.

In some embodiments, the MR1 PK profile and the MR2 PK profile are obtained from an individual of the same species. In some embodiments, the MR1 PK profile and the MR2 PK profile are obtained from the same individual, and the administration of the MR1 precursor dosage form and the MR2 precursor dosage form are separated by an appropriate time to allow clearance of the drug, e.g., at least about 5 drug half-lives.

In some embodiments, the relative amounts of the drug in the MR1 and MR2 fractions are determined based on point-to-point comparisons between the MR1 PK profile and/or the MR2 PK profile and the composite target PK profile. In some embodiments, the relative amounts of the drugs in the MR1 and MR2 fractions are determined based on in vivo kinetic information of the drugs.

Oral pharmaceutical dosage form and dosage unit

In some aspects, provided herein are oral pharmaceutical dosage forms and dosage units having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, in some embodiments, the oral pharmaceutical dosage forms are designed according to the methods described herein. In some embodiments, the dosage unit is designed according to the methods described herein.

In some embodiments, the oral pharmaceutical dosage form comprises a dosage unit comprising: an MR1 portion including a drug (such as an IR portion with an immediate release profile or an ER portion with a sustained release profile) and an MR2 portion including a drug (such as an ER portion with a sustained release profile). In some embodiments, the oral pharmaceutical dosage form comprises a dosage unit comprising: an IR portion (such as an IR layer) comprising the drug, the IR portion having an immediate release profile, and an ER portion (such as an ER layer) comprising the drug, the ER portion having a sustained release profile. In some embodiments, the oral pharmaceutical dosage form comprises a dosage unit comprising: a first ER portion (such as an ER layer) comprising the drug, the first ER portion having a sustained release profile, and a second ER portion (such as an ER layer) comprising the drug, the second ER portion having a sustained release profile. In some embodiments, the term "dosage unit" refers to a portion of an oral pharmaceutical dosage form that includes an IR portion and an ER portion. In some embodiments described herein, the term dosage unit may be used to describe and/or test a portion of an oral pharmaceutical dosage form, for example, to simplify the design and/or testing of the oral pharmaceutical dosage form. For example, in some embodiments, where an oral pharmaceutical dosage form includes two or more identical dosage units, the design of the oral pharmaceutical dosage form may be based on the detection of a single dosage unit. In some embodiments, the dosage unit further comprises other components, such as another IR portion, another ER portion, a shell, or an intermediate portion. In some embodiments, when the oral pharmaceutical dosage form includes only one dosage unit, the terms oral pharmaceutical dosage form and dosage unit are used interchangeably to describe the dosage form.

The orientations of the dosage units of the oral pharmaceutical dosage forms described herein may be assembled in a variety of orientations relative to one another. In some embodiments, to facilitate description of oral pharmaceutical dosage forms within the scope of the present invention, the orientation of a first dosage unit relative to another dosage unit may be described based on the surface of the dosage unit that does not release drug after administration (e.g., the shell surface) or the surface of the dosage unit that is not exposed to, for example, GI fluids. For example, in some embodiments, two dosage units are positioned on each other on the non-drug releasing surface of each dosage unit, such as stacked, back-to-back in contact. In some embodiments, the orientation of two dosage units of an oral pharmaceutical dosage form may be described as being placed side-by-side, wherein the two dosage units are in contact with each other on a surface that does not release drug or is not exposed to, for example, GI fluid after administration of each dosage unit, wherein each dosage unit comprises an upper surface from which drug is released or exposed to, for example, GI fluid, and wherein the upper surfaces of the dosage units are on the same surface of the oral pharmaceutical dosage form. In some embodiments, the boundary between two dosage units of an oral pharmaceutical dosage form is arbitrary due to, for example, the nature of 3D printing.

In some embodiments, the oral pharmaceutical dosage form comprises a single dosage unit. In some embodiments, the oral pharmaceutical dosage form comprises more than one (such as any of 2, 3, 4,5 or 6) dosage units. In some embodiments, wherein the oral pharmaceutical dosage form comprises more than one dosage unit, each dosage unit is the same. In some embodiments, wherein the oral pharmaceutical dosage form comprises more than one dosage unit, at least one dosage unit is different from the other dosage units of the oral pharmaceutical dosage form.

In some embodiments, the oral pharmaceutical dosage form comprises two dosage units. In some embodiments, the two dosage units are the same. In some embodiments, wherein the oral pharmaceutical dosage form comprises two dosage units, the two dosage units are different. In some embodiments, the two dosage units are stacked back-to-back. In some embodiments, wherein the two dosage units are stacked back-to-back, the drug is released from a first dosage form on a first side of the oral pharmaceutical dosage form and the drug is released from a second dosage form on a second side of the oral pharmaceutical dosage form. In some embodiments, the two dosage units are placed side by side. One of ordinary skill in the art will readily appreciate that the oral pharmaceutical dosage forms described herein may have a variety of configurations, including more complex arrangements of dosage units and oral pharmaceutical dosage forms comprising a plurality of dosage units. For example, in some embodiments, the oral pharmaceutical dosage form comprises four dosage units, wherein the first dosage unit and the second dosage unit are placed side-by-side, wherein the third dosage unit and the fourth dosage unit are placed side-by-side, and wherein the first and second dosage units are stacked back-to-back with the third and fourth dosage units.

In some embodiments, the dosage units of an oral pharmaceutical dosage form are separated in whole or in part by a component, such as a shell or an intermediate portion. In some embodiments, wherein the oral pharmaceutical dosage form comprises two dosage units stacked back-to-back, the two dosage units are separated in whole or in part by a component, such as a shell or an intermediate portion. In some embodiments, wherein the oral pharmaceutical dosage form comprises two dosage units placed side by side, the two dosage units are separated in whole or in part by a component, such as a shell or an intermediate part.

In some embodiments, the oral pharmaceutical dosage form comprises one or more drugs. In some embodiments, where an oral pharmaceutical dosage form comprises more than one dosage unit, the dosage units of the oral pharmaceutical dosage form may comprise different drugs or drug combinations. In some embodiments, wherein the oral pharmaceutical dosage form comprises a first dosage unit and a second dosage unit, the first dosage unit comprises a different drug or combination of drugs than the second dosage unit. In some embodiments, the oral pharmaceutical dosage form comprises one drug.

In some embodiments, the oral pharmaceutical dosage form is suitable for oral administration. The pharmaceutical dosage form of the present invention may be, for example, of any size, shape or weight suitable for oral administration to a particular individual, such as children and adults. In some embodiments, the size, shape, or weight of the oral pharmaceutical dosage form is selected based on the attributes of the individual receiving administration of the oral pharmaceutical dosage form. In some embodiments, the attribute of the individual is one or more of height, weight, or age. In some embodiments, the shape of the oral pharmaceutical dosage form comprises a cylinder, an oval, a bullet, an arrow, a triangle, an arc triangle, a square, an arc square, a rectangle, an arc rectangle, a diamond, a pentagon, a hexagon, an octagon, a half moon, an almond, or combinations thereof. In some embodiments, the oral pharmaceutical dosage form is sized and shaped for oral administration to an individual.

In some embodiments, the oral pharmaceutical dosage form has a size of less than about 22mm, such as less than about 21mm, less than about 20mm, less than about 19mm, less than about 18mm, less than about 17mm, less than about 16mm, less than about 15mm, less than about 14mm, less than about 13mm, less than about 12mm, less than about 11mm, less than about 10mm, less than about 9mm, less than about 8mm, less than about 7mm, less than about 6mm, less than about 5mm, less than about 4mm, less than about 3mm, less than about 2mm, or less than about 1 mm. In some embodiments, the pharmaceutical dosage form has a size of about 1mm to about 22mm, such as about 21mm, about 20mm, about 19mm, about 18mm, about 17mm, about 16mm, about 15mm, about 14mm, about 13mm, about 12mm, about 11mm, about 10mm, about 9mm, about 8mm, about 7mm, about 6mm, about 5mm, about 4mm, about 3mm, or about 2 mm.

In some embodiments, the fixed amount of drug in an oral pharmaceutical dosage form is from about 2000mg to about 0.01 mg. In some embodiments, the fixed amount of drug in the oral dosage form is less than 2000mg, such as less than any of about 1900mg, 1800mg, 1700mg, 1600mg, 1500mg, 1400mg, 1300mg, 1200mg, 1100mg, 1000mg, 900mg, 800mg, 700mg, 600mg, 500mg, 450mg, 400mg, 350mg, 300mg, 250mg, 200mg, 150mg, 100mg, 75mg, 50mg, 45mg, 40mg, 35mg, 30mg, 25mg, 20mg, 15mg, 10mg, 5mg, 4mg, 3mg, 2mg, 1mg, 0.75mg, 0.5mg, 0.25mg, or 0.1 mg. In some embodiments, the fixed amount of drug in the oral dosage form is about 2000mg, such as any of about 1900mg, 1800mg, 1700mg, 1600mg, 1500mg, 1400mg, 1300mg, 1200mg, 1100mg, 1000mg, 900mg, 800mg, 700mg, 600mg, 500mg, 450mg, 400mg, 350mg, 300mg, 250mg, 200mg, 150mg, 100mg, 75mg, 50mg, 45mg, 40mg, 35mg, 30mg, 25mg, 20mg, 15mg, 10mg, 5mg, 4mg, 3mg, 2mg, 1mg, 0.75mg, 0.5mg, 0.25mg, or 0.1 mg.

In some embodiments, the total weight of the pharmaceutical dosage form is any one of about 50mg to about 2500mg, such as about 50mg to about 150mg, about 150mg to about 250mg, about 250mg to about 350mg, about 350mg to about 450mg, about 450mg to about 550mg, about 550mg to about 650mg, about 650mg to about 750mg, about 750mg to about 850mg, about 850mg to about 950mg, about 950mg to about 1050mg, about 1050mg to about 1150mg, about 1150mg to about 1250mg, about 1250mg to about 1350mg, about 1350mg to about 1450mg, about 1450mg to about 1550mg, about 1550mg to about 1650mg, about 1650mg to about 1750mg, about 1750mg to about 1850mg, about 2050mg to about 1950mg, about 1950mg to about 2450mg, about 1950mg to about 2050mg, about 2150mg to about 2150mg, about 2050mg to about 2150mg, about 2050mg, or about 2350mg to about 2350 mg. In some embodiments, the total weight of the oral pharmaceutical dosage form is at least about 50mg, such as at least any one of at least about 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, or 2500 mg. In some embodiments, the total weight of the oral pharmaceutical dosage form is less than about 2500mg, such as less than any of about 2400mg, 2300mg, 2200mg, 2100mg, 2000mg, 1900mg, 1800mg, 1700mg, 1600mg, 1500mg, 1400mg, 1300mg, 1200mg, 1100mg, 1000mg, 950mg, 900mg, 850mg, 800mg, 750mg, 700mg, 650mg, 600mg, 550mg, 500mg, 450mg, 400mg, 350mg, 300mg, 250mg, 200mg, 150mg, 100mg, or 50 mg.

The dosage unit described herein comprises: a first modified release (MR1) portion comprising a drug; and a second modified release (MR2) portion. In some embodiments, the dosage unit comprises one or more additional modified release portions. In some embodiments, the dosage unit comprises one or more other components, such as a shell or an intermediate portion.

For example, in some embodiments, a dosage unit described herein comprises: an Immediate Release (IR) portion (such as an IR layer) comprising the drug and having an immediate release profile; and a sustained release (ER) portion (such as an ER layer) comprising the drug and having a sustained release profile. In some embodiments, the dosage unit further comprises a shell, wherein the IR portion and the ER portion are partially surrounded by the shell. In some embodiments, a dosage unit described herein comprises: a first ER portion (such as an ER layer) comprising the drug and having a sustained release profile; and a second ER portion (such as an ER layer) comprising the drug and having a sustained release profile. In some embodiments, the dosage unit further comprises a shell, wherein the first ER portion and the second ER portion are partially surrounded by the shell. In some embodiments, the dosage unit further comprises an intermediate portion, such as an intermediate layer. In some embodiments, the dosage unit comprises another drug.

The dosage units described herein can include various combinations of their components (e.g., one or more IR moieties, one or more ER moieties, one or more intermediate moieties, and a shell), and can be arranged in various configurations. The components of the dosage unit (such as the IR portion, ER portion, intermediate portion, shell) may be arranged and combined in various configurations. In some embodiments, to facilitate the description of the components of a dosage unit within the scope of the invention, the multi-directional assembly of a first component (such as the IR portion) relative to another component (such as the ER portion) may be described based on the use of an imaginary axis that is perpendicular to the erosion surface (e.g., after exposure to GI fluids) of one or more, or all, of the IR portion, the ER portion, and the intermediate portion of the dosage unit. In some embodiments, the erosion surfaces of two components (whether or not erosion occurs simultaneously) may substantially or partially overlap when evaluated along an imaginary vertical axis, and the two components may be referred to as a stack. In some embodiments, the erosion surfaces of two components (whether or not erosion occurs simultaneously) may not overlap when evaluated along an imaginary vertical axis, and thus the two components may be referred to as being placed side-by-side.

As discussed herein, for the sake of brevity, in many of the embodiments disclosed herein, dosage forms comprising an IR portion (as part of MR1) and an ER portion (as part of MR2) are described to illustrate the present invention. The present disclosure should not be construed as limiting the description herein and such teachings are also applicable to other configurations in which MR1 portion and/or MR2 portion are different debug portions.

In some embodiments, the IR and ER moieties are in direct contact with each other. In some embodiments, the IR portion and the ER portion are separated, in whole or in part, by another component (e.g., a shell and/or an intermediate portion). In some embodiments, the IR and ER portions of a dosage unit are stacked on top of each other. In some embodiments, said IR and said ER portions of a dosage unit are placed alongside each other.

In some embodiments, the IR and ER portions are partially surrounded by a shell. In some embodiments, the shell is in direct contact with the IR portion and the ER portion. In some embodiments, the shell has a slower dissolution rate than the ER portion. In some embodiments, the shell is not in direct contact with the IR portion and/or the ER portion. In some embodiments, the shell is in direct contact with the intermediate portion.

In some embodiments, the dosage unit comprises an IR portion, an ER portion, and a shell, wherein the IR portion has an upper surface and a lower surface, wherein the ER portion has an upper surface and a lower surface, and wherein the shell is in direct contact with the IR portion and the ER portion, and leaves one surface of the IR portion and/or one surface of the ER portion exposed. In some embodiments, the IR portion is stacked over the ER portion, wherein the shell leaves only an upper surface of the IR portion exposed. In some embodiments, the lower surface of the IR is in direct contact with the upper surface of the ER portion. In some embodiments, the lower surface of the ER is in direct contact with the shell. In some embodiments, the IR portion is stacked over the ER portion, and wherein the shell leaves an upper surface of the IR portion exposed and a lower surface of the ER portion exposed. In some embodiments, the dosage unit further comprises an intermediate layer, wherein the intermediate portion is located between the IR portion and the ER.

In some embodiments, the dosage unit further comprises a second IR portion, wherein the second IR portion has an upper surface and a lower surface, wherein the ER portion is stacked over the second IR portion, and wherein the shell leaves only the upper surface of the IR portion exposed. In some embodiments, the lower surface of the ER is in direct contact with the upper surface of the second IR moiety. In some embodiments, the inferior surface of the second ER is in direct contact with the shell.

In some embodiments, the ER portion is stacked over the IR portion, wherein the shell leaves only an upper surface of the ER portion exposed. In some embodiments, the lower surface of the ER is in direct contact with the upper surface of the IR moiety. In some embodiments, the lower surface of the IR is in direct contact with the shell.

In some embodiments, the IR portion is stacked over the ER portion, and wherein the shell leaves an upper surface of the IR portion and a lower surface of the ER portion exposed. In some embodiments, the lower surface of the IR is in direct contact with the upper surface of the ER portion. In some embodiments, wherein the shell leaves exposed an upper surface of the IR portion and a lower surface of the ER portion, wherein the dosage unit further comprises an intermediate portion, wherein an intermediate layer is between the IR portion and the ER. In some embodiments, wherein the shell leaves exposed an upper surface of the IR portion and a lower surface of the ER portion, and wherein a portion of the shell is located between the IR portion and the ER.

In some embodiments, the dosage unit further comprises an intermediate portion. In some embodiments, the intermediate portion is between the IR portion and the ER portion. In some embodiments, the intermediate portion is in direct contact with the IR portion and the ER portion. In some embodiments, the intermediate portion is in direct contact with the IR portion. In some embodiments, the intermediate portion is in direct contact with only the ER portion. In some embodiments, the middle portion is stacked on top of the ER portion. In some embodiments, the intermediate portion is stacked above the IR portion.

In some embodiments, said IR and said ER portions of a dosage unit are placed alongside each other. In some embodiments, the MR1 portion and the MR2 portion are placed side-by-side with each other and partially surrounded by (e.g., in direct contact with) a shell, wherein the shell leaves exposed the upper surfaces of the MR1 portion and the MR2 portion. In some embodiments, the lower surfaces of the IR portion and the ER portion are in direct contact with the shell. In some embodiments, the dosage unit further comprises an intermediate layer, wherein the intermediate layer is located between the IR moiety and the ER. In some embodiments, the IR portion and the ER portion are placed alongside each other, wherein the shell leaves an upper surface of the IR portion and the ER portion exposed, and wherein the shell leaves a lower surface of the IR portion and the ER portion exposed. In some embodiments, the IR portion and the ER portion are positioned alongside one another, wherein the shell leaves an upper surface of the IR portion and the ER portion exposed, and wherein the shell lower single portion is located between the IR portion and the ER portion.

In some embodiments, the IR portion fully or partially surrounds the ER portion. In some embodiments, the ER portion fully or partially surrounds the IR portion. In some embodiments, the IR portion and/or the ER portion wholly or partially surrounds another component of the dosage unit, such as an intermediate portion or cavity, such as an inflatable cavity. In some embodiments, at least a portion of the IR is in direct contact with a portion of the ER moiety. In some embodiments, at least a portion of the ER is in direct contact with a portion of the IR moiety. In some embodiments, the IR and ER moieties are not in direct contact.

In some embodiments, the IR and ER portions of a dosage unit are configured as concentric types. In some embodiments, other components of the dosage unit are also configured in concentric circles, such as a middle portion, shell, or cavity. In some embodiments, at least a portion of the IR is in direct contact with a portion of the ER moiety. In some embodiments, at least a portion of the ER is in direct contact with a portion of the IR moiety. In some embodiments, the IR and ER moieties are not in direct contact.

In some embodiments, the oral pharmaceutical dosage form comprises more than one (such as any of 2, 3, 4,5, or 6) IR portion, e.g., layer. In some embodiments, the oral pharmaceutical dosage form comprises more than one (such as any of 2, 3, 4,5, or 6) ER portion, e.g., layer. In some embodiments, the oral pharmaceutical dosage form comprises more than one (such as any of 2, 3, 4,5, or 6) intermediate portions, e.g., layers. In some embodiments, when used in an IR layer, ER layer, or intermediate layer, a layer refers to the configuration of the components of the dosage unit, and each layer may comprise multiple printed layers of the same material. In some embodiments, the portion or layer has a packing density, such as a packing density of three-dimensional printing. In some embodiments, the components described herein, e.g., the IR portion, the ER portion, the middle portion, and the shell, each comprise a plurality of printed layers. In some embodiments, the plurality of print layers is between about 5 print layers and about 2500 print layers, such as between any of about 10 print layers to about 2500 print layers, about 25 print layers to about 100 print layers, about 50 print layers to about 200 print layers, about 100 print layers to about 200 print layers, about 150 print layers to about 250 print layers, about 200 print layers to about 250 print layers, about 500 print layers to about 1000 print layers, or about 2000 print layers to about 2400 print layers. In some embodiments, the print layer has a thickness of no more than about 5mm, such as no more than any of about 4mm, 3mm, 2mm, 1mm, 0.9mm, 0.8mm, 0.7mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm, 0.1mm, 0.09mm, 0.08mm, 0.07mm, 0.06mm, 0.05mm, 0.04mm, 0.03mm, 0.02mm, or 0.01 mm. In some embodiments, the print layer has a thickness of any one of about 5mm, 4mm, 3mm, 2mm, 1mm, 0.9mm, 0.8mm, 0.7mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm, 0.1mm, 0.09mm, 0.08mm, 0.07mm, 0.06mm, 0.05mm, 0.04mm, 0.03mm, 0.02mm, or 0.01 mm.

In some embodiments, the total amount of drug contained in a dosage unit is divided between the IR portion and the ER portion in any target ratio. In some embodiments, a portion of the total amount of drug contained in a dosage unit is divided between the IR portion and the ER portion in any targeted ratio. In some embodiments, the IR to ER drug ratio is about 1:100 to about 100: 1. In some embodiments, the IR: ER drug ratio is about any one of 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1: 10. In some embodiments, the drug ratio between the IR moiety and the ER moiety is from about 1:100 to about 100: 1. In some embodiments, the drug ratio between the IR portion and the ER portion is about any one of 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1: 10.

The dosage units described herein may be of any shape or size suitable for oral administration. In some embodiments, at least a portion of a dosage unit, such as size and/or shape, is based on interaction with one or more other dosage units. For example, in some embodiments, the shape of the bottom of a dosage unit (such as the shape of a shell) matches the shape of the bottom of another dosage unit, wherein the bottoms of two dosage units are bonded to each other, such as in direct contact with each other. In some embodiments, the shape of the dosage unit comprises a cylinder, an oval, a bullet, an arrow, a triangle, an arc triangle, a square, an arc square, a rectangle, an arc rectangle, a diamond, a pentagon, a hexagon, an octagon, a half moon, an almond, or combinations thereof.

In some embodiments, the maximum dimension (such as the maximum diameter) of the dosage unit is from about 1mm to about 25mm, such as any of from about 2mm to about 10mm, from about 5mm to about 12mm, from about 8mm to about 15mm, from about 5mm to about 10mm, or from about 7mm to about 9 mm. In some embodiments, the maximum dimension (such as the maximum diameter) of the dosage unit is less than 25mm, such as less than about any one of 24mm, 23mm, 22mm, 21mm, 20mm, 19mm, 18mm, 17mm, 16mm, 15mm, 14mm, 13mm, 12mm, 11mm, 10mm, 9mm, 8mm, 7mm, 6mm, 5mm, 4mm, 3mm, 2mm or 1 mm. In some embodiments, the maximum dimension (such as the maximum diameter) of the dosage unit is greater than about 1mm, such as greater than any one of about 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm, 19mm, 20mm, 21mm, 22mm, 23mm, 24mm or 25 mm. In some embodiments, the oral pharmaceutical dosage form has a maximum dimension (such as a maximum diameter) of any one of about 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm, 19mm, 20mm, 21mm, 22mm, 23mm, 24mm, or 25 mm.

In some embodiments, the thickness of the dosage unit is from about 1mm to about 25mm, such as any of from about 2mm to about 10mm, from about 5mm to about 12mm, from about 8mm to about 15mm, from about 5mm to about 10mm, or from about 7mm to about 9 mm. In some embodiments, the thickness of the dosage unit is less than about 25mm, such as less than any of about 24mm, 23mm, 22mm, 21mm, 20mm, 19mm, 18mm, 17mm, 16mm, 15mm, 14mm, 13mm, 12mm, 11mm, 10mm, 9mm, 8mm, 7mm, 6mm, 5mm, 4mm, 3mm, 2mm or 1 mm. In some embodiments, the thickness of the dosage unit is greater than about 1mm, such as greater than any one of about 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm, 19mm, 20mm, 21mm, 22mm, 23mm, 24mm or 25 mm. In some embodiments, the dosage unit has a thickness of any one of about 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm, 19mm, 20mm, 21mm, 22mm, 23mm, 24mm, or 25 mm.

In some embodiments, the total weight of a dosage unit is any one of about 20mg to about 1500mg, such as about 50mg to about 150mg, about 150mg to about 250mg, about 160mg to about 170mg, about 250mg to about 350mg, about 350mg to about 450mg, about 450mg to about 550mg, about 550mg to about 650mg, about 650mg to about 750mg, about 750mg to about 850mg, about 850mg to about 950mg, about 950mg to about 1050mg, about 1050mg to about 1150mg, about 1150mg to about 1250mg, about 1250mg to about 1350mg, or about 1350mg to about 1450 mg. In some embodiments, the total weight of a dosage unit is less than about 1500mg, such as less than any of about 1450mg, 1400mg, 1350mg, 1300mg, 1250mg, 1200mg, 1150mg, 1100mg, 1050mg, 1000mg, 950mg, 900mg, 850mg, 800mg, 750mg, 700mg, 650mg, 600mg, 550mg, 500mg, 475mg, 450mg, 425mg, 400mg, 375mg, 350mg, 325mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 95mg, 90mg, 85mg, 80mg, 75mg, 70mg, 65mg, 60mg, 55mg, 50mg, 45mg, 40mg, 35mg, 30mg, or 25 mg. In some embodiments, the total weight of a dosage unit is greater than about 20mg, such as greater than any one of about 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, or 1450 mg. In some embodiments, the total weight of a dosage unit is any one of about 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 160mg, 165mg, 170mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, or 1450 mg.

In some embodiments, one or more dosage units described herein, such as 2, 3, or 4 dosage units, may be configured to form an oral pharmaceutical dosage form, wherein each dosage unit comprises an IR portion (such as an IR layer), and an ER portion (such as an ER layer) and optionally an intermediate portion (such as an intermediate layer) and/or a shell. In some embodiments, the dosage units of the oral pharmaceutical dosage forms are the same.

In some embodiments, the oral pharmaceutical dosage form comprises a fixed amount of drug formulated and configured to have a composite target Pharmacokinetic (PK) profile, the oral pharmaceutical dosage form having two dosage units stacked back-to-back. In some embodiments, the dosage units each comprise: an Immediate Release (IR) layer comprising a drug, the IR layer having an immediate release profile; a sustained release (ER) layer comprising a drug, the ER layer having a sustained release profile; and a shell, wherein the IR layer has an upper surface and a lower surface, wherein the ER layer has an upper surface and a lower surface, wherein the shell partially surrounds the IR layer and the ER layer, and wherein the shell is in direct contact with the IR layer and the ER layer and leaves one surface of the IR layer and/or one surface of the ER layer exposed. In some embodiments, the dosage units each comprise: a first ER layer comprising a drug, the first ER layer having a sustained release profile; a second ER layer comprising a drug, the second ER layer having a sustained release profile; and a shell, wherein the first ER layer has an upper surface and a lower surface, wherein the second ER layer has an upper surface and a lower surface, wherein the shell partially surrounds the first ER layer and the second ER layer, and wherein the shell is in direct contact with the first ER layer and the second ER layer and leaves one surface (e.g., the upper surface or the lower surface) of the first ER layer and/or one surface (e.g., the upper surface or the lower surface) of the second ER layer exposed. In some embodiments, the drug has linear pharmacokinetics. In some embodiments, the shell is not erodible.

In some embodiments, the IR layer and the ER layer are stacked on top of each other in at least one dosage unit of the oral pharmaceutical dosage form. In some embodiments, in at least one of the dosage units of the oral pharmaceutical dosage form, the IR layer is stacked on top of the ER layer, the shell leaving only the upper surface of the IR layer exposed. In some embodiments, the lower surface of the IR layer is in direct contact with the upper surface of the ER layer. In some embodiments, in at least one of the dosage units of an oral pharmaceutical dosage form, the dosage unit further comprises a second IR layer, wherein the second IR layer has an upper surface and a lower surface, wherein the ER layer is stacked over the second IR layer, and wherein the shell leaves only the upper surface of the IR layer exposed. In some embodiments, the lower surface of the ER layer is in direct contact with the upper surface of the second IR layer. In some embodiments, in at least one of the dosage units of the oral pharmaceutical dosage form, the ER layer is stacked over the IR layer, and wherein the shell leaves only an upper surface of the ER layer exposed. In some embodiments, the lower surface of the ER layer is in direct contact with the upper surface of the IR layer.

In some embodiments, the IR layer and the ER layer are positioned alongside each other in at least one dosage unit of the oral pharmaceutical dosage form. In some embodiments, in at least one of the dosage units of the oral pharmaceutical dosage form, the IR layer and the ER layer are placed side by side to each other, wherein the shell leaves exposed an upper surface of the IR layer and the ER layer. In some embodiments, in at least one of the dosage units of an oral pharmaceutical dosage form, the dosage unit further comprises a second IR layer, wherein the second IR layer has an upper surface and a lower surface, wherein the IR layer and the ER layer are stacked over the second IR layer, and wherein the shell leaves exposed the upper surface of the IR layer and the ER layer. In some embodiments, the lower surfaces of the IR layer and the ER layer are in direct contact with the upper surface of the second IR layer. In some embodiments, in at least one of the dosage units of the oral pharmaceutical dosage form, the dosage unit further comprises an intermediate layer, wherein the intermediate layer is located between the IR layer and the ER layer.

In some embodiments, in at least one of the dosage units of the oral pharmaceutical dosage form, the first ER portion (such as the first ER layer) and the second ER portion (such as the second ER layer) are placed side by side to each other. In some embodiments, in at least one of the dosage units of the oral pharmaceutical dosage form, the first ER portion and the second ER portion are positioned alongside each other, wherein the shell leaves exposed an upper surface of the first ER portion and the second ER portion. In some embodiments, in at least one of the dosage units of the oral pharmaceutical dosage form, the dosage unit further comprises an IR moiety. In some embodiments, the shell separates the first ER portion from the second ER portion in at least one of the dosage units of the oral pharmaceutical dosage form. In some embodiments, in at least one of the dosage units of the oral pharmaceutical dosage form, the dosage unit further comprises an intermediate layer, wherein the intermediate layer is located between the first ER portion and the second ER portion.

In some embodiments, wherein the oral pharmaceutical dosage form comprises two dosage units stacked back-to-back, the two dosage units being identical. In some embodiments, wherein the oral pharmaceutical dosage form comprises two dosage units stacked back-to-back, the two dosage units being different. In some embodiments, wherein the oral pharmaceutical dosage form comprises two dosage units placed side by side, the two dosage units are identical. In some embodiments, wherein the oral pharmaceutical dosage form comprises two dosage units placed side by side, the two dosage units being different. In some embodiments, substantially all of the IR portion (such as the IR layer) erodes within at least about 20 minutes after administration of the oral pharmaceutical dosage form to a subject. In some embodiments, the IR portion (such as an IR layer) includes an etchable material. In some embodiments, the ER portion (such as the ER portion) comprises an erodable material, and wherein the drug contained in the ER portion is released from the oral pharmaceutical dosage form over a period of at least about 6 hours.

In some embodiments, components of the dosage units and/or oral pharmaceutical dosage forms described herein, such as the IR portion, ER portion, intermediate portion, and shell, are integrated (e.g., do not form components that may be readily separated).

In some embodiments, the dosage unit and/or oral pharmaceutical dosage form comprises a coating, such as an outer coating. In some embodiments, the outer coating is a sugar coating. In some embodiments, the outer coating is a decorative coating. In some embodiments, the outer coating is a film coating. In some embodiments, the outer coating is a polymeric coating.

Certain configurations and aspects of the components of the dosage unit are exemplified herein. One of ordinary skill in the art will appreciate, in view of the disclosure provided herein, that exemplary configurations do not limit the scope of oral pharmaceutical dosage forms having a fixed amount of drug and having a composite target Pharmacokinetic (PK) profile in an individual as provided herein. Some aspects of oral pharmaceutical dosage forms are described herein in a modular fashion and may be combined to obtain the resulting oral pharmaceutical dosage forms contemplated within the scope of the present application.

For purposes of illustration and explanation of the present disclosure, an exemplary oral pharmaceutical dosage form is shown in fig. 1. As shown in fig. 1A and 1B, in some embodiments, an oral pharmaceutical dosage form includes a dosage unit 100 comprising: an IR portion, such as IR layer 101; and an ER portion, such as ER layer 102, wherein IR portion 101 and ER portion 102 are stacked on top of each other. FIG. 1A shows an exploded view of IR portion 101 and ER portion 102. FIG. 1B shows a block diagram of IR segment 101 and ER segment 102.

As shown in fig. 1C, in some embodiments, an oral pharmaceutical dosage form includes a dosage unit 105 comprising: an IR portion 106; and an ER portion 107, wherein the IR portion 106 and the ER portion 107 are positioned alongside one another.

As shown in fig. 1D, in some embodiments, an oral pharmaceutical dosage form includes a dosage unit 110 comprising: an IR portion, such as IR layer 112; and an ER portion, such as an ER layer, wherein the IR portion 112 and the ER portion are stacked on top of each other, and wherein the IR portion 112 and the ER portion are partially surrounded by the shell 111. As shown in fig. 1E, in some embodiments, an oral pharmaceutical dosage form includes a dosage unit 115 comprising: an IR portion 117; and an ER portion 118, wherein the IR portion 117 and the ER portion 118 are positioned alongside one another, and wherein the IR portion 117 and the ER layer 118 are partially surrounded by the shell 116. As shown in fig. 1F, in some embodiments, an oral pharmaceutical dosage form includes a dosage unit 120 comprising: an IR portion 121; and an ER portion 123, wherein the IR portion 121 and the ER portion 123 are positioned alongside one another, wherein the IR portion 121 and the ER portion 123 are separated by a component, such as a shell or middle portion 122, and wherein the IR portion 121 and the ER layer 123 are partially surrounded by the shell 124.

As shown in fig. 1G, in some embodiments, an oral pharmaceutical dosage form includes a dosage unit 125 that includes components that surround another component, e.g., (i) an IR portion 126 surrounded by an ER portion 127, or (ii) an ER portion 126 surrounded by an IR portion 127.

As shown in fig. 1H, in some embodiments, an oral pharmaceutical dosage form includes dosage unit 130 comprising components configured in concentric fashion, e.g., (i) IR portion 131 is partially surrounded by ER portion 132, which is partially surrounded by shell 133, (ii) ER portion 131 is partially surrounded by IR portion 132, which is partially surrounded by shell 133, (iii) IR portion 132 is partially surrounded by ER portion 133, wherein IR portion partially surrounds a core, such as middle portion 131, (iv) IR portion 132 is partially surrounded by ER portion 133, wherein the dosage unit comprises cavity 131, (v) ER portion 132 is partially surrounded by IR portion 133, wherein ER portion partially surrounds a core, such as middle portion 131, (vi) ER portion 132 is partially surrounded by IR portion 133, wherein the dosage unit comprises cavity 131, or (vii) IR portion 131 is partially surrounded by middle portion 132, the latter being partially surrounded by ER portion 133.

As shown in fig. 1I, in some embodiments, the oral pharmaceutical dosage form comprises a dosage unit 135 comprising components that surround one or more other components, e.g., (I) IR portion 136 is partially surrounded by ER portion 137, ER portion 137 is surrounded by IR portion or intermediate portion 138, (ii) ER portion 136 is partially surrounded by IR portion or intermediate portion 137, IR portion or intermediate portion 137 is surrounded by IR portion or intermediate portion 138, (iii) IR portion 137 is surrounded by ER portion 138, wherein IR portion partially surrounds a core, such as intermediate portion 136, (iv) IR portion 137 is surrounded by ER portion 138, wherein the dosage unit comprises a cavity 136, (v) ER portion 137 is surrounded by IR portion 138, wherein partially surrounds a core, such as intermediate portion 136, (vi) ER portion 137 is surrounded by IR portion 138, wherein the dosage unit comprises cavity 136, or (vii) IR portion 136 is partially surrounded by middle portion 137 and middle portion 137 is surrounded by ER portion 138.

As shown in fig. 1J, in some embodiments, an oral pharmaceutical dosage form includes a dosage unit 140 comprising: (i) ER portion 142 is surrounded by IR portion 141, IR portion 141 being partially surrounded by shell 143, or (ii) ER portion 142 is surrounded by intermediate portion 141, intermediate portion 141 being partially surrounded by ER portion, intermediate portion, or shell 143.

Additional multipart oral pharmaceutical dosage forms and dosage units are contemplated herein. For example, as shown in fig. 2A-2E, in some embodiments, an oral pharmaceutical dosage form includes more than one ER portion, such as an ER layer, and/or more than one IR portion, such as an IR layer.

As shown in fig. 2D, the oral pharmaceutical dosage form comprises a dosage unit comprising a MR1 portion and a MR2 portion, wherein a shell or intermediate portion separates the two debugging portions. In some embodiments, the oral pharmaceutical dosage form or dosage unit comprises an ER portion, such as an ER layer, and an IR portion, such as an IR layer, or a second ER portion, such as an ER layer, wherein the two debugging portions are separated by a portion of the shell or an intermediate portion. See, for example, fig. 2D and 2E.

IR moiety

The IR portion described herein, such as the IR layer, includes a drug and has an immediate release profile. In some embodiments, at least about 60% (such as at least any of about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the drug in the IR portion is released from the dosage unit within about 60 minutes (such as any of about 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, or 5 minutes) after administration of the dosage unit to the subject. In some embodiments, at least about 80% (such as at least any one of about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the drug in the IR portion is released from the dosage unit within 60 minutes (such as at least any one of about 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, or 5 minutes) after administration of the dosage unit to the individual. In some embodiments, at least about 60% (such as at least about any of 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the IR portion erodes within 60 minutes (such as at least about any of 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, or 5 minutes) after administration of the dosage unit to the subject. In some embodiments, at least about 80% (such as at least any one of about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the IR layer erodes at 60 minutes (such as at least any one of about 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, or 5 minutes) after administration of the dosage unit to the subject.

In some embodiments, the drug mass fraction (mass) of the IR portion (such as the IR layer)_MedicineMass/mass_Layer(s)) From about 0.05 to about 1, such as any one of from about 0.1 to about 0.5, from about 0.2 to about 0.6, from about 0.3 to about 0.7, from about 0.4 to about 0.8, from about 0.5 to about 0.9, from about 0.5 to about 1. In some embodiments, the drug mass fraction of the IR moiety is at least about 0.05, such as at least any one of about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1. In some embodiments, the drug mass fraction of the IR moiety is 1 or less, such as 0.95 or less, 0.9 or less, 0.85 or less, 0.8 or less, 0.75 or less, 0.7 or moreAny of less, 0.65 or less, 0.6 or less, 0.55 or less, 0.5 or less, 0.45 or less, 0.4 or less, 0.35 or less, 0.3 or less, 0.25 or less, 0.2 or less, 0.15 or less, 0.1 or less, or 0.05 or less.

In some embodiments, the IR portion (such as the IR layer) comprises at least about 0.001% drug, such as at least about any one of 0.005% drug, 0.01% drug, 0.05% drug, 0.1% drug, 0.5% drug, 1% drug, 2% drug, 3% drug, 4% drug, or 5% drug. In some embodiments, the IR portion (such as the IR layer) comprises about 0.001% to 100% drug.

The IR portion of the oral pharmaceutical dosage form described herein may include any amount of drug. As described herein, the amount of drug in the IR layer may depend on, for example, the total amount of drug in the oral pharmaceutical dosage form, the target release profile, and the target PK profile. In some embodiments, the amount of drug in the IR layer is from about 0.001mg to about 2000 mg. In some embodiments, the amount of drug in the IR layer is at least about 0.001mg, such as at least about any one of 0.01mg, 0.1mg, 0.25mg, 0.5mg, 0.75mg, 1mg, 2mg, 3mg, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, 1250mg, or 1500 mg.

In some embodiments, the IR layer further comprises at least one other component, such as 2, 3, 4,5, or 6 other components. In some embodiments, the IR layer includes at least one other component mixed with the drug. In some embodiments, the IR layer further comprises an etchable material. In some embodiments, the IR layer further comprises a material, such as a filler, a binder, a controlled release polymer, a lubricant, a glidant, a disintegrant, a thermoplastic, or a plasticizer.

In some embodiments, the IR portion further comprises an adjuvant. In some embodiments, the adjuvant is selected from the group consisting of: acacia, alginate, alginic acid, aluminum acetate, benzyl alcohol, butyl p-hydroxybenzoate, butylated hydroxytoluene, citric acid, calcium carbonate, candelilla wax, croscarmellose sodium, fructosyl, colloidal silicon dioxide, cellulose, pure or anhydrous calcium phosphate, carnauba wax, corn starch, carboxymethylcellulose calcium, calcium stearate, calcium disodium Edetate (EDTA), povidone, hydrogenated castor oil, dibasic calcium phosphate dihydrate, cetylpyridinium chloride, cysteine HCl, crospovidone, dibasic calcium phosphate, dibasic sodium phosphate, polydimethylsiloxane, sodium erythritol, ethylcellulose, ethylenediaminetetraacetic acid (EDTA), gelatin, glycerol monooleate, glycerol, glyceryl monostearate, glyceryl behenate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, sodium alginate, hydroxypropyl methylcellulose (HPMC) phthalate, iron oxide, ferric oxide, yellow iron oxide, red iron oxide, lactose (aqueous, anhydrous, monohydrate, or spray-dried), magnesium stearate, microcrystalline cellulose, mannitol, methylcellulose, magnesium carbonate, mineral oil, methacrylic acid copolymers, magnesium oxide, methyl paraben, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polysorbate 80, propylene glycol, polyethylene oxide, propyl paraben, poloxamer 407, poloxamer 188, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyl 140 stearate, sodium starch glycolate, pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, stearic acid, sucrose, sorbic acid, sodium carbonate, sodium saccharin, Sodium alginate, silica gel, sorbitan oleate, sodium stearyl fumarate, sodium chloride, sodium metabisulfite, sodium citrate dihydrate, sodium starch, sodium carboxymethylcellulose, succinic acid, sodium propionate, titanium dioxide, talc, triacetin and triethyl citrate.

In some embodiments, the IR portion further comprises an erodable material, such as an immediate release material. In some embodiments, the immediate release material is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57/30/13, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA)60/40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), and polyvinyl pyrrolidone (PVP)80/20, vinyl pyrrolidone-vinyl acetate copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PVA or PV-OH), polyethylene oxide (PEO), polyethylene glycol (PEG), cellulose or cellulose derivatives, hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose succinate (HPMCAS), One or a combination of carbomer, hydroxypropyl cellulose (HPC), poloxamer, hydroxypropylmethyl cellulose phthalate (HPMCP), poloxamer, polyglycolic acid (PGA), sugars, glucose, hydrogels, gelatin, sodium alginate, gum arabic, and xanthan gum.

In some embodiments, the IR moiety further comprises a releasing agent. In some embodiments, the release agent is a release rate enhancer, such as lactose, mannitol, or a combination thereof. In some embodiments, the release agent is an excipient. In some embodiments, the release agent is an erodable material.

In some embodiments, the IR portion further comprises a thermoplastic material. In some embodiments, the thermoplastic material is mixed with a plasticizer. In some embodiments, the IR portion further comprises a plasticizer. In some embodiments, the plasticizer is triethyl citrate (TEC). In some embodiments, the plasticizer is selected from one or a combination of polyoxyethylene-polyoxypropylene block copolymer, vitamin E polyethylene glycol succinate, hydroxystearate, polyethylene glycol (e.g., PEG400), polyethylene glycol cetostearyl ether 12, polyethylene glycol 20 cetostearyl ether, polysorbate 20, polysorbate 60, polysorbate 80, acetin, acetylated triethyl citrate, tributyl citrate, acetylated tributyl citrate, triethyl citrate, polyoxyethylene 15 hydroxystearate, polyethylene glycol-40 hydrogenated castor oil, polyoxyethylene 35 castor oil, dibutyl sebacate, diethyl phthalate, glycerol, methyl 4-hydroxybenzoate, glycerol, castor oil, oleic acid, triacetin, and polyalkylene glycol.

In some embodiments, the IR layer is printed by dispensing IR material, such as IR material that is an IR material comprising the components described herein.

ER moieties

The ER moieties described herein, such as the ER layer, include a drug and have a sustained release profile.

In some embodiments, the drug included in the ER portion (such as a layer) is released from the dosage unit over a period of time beginning from exposure of the ER portion to GI fluids.

In some embodiments, the drug contained in the ER portion (such as the ER layer) is released from the dosage unit over a period of at least about 3 hours, such as at least any one of at least about 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, 192 hours, 216 hours, 240 hours, 264 hours, 288 hours, 312 hours, 336 hours, 360 hours, 384 hours, 408 hours, 432 hours, 456 hours, 480 hours, 504 hours, 528 hours, 552 hours, 576 hours, 600 hours, 648 hours, 624 hours, 696 hours, or 720 hours. In some embodiments, the ER portion (such as the ER layer) of the dosage unit erodes over a period of at least about 3 hours, such as any one of at least about 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, 192 hours, 216 hours, 240 hours, 264 hours, 288 hours, 312 hours, 336 hours, 360 hours, 384 hours, 408 hours, 432 hours, 456 hours, 480 hours, 504 hours, 528 hours, 552 hours, 576 hours, 600 hours, 624 hours, 648 hours, 696 hours, or 720 hours.

In some embodiments, the dissolution rate (or erosion rate) of the ER layer is about 0.05 mm/hour to about 0.5 mm/hour. In some embodiments, the dissolution rate (or erosion rate) of the ER layer is at least about 0.05 mm/hour, such as at least any one of about 0.1 mm/hour, 0.2 mm/hour, 0.3 mm/hour, 0.4 mm/hour, or 0.5 mm/hour.

In some embodiments, the sustained release profile comprises a zero order release profile, a first order release profile, a sustained release profile, a pulsatile release profile, an iterative pulsatile release profile, or a combination thereof.

In some embodiments, the drug mass fraction (mass) of the ER layer_MedicineMass/mass_Layer(s)) From about 0.05 to about 1, such as any one of from about 0.1 to about 0.5, from about 0.2 to about 0.6, from about 0.3 to about 0.7, from about 0.4 to about 0.8, from about 0.5 to about 0.9, from about 0.5 to about 1. In some embodiments, the ER layer has a drug mass fraction of at least about 0.05, such as at least about any one of 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1. In some embodiments, the ER layer has a drug mass fraction of 1 or less, such as any of 0.95 or less, 0.9 or less, 0.85 or less, 0.8 or less, 0.75 or less, 0.7 or less, 0.65 or less, 0.6 or less, 0.55 or less, 0.5 or less, 0.45 or less, 0.4 or less, 0.35 or less, 0.3 or less, 0.25 or less, 0.2 or less, 0.15 or less, 0.1 or less, or 0.05 or less.

In some embodiments, the ER portion (such as the ER layer) comprises at least about 0.001% drug, such as at least about any one of 0.005% drug, 0.01% drug, 0.05% drug, 0.1% drug, 0.5% drug, 1% drug, 2% drug, 3% drug, 4% drug, or 5% drug. In some embodiments, the ER portion (such as the ER layer) comprises about 0.001% to 100% drug.

The ER layer of the oral pharmaceutical dosage forms described herein can include any amount of drug. As described herein, the amount of drug in the ER layer may depend on, for example, the total amount of drug in the oral pharmaceutical dosage form, the target release profile, and the target PK profile. In some embodiments, the amount of drug in the ER layer is from about 0.001mg to about 2000 mg. In some embodiments, the amount of drug in the ER layer is at least about 0.001mg, such as at least about any one of 0.01mg, 0.1mg, 0.25mg, 0.5mg, 0.75mg, 1mg, 2mg, 3mg, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, 1250mg, or 1500 mg.

In some embodiments, the drug included in the ER portion (such as the ER layer) is released from the dosage unit at a release rate of about 0.00001 mg/hour to 500 mg/hour. In some embodiments, the drug included in the ER portion (such as the ER layer) is released from the dosage unit at a release rate of less than about 500 mg/hour (such as any of about 400 mg/hour, 300 mg/hour, 200 mg/hour, 100 mg/hour, 50 mg/hour, 25 mg/hour, 10 mg/hour, 5 mg/hour, or 1 mg/hour).

In some embodiments, the ER portion (such as the ER layer) includes at least one other component. In some embodiments, the ER layer comprises at least one other component mixed with the drug. In some embodiments, the ER layer further comprises an erodible material. In some embodiments, the ER layer further comprises a material, such as a filler, a binder, a controlled release polymer, a lubricant, a glidant, a disintegrant, a thermoplastic, or a plasticizer.

In some embodiments, the ER layer further comprises an adjuvant. In some embodiments, the adjuvant is selected from the group consisting of: acacia, alginate, alginic acid, aluminum acetate, benzyl alcohol, butyl p-hydroxybenzoate, butylated hydroxytoluene, citric acid, calcium carbonate, candelilla wax, croscarmellose sodium, fructosyl, colloidal silicon dioxide, cellulose, pure or anhydrous calcium phosphate, carnauba wax, corn starch, carboxymethylcellulose calcium, calcium stearate, calcium disodium Edetate (EDTA), povidone, hydrogenated castor oil, dibasic calcium phosphate dihydrate, cetylpyridinium chloride, cysteine HCl, crospovidone, dibasic calcium phosphate, dibasic sodium phosphate, polydimethylsiloxane, sodium erythritol, ethylcellulose, ethylenediaminetetraacetic acid (EDTA), gelatin, glycerol monooleate, glycerol, glyceryl monostearate, glyceryl behenate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, sodium alginate, hydroxypropyl methylcellulose (HPMC) phthalate, iron oxide, ferric oxide, yellow iron oxide, red iron oxide, lactose (aqueous, anhydrous, monohydrate, or spray-dried), magnesium stearate, microcrystalline cellulose, mannitol, methylcellulose, magnesium carbonate, mineral oil, methacrylic acid copolymers, magnesium oxide, methyl paraben, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polysorbate 80, propylene glycol, polyethylene oxide, propyl paraben, poloxamer 407, poloxamer 188, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyl 140 stearate, sodium starch glycolate, pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, stearic acid, sucrose, sorbic acid, sodium carbonate, sodium saccharin, Sodium alginate, silica gel, sorbitan oleate, sodium stearyl fumarate, sodium chloride, sodium metabisulfite, sodium citrate dihydrate, sodium starch, sodium carboxymethylcellulose, succinic acid, sodium propionate, titanium dioxide, talc, triacetin and triethyl citrate.

In some embodiments, the ER layer further comprises an erodible material, such as a slow release material. In some embodiments, the sustained release material is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57/30/13, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA)60/40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), and polyvinyl pyrrolidone (PVP)80/20, vinyl pyrrolidone-vinyl acetate copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PVA or PV-OH), poly (vinyl acetate) (PVAc), poly (optionally alkyl-, methyl-, or ethyl-) acrylates, polyvinyl alcohol (PVAc), polyvinyl alcohol (optionally alkyl-, methyl-, or ethyl-) acrylates, polyvinyl alcohol (PVAc), methacrylate copolymers, ethyl acrylate copolymers, butyl methacrylate-2-dimethylaminoethyl methacrylate-methyl methacrylate copolymers 1:2:1, dimethylaminoethyl methacrylate-methacrylate copolymers, ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride copolymers, methyl acrylate-methyl methacrylate-methacrylic acid copolymers 7:3:1, methacrylic acid-methyl methacrylate copolymers 1:2, methacrylic acid-ethyl acrylate copolymers 1:1, methacrylic acid-methyl methacrylate copolymers 1:1, polyethylene oxide (PEO), polyethylene glycol (PEG), hyperbranched polyesteramides, hydroxypropyl methylcellulose phthalate, poly (ethylene oxide) polyethylene glycol (PEO), poly (ethylene glycol) polyethylene glycol (PEG), poly (ethylene glycol) polyethylene glycol (PEG), poly (ethylene glycol, Hypromellose phthalate, hydroxypropylmethylcellulose or Hypromellose (HMPC), hydroxypropylmethylcellulose acetate succinate or hypromellose succinate (HPMCAS), lactide-glycolide copolymer (PLGA), carbomer, ethylene-vinyl acetate copolymer, Polyethylene (PE) and Polycaprolactone (PCL), cellulose or cellulose derivatives, Hydroxypropylcellulose (HPC), polyoxyethylene 40 hydrogenated castor oil, Methylcellulose (MC), Ethylcellulose (EC), poloxamers, hydroxypropylmethylcellulose phthalate (HPMCP), poloxamers, hydrogenated castor oil and soybean oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), Cellulose Acetate Butyrate (CAB), colloidal silicon dioxide, saccharides, glucose, polyvinyl acetate phthalate (PVAP), Wax, beeswax, hydrogel, gelatin, hydrogenated vegetable oil, polyvinyl acetal diethylamine acetate (AEA), paraffin, shellac, sodium alginate, Cellulose Acetate Phthalate (CAP), fatty oil, gum arabic, xanthan gum, glyceryl monostearate, stearic acid, or a combination thereof.

In some embodiments, the ER layer further comprises a thermoplastic material. In some embodiments, the thermoplastic material is mixed with a plasticizer. In some embodiments, the other component is a plasticizer. In some embodiments, the plasticizer is triethyl citrate (TEC). In some embodiments, the plasticizer is selected from one or a combination of polyoxyethylene-polyoxypropylene block copolymer, vitamin E polyethylene glycol succinate, hydroxystearate, polyethylene glycol (e.g., PEG400), polyethylene glycol cetostearyl ether 12, polyethylene glycol 20 cetostearyl ether, polysorbate 20, polysorbate 60, polysorbate 80, acetin, acetylated triethyl citrate, tributyl citrate, acetylated tributyl citrate, triethyl citrate, polyoxyethylene 15 hydroxystearate, polyethylene glycol-40 hydrogenated castor oil, polyoxyethylene 35 castor oil, dibutyl sebacate, diethyl phthalate, glycerol, methyl 4-hydroxybenzoate, glycerol, castor oil, oleic acid, triacetin, and polyalkylene glycol.

Middle part

In some embodiments, a dosage unit described herein further comprises one or more intermediate portions, such as an intermediate layer. In some embodiments, the intermediate layer is in direct contact with the IR layer. In some embodiments, the intermediate layer is in direct contact with the ER layer. In some embodiments, the intermediate layer is in direct contact with the shell. In some embodiments, the intermediate layer is in direct contact with the IR layer and the ER layer. In some embodiments, the intermediate layer is in direct contact with the IR layer, the ER layer, and the shell. In some embodiments, the intermediate layer is located between the IR layer and the ER layer. In some embodiments, the intermediate layer is located between the IR layer and the shell. In some embodiments, the intermediate layer is located between the ER layer and the shell.

In some embodiments, the intermediate layer drug is slowly released from the dosage unit. In some embodiments, the intermediate layer drug is sustained released from the dosage unit for about 5 minutes to about 12 hours, such as any of about 5 minutes to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 6 hours, about 6 hours to about 9 hours, or about 9 hours to about 12 hours. In some embodiments, the intermediate layer reduces interference between two or more components contacting the intermediate layer.

In some embodiments, the dissolution rate (or erosion rate) of the intermediate portion is about 0.1 mm/hour to about 50 mm/hour. In some embodiments, the dissolution rate (or erosion rate) of the intermediate portion is at least about 0.1 mm/hour, such as at least any one of about 1 mm/hour, 5 mm/hour, 10 mm/hour, 20 mm/hour, 30 mm/hour, or 40 mm/hour. In some embodiments, the dissolution rate (or erosion rate) of the intermediate portion is less than about 50 mm/hour, such as any of less than about 40 mm/hour, 30 mm/hour, 20 mm/hour, 10 mm/hour, 5 mm/hour, or 1 mm/hour.

In some embodiments, the intermediate layer is stacked on top of the IR layer, wherein the intermediate layer has an upper surface and a lower surface, wherein the IR layer has an upper surface and a lower surface, and wherein the shell is in direct contact with both the intermediate layer and the IR layer. In some embodiments, the ER layer is stacked on top of the intermediate layer. In some embodiments, the shell exposes an upper surface of the intermediate layer.

In some embodiments, the intermediate layer is stacked on top of the ER layer, wherein the intermediate layer has an upper surface and a lower surface, wherein the ER layer has an upper surface and a lower surface, and wherein the shell is in direct contact with both the intermediate layer and the ER layer and exposes the upper surface of the intermediate layer.

In some embodiments, the intermediate layer is erodible. In some embodiments, the intermediate layer comprises an etchable material. In some embodiments, the intermediate layer is not mixed with a drug. In some embodiments, the intermediate layer is mixed with a different drug. In some embodiments, the intermediate layer blocks drug interaction in the IR layer and the ER layer. In some embodiments, the intermediate layer blocks the interaction of one or more other components (such as excipients) in the IR layer and the ER layer. In some embodiments, the intermediate layer blocks migration of the drug and/or one or more other components (such as excipients) in the IR layer and the ER layer.

In some embodiments, the intermediate layer has a slower dissolution rate than the IR layer. In some embodiments, the intermediate layer has a faster dissolution rate than the IR layer. In some embodiments, the intermediate layer has a slower dissolution rate than the ER layer. In some embodiments, the intermediate layer has a faster dissolution rate than the ER layer. In some embodiments, the intermediate layer has a slower dissolution rate than the IR layer and a faster dissolution rate than the ER layer. In some embodiments, the dissolution rate of the intermediate layer is selected based on the target dissolution rate. In some embodiments, the dissolution rate of the intermediate layer is selected based on a target drug release rate from the oral pharmaceutical dosage form.

In some embodiments, the intermediate layer does not include a drug. In some embodiments, the intermediate layer comprises a second drug.

In some embodiments, the intermediate portion (such as the intermediate layer) further comprises one or more components, such as 2, 3, 4,5, or 6 components. In some embodiments, the intermediate layer comprises a structural material. In some embodiments, the intermediate portion includes any one or more materials, such as fillers, binders, controlled release polymers, lubricants, glidants, disintegrants, thermoplastic materials, or plasticizers.

In some embodiments, the intermediate portion includes an excipient. In some embodiments, the adjuvant is selected from the group consisting of: acacia, alginate, alginic acid, aluminum acetate, benzyl alcohol, butyl p-hydroxybenzoate, butylated hydroxytoluene, citric acid, calcium carbonate, candelilla wax, croscarmellose sodium, fructosyl, colloidal silicon dioxide, cellulose, pure or anhydrous calcium phosphate, carnauba wax, corn starch, carboxymethylcellulose calcium, calcium stearate, calcium disodium Edetate (EDTA), povidone, hydrogenated castor oil, dibasic calcium phosphate dihydrate, cetylpyridinium chloride, cysteine HCl, crospovidone, dibasic calcium phosphate, dibasic sodium phosphate, polydimethylsiloxane, sodium erythritol, ethylcellulose, ethylenediaminetetraacetic acid (EDTA), gelatin, glycerol monooleate, glycerol, glyceryl monostearate, glyceryl behenate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, sodium alginate, hydroxypropyl methylcellulose (HPMC) phthalate, iron oxide, ferric oxide, yellow iron oxide, red iron oxide, lactose (aqueous, anhydrous, monohydrate, or spray-dried), magnesium stearate, microcrystalline cellulose, mannitol, methylcellulose, magnesium carbonate, mineral oil, methacrylic acid copolymers, magnesium oxide, methyl paraben, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polysorbate 80, propylene glycol, polyethylene oxide, propyl paraben, poloxamer 407, poloxamer 188, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyl 140 stearate, sodium starch glycolate, pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, stearic acid, sucrose, sorbic acid, sodium carbonate, sodium saccharin, Sodium alginate, silica gel, sorbitan oleate, sodium stearyl fumarate, sodium chloride, sodium metabisulfite, sodium citrate dihydrate, sodium starch, sodium carboxymethylcellulose, succinic acid, sodium propionate, titanium dioxide, talc, triacetin and triethyl citrate.

In some embodiments, the intermediate portion comprises an erodable material. In some embodiments, the erodible material is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57/30/13, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA)60/40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), and polyvinyl pyrrolidone (PVP)80/20, vinyl pyrrolidone-vinyl acetate copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PVA or PV-OH), polyethylene oxide (PEO), polyethylene glycol (PEG), cellulose or cellulose derivatives, hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose succinate (HPMCAS), One or a combination of carbomer, hydroxypropyl cellulose (HPC), poloxamer, hydroxypropylmethyl cellulose phthalate (HPMCP), poloxamer, polyglycolic acid (PGA), sugars, glucose, hydrogels, gelatin, sodium alginate, gum arabic, and xanthan gum. In some embodiments, the erodible material is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57/30/13, vinyl pyrrolidone-vinyl acetate copolymer (PVP-VA)60/40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), and polyvinyl pyrrolidone (PVP)80/20, vinyl pyrrolidone-vinyl acetate copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PVA or PV-OH), poly (vinyl acetate) (PVAc), poly (optionally alkyl-, methyl-, or ethyl-) acrylates, polyvinyl alcohol (PVAc), polyvinyl pyrrolidone-vinyl acetate copolymers (PVP-VA), polyvinyl alcohol-polyvinyl alcohol graft copolymers (PVP-VA), polyvinyl alcohol-polyvinyl alcohol copolymers (PVAc), polyvinyl alcohol (PVA or polyvinyl alcohol, Methacrylate copolymers, ethyl acrylate copolymers, butyl methacrylate-2-dimethylaminoethyl methacrylate-methyl methacrylate copolymers 1:2:1, dimethylaminoethyl methacrylate-methacrylate copolymers, ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride copolymers, methyl acrylate-methyl methacrylate-methacrylic acid copolymers 7:3:1, methacrylic acid-methyl methacrylate copolymers 1:2, methacrylic acid-ethyl acrylate copolymers 1:1, methacrylic acid-methyl methacrylate copolymers 1:1, polyethylene oxide (PEO), polyethylene glycol (PEG), hyperbranched polyesteramides, hydroxypropyl methylcellulose phthalate, poly (ethylene oxide) polyethylene glycol (PEO), poly (ethylene glycol) polyethylene glycol (PEG), poly (ethylene glycol) polyethylene glycol (PEG), poly (ethylene glycol, Hypromellose phthalate, hydroxypropylmethylcellulose or Hypromellose (HMPC), hydroxypropylmethylcellulose acetate succinate or hypromellose succinate (HPMCAS), lactide-glycolide copolymer (PLGA), carbomer, ethylene-vinyl acetate copolymer, Polyethylene (PE) and Polycaprolactone (PCL), cellulose or cellulose derivatives, Hydroxypropylcellulose (HPC), polyoxyethylene 40 hydrogenated castor oil, Methylcellulose (MC), Ethylcellulose (EC), poloxamers, hydroxypropylmethylcellulose phthalate (HPMCP), poloxamers, hydrogenated castor oil and soybean oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), Cellulose Acetate Butyrate (CAB), colloidal silicon dioxide, saccharides, glucose, polyvinyl acetate phthalate (PVAP), Wax, beeswax, hydrogel, gelatin, hydrogenated vegetable oil, polyvinyl acetal diethylamine acetate (AEA), paraffin, shellac, sodium alginate, Cellulose Acetate Phthalate (CAP), fatty oil, gum arabic, xanthan gum, glyceryl monostearate, stearic acid, or a combination thereof.

In some embodiments, the intermediate portion comprises a release agent. In some embodiments, the release agent is a release rate enhancer, such as lactose, mannitol, or a combination thereof. In some embodiments, the release agent is an excipient. In some embodiments, the release agent is an erodable material.

In some embodiments, the intermediate layer comprises a thermoplastic material. In some embodiments, the thermoplastic material is mixed with a plasticizer. In some embodiments, the plasticizer is triethyl citrate (TEC). In some embodiments, the plasticizer is selected from one or a combination of polyoxyethylene-polyoxypropylene block copolymer, vitamin E polyethylene glycol succinate, hydroxystearate, polyethylene glycol (e.g., PEG400), polyethylene glycol cetostearyl ether 12, polyethylene glycol 20 cetostearyl ether, polysorbate 20, polysorbate 60, polysorbate 80, acetin, acetylated triethyl citrate, tributyl citrate, acetylated tributyl citrate, triethyl citrate, polyoxyethylene 15 hydroxystearate, polyethylene glycol-40 hydrogenated castor oil, polyoxyethylene 35 castor oil, dibutyl sebacate, diethyl phthalate, glycerol, methyl 4-hydroxybenzoate, glycerol, castor oil, oleic acid, triacetin, and polyalkylene glycol.

In some embodiments, the intermediate layer is printed by dispensing an intermediate material, such as an intermediate material that is an intermediate material comprising the components described herein.

Shell

In some embodiments, the dosage unit of the oral pharmaceutical dosage form comprises a shell. In some embodiments, the IR layer and the ER layer of the dosage unit are partially surrounded by the shell. In some embodiments, the shell partially surrounds the IR layer, the ER layer, and the intermediate layer.

In some embodiments, the shell is not mixed with the drug. In some embodiments, the shell is mixed with a different drug.

In some embodiments, the shell is not erodible. In some embodiments, the shell has a slower erosion rate than the ER layer. In some embodiments, the shell does not substantially erode until after substantially all of the drug in the ER layer has been released therefrom. In some embodiments, the shell is substantially non-eroding for a period of at least about 6 hours (such as at least about any one of 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, or 72 hours) after administration of the dosage unit to the subject. In some embodiments, the shell comprises a pH sensitive material, such as a material that erodes within a particular pH range.

In some embodiments, the shell is impermeable, such as impermeable to water or gastrointestinal fluids. In some embodiments, the shell is substantially impermeable.

In some embodiments, the shell comprises a material selected from the group consisting of:RL、RS, polyvinyl acetate and povidone mixture, methacrylic acid copolymer, amino methacrylic acid copolymer, methacrylate ester copolymer, butyl acrylate, methyl methacrylate copolymer, ethyl methacrylate-methacrylic acid copolymer, butyl acrylate-monobutyl acrylate copolymer, ethyl acrylate-monomethacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, ethyl acrylate/methyl methacrylate/trimethylaminoethyl methacrylate polymer, methylcellulose, ethylcellulose, ethylene phthalate, hypromellose succinate, polyethylene glycol-polyvinyl alcohol copolymer, hydroxypropyl methylcellulose phthalate or hypromellose phthalate, polyethylene glycol 15-hydroxystearate, polyvinyl alcohol-methyl acrylate copolymer, polyvinyl alcohol-methyl acrylate, Copolymers of methyl methacrylate and diethylaminoethyl methacrylate, polymethyl acrylate-polymethyl methacrylate copolymers, N-dimethylaminoethyl methacrylate, polyvinyl caprolactam-vinyl acetate-polyethylene glycol graft copolymers, polybutyl methacrylate-poly-N, N-dimethylaminoethyl methacrylate copolymers, polyvinyl alcohol, polyethylene oxide, hyperbranched polyesteramides, hydroxypropyl methylcelluloseOr hypromellose, hydroxyethyl cellulose, cellulose acetate, vitamin E polyethylene glycol succinate, polydimethylsiloxane alkanes, xanthan gum, polylactic acid, polylactide-polylactic acid copolymer, polycaprolactone, carnauba wax, glyceryl palmitostearate, hydrogenated castor oil, cellulose acetate butyrate, polyvinyl acetate, polyethylacrylate-polymethylmethacrylate-polytrimethylammonium chloride ethyl methacrylate copolymer, polyethylene-polyvinylacetate copolymer, and chitosan, and combinations thereof.

In some embodiments, shell dissolution is pH dependent. In some embodiments, shell dissolution occurs above a pH of about 5.5 to about 7. In some embodiments, shell dissolution occurs at a pH above about 5.5, about 6, about 6.5, or about 7. In some embodiments, the shell comprises an enteric material.

In some embodiments, the shell is printed by dispensing shell material, such as shell material that is an IR material that includes the components described herein.

Medicine

The dosage unit disclosed herein comprises: an IR layer comprising a drug and an ER layer comprising a drug.

In some embodiments, the drug has linear or dose-dependent pharmacokinetics (the drug exhibits a plasma concentration of the drug that is directly proportional to the administered dose). In some embodiments, the dosage unit, such as the IR layer and the ER layer, includes an amount of the drug within the linear pharmacokinetic region of the drug. In some embodiments, the dosage unit releases an amount of the drug within a linear pharmacokinetic region of the drug over time. Methods of determining whether a drug has linear or non-dose dependent pharmacokinetics are known in the art, and thus, one of ordinary skill in the art can readily evaluate drugs encompassed by the present disclosure for either linear or dose dependent pharmacokinetic drugs. See, e.g., Jeong et al, Biopharm Drug Dispos,28,2007.

In some embodiments, the dosage unit comprises one or more additional drugs. In some embodiments, the IR layer includes one or more additional drugs. In some embodiments, the ER layer comprises one or more additional drugs. In some embodiments, the IR layer comprises an additional drug and the ER layer comprises an additional drug, wherein the additional drug in the IR layer is different from the additional drug in the ER layer. In some embodiments, the IR layer comprises an additional drug and the ER layer comprises an additional drug, wherein the additional drug in the IR layer is the same as the additional drug in the ER layer. In some embodiments, wherein the IR layer and the ER layer comprise additional drugs, the amount of the additional drugs may be apportioned between the IR layer and the ER layer independent of the amount of the drugs in the IR layer and the ER layer.

Composite target PK curves

In some aspects, the invention provides methods of designing an oral pharmaceutical dosage form described herein with a composite target Pharmacokinetic (PK) profile. Generally, pharmacokinetics refers to the movement of a drug in an individual after administration and may be characterized, for example, by the time course of drug absorption, bioavailability, blood, serum and/or plasma drug concentration over time, drug profile, drug metabolism, and drug excretion.

In some embodiments, the composite target PK profile for an oral pharmaceutical dosage form as described herein comprises one or more pharmacokinetic parameters. In some embodiments, the pharmacokinetic parameter is a blood, plasma, or serum-based parameter. In some embodiments, the composite target PK profile comprises a PK profile selected from C_max(e.g., peak drug concentration in plasma after administration), t_max(to C)_maxTime) area under the curve (AUC; integral of concentration time curve), C_min(e.g., the lowest (trough) drug concentration in plasma prior to the next administration), dispensed amount, elimination half-life, elimination rate constant, and clearance rate. In some embodiments, the composite target PK profile comprises C_maxAnd AUC parameters. In some embodiments, the composite target PK profile comprises C_max、t_maxAnd AUC parameters.

In some embodiments, the mouth described hereinThe composite target PK profile for an oral pharmaceutical dosage form comprises a series of values for each of one or more pharmacokinetic parameters, such as C_max、t_maxAnd AUC. In some embodiments, the range of values for the pharmacokinetic parameter of the drug is an acceptable threshold, such as an acceptable threshold for the pharmacokinetic parameter based on a reference PK profile for the drug or a target PK profile for the drug. In some embodiments, the value of the pharmacokinetic parameter of the drug ranges from about 60% to about 145%, such as any one of about 65% to about 140%, about 70% to about 135%, about 75% to about 130%, about 80% to about 125%, about 85% to about 120%, or about 90% to about 115% of the pharmacokinetic parameter of the reference PK profile of the drug. In some embodiments, each pharmacokinetic parameter of the composite target PK profile may have the same or different acceptable thresholds. For example, in some embodiments, the composite target curve includes more than one pharmacokinetic parameter, where one pharmacokinetic parameter has a greater acceptable threshold than another pharmacokinetic parameter.

In some embodiments, the composite target PK profile is based on having C within a reference acceptable threshold for the drug (such as the reference PK profile or the target PK profile)_maxAnd (4) determining. In some embodiments, a composite target PK profile is determined based on the AUC that is possessed within a reference acceptable threshold for the drug (such as a reference PK profile or a target PK profile). In some embodiments, the composite target PK profile is based on having t within a reference acceptable threshold for the drug (such as the reference PK profile or the target PK profile)_maxAnd (4) determining. In some embodiments, the composite target PK profile is based on having an AUC and C within a reference acceptable threshold (such as a reference PK profile or target PK profile for the drug)_maxAnd (4) determining. In some embodiments, the composite target PK profile is based on having an AUC, C, within an acceptable threshold of reference for the drug (such as the reference PK profile or the target PK profile)_maxAnd t_maxAnd (4) determining. In some embodiments, the composite target PK profile is based on pharmacokinetics within an acceptable threshold of the drug reference PK profileParameters (such as AUC, C)_maxAnd t_maxAny one or more of), wherein the acceptable threshold for the pharmacokinetic parameter for the drug reference PK profile is any one of about 60% to about 145%, such as about 65% to about 140%, about 70% to about 135%, about 75% to about 130%, about 80% to about 125%, about 85% to about 120%, or about 90% to about 115%. In some embodiments, the composite target PK profile is based on pharmacokinetic parameters (such as AUC, C) within acceptable thresholds of the drug reference PK profile_maxAnd t_maxAny one or more of) wherein the acceptable threshold for the pharmacokinetic parameter of the drug reference PK profile is at least about 80%, such as at least about 85%, 90% or 95%, with a confidence interval between about 60% to about 145%, such as any one of about 65% to about 140%, about 70% to about 135%, about 75% to about 130%, about 80% to about 125%, about 85% to about 120%, or about 90% to about 115%. In some embodiments, the composite target PK profile is based on pharmacokinetic parameters (such as AUC, C) within acceptable thresholds of the drug reference PK profile_maxAnd t_maxAny one or more of) wherein the acceptable threshold for the pharmacokinetic parameter of the drug reference PK profile is within about 90% confidence interval, which is within about 80% to about 125%.

In some embodiments, the composite target PK profile is bioequivalent to a reference oral pharmaceutical dosage form or dosing regimen thereof, e.g., the reference oral pharmaceutical dosage form is administered on a twice-a-day schedule. In some embodiments, the composite target PK profile is bioequivalent to a reference oral pharmaceutical dosage form, wherein the oral pharmaceutical dosage form and the reference oral pharmaceutical dosage form are administered at the same molar dose of drug under the same conditions. In some embodiments, the composite target PK profile is bioequivalent to a reference oral pharmaceutical dosage form regimen, wherein the oral pharmaceutical dosage form and the reference oral pharmaceutical dosage form regimen are administered at the same molar dose of drug under the same conditions. In some embodiments, the composite target PK profile is a drug replacement for a reference oral drug dosage form or dosing regimen thereof, e.g., administration of the reference oral drug dosage form twice daily. In some embodiments, when compared to a reference (such as a reference oral pharmaceutical dosage form or dosing regimen thereof), e.g., in a properly designed study, the reference oral pharmaceutical dosage form is administered twice daily, administered at the same molar dose under similar conditions, the composite target PK profile is not significantly different in the rate and extent to which the active ingredient or active moiety in the oral pharmaceutical dosage form is available at the site of drug action.

In some embodiments, an oral pharmaceutical dosage form described herein having a target PK profile is bioequivalent to a reference oral pharmaceutical dosage form or dosing regimen thereof, wherein the ratio of the oral pharmaceutical dosage form and the reference oral pharmaceutical dosage form or AUC and C of the dosing regimen thereof_maxThe 90% confidence interval of (a) falls within the acceptance range of about 80% to about 125%. In some embodiments, an oral pharmaceutical dosage form described herein having a target PK profile is bioequivalent to a reference oral pharmaceutical dosage form or dosing regimen thereof, wherein the ratio of the oral pharmaceutical dosage form and the reference oral pharmaceutical dosage form or AUC, C of the dosing regimen thereof_maxAnd t_maxThe 90% confidence interval of (a) falls within the acceptance range of about 80% to about 125%.

In some embodiments, the target PK profile for an oral pharmaceutical dosage form described herein comprises improved PK parameters compared to a reference (such as a reference oral pharmaceutical dosage form or dosing regimen thereof). In some embodiments, the improved PK parameter is earlier T_maxAnd/or a longer plateau.

In some embodiments, the composite target PK profile is a composite target PK profile over a period of time. In some embodiments, the composite target PK profile is at least about 4 hours, such as at least any one of about 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, or 24 hours. In some embodiments, the composite target PK profile is at least about 4 hours, such as at least any one of about 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, or 24 hours after administration of the dosage unit to the individual.

In some embodiments, the reference (such as a reference PK profile for a drug) is a theoretical reference PK profile. In some embodiments, the reference PK profile for the drug is a measured reference PK profile. In some embodiments, the reference PK profile for the drug is a composite PK profile, e.g., based on two or more PK profiles. In some embodiments, the reference PK profile is based on the dosing regimen of the drug, e.g., at least two or more administrations per day. In some embodiments, the reference oral pharmaceutical dosage form or dosing regimen thereof is an oral pharmaceutical dosage form or dosing regimen thereof approved by a governmental regulatory agency, e.g., the united states Food and Drug Administration (FDA). Techniques for measuring PK profiles for drugs are known in the art, such as from an oral drug dosage form or a reference oral drug dosage form described herein. See, e.g., Heller et al, Annu Rev Anal Chem,11,2018; and Ghand from mouth-Sattari et al, J Amino Acids, Article ID 346237, Volume 2010.

In some embodiments, the composite target PK profile is predefined. In some embodiments, the composite target PK profile is based on a theoretical PK profile or PK profile. In some embodiments, the composite target PK profile is based on a reference oral pharmaceutical dosage form or dosing regimen thereof, e.g., the reference oral pharmaceutical dosage form is administered twice daily. In some embodiments, the composite target PK profile is based on the PK profile of a reference oral pharmaceutical dosage form or dosing regimen thereof, e.g., the reference oral pharmaceutical dosage form is administered twice daily. In some embodiments, the composite target PK profile is based on a composite PK profile of a reference oral drug dosage form dosing regimen, e.g., the reference oral drug dosage form is administered twice daily.

In some embodiments, the composite target PK profile is individual specific. In some embodiments, the individual is a human. In some embodiments, the subject is selected from the group consisting of a dog, a rodent, a mouse, a rat, a ferret, a pig, a guinea pig, a rabbit, and a non-human primate. In some embodiments, the composite target PK profile is designed for humans.

In some embodiments, the dosage unit has a composite target PK profile. In some embodiments, the PK profile for each of the plurality of dosage units is formulated into an oral pharmaceutical dosage form having a composite target PK profile. In some embodiments, the PK profile for each of the plurality of dose units (wherein each dose unit is the same) is formulated into an oral pharmaceutical dosage form having a composite target PK profile.

Initial design of dosage units described herein

In some aspects, provided herein are methods of designing and/or producing an initial oral pharmaceutical dosage form or dosage unit having a release profile that can be adjusted based on the methods described herein to have a composite target PK profile in a subject. In some embodiments, the initial dose unit is adjusted by determining the relative amounts of drug in the MR1 and MR2 fractions based on the MR1 PK profile and the MR2 PK profile, such that the MR1 fraction and the MR2 fraction when combined together make a composite target PK profile. In some embodiments, the initial dose unit is adjusted by determining the relative amounts of drug in the IR layer and the ER layer based on the IR PK profile and the ER PK profile such that the IR layer and the ER layer when combined together make a composite target PK profile.

In some embodiments, the initial dosage unit has a target drug release profile, such as an in vitro drug release profile. Methods of designing and producing dosage units having a target release profile are known in the art. See, e.g., Goole et al, Int J Pharm,499,2016; and U.S. patent No. 10,350,822, which are incorporated herein by reference in their entirety. Methods for in vitro dissolution testing include logarithmic curves, probability units, exponential models, Weibull and Gompertz. Statistical analysis methods for determining dissolution similarity of two dissolution profiles, e.g., experimentally determined dissolution profiles and target drug release profiles, including regression analysis, ANOVA, the similarity factor method, the variable factor method, the splitport method, and the Chow method. In some embodiments, the dissolution similarity is assessed using a similarity factor. In some embodiments, the dissolution similarity is assessed using the Chow method.

In some embodiments, the method for designing an initial dosage unit comprises a step based on dissolution testing (such as in vitro dissolution testing). In some embodiments, the method comprises selecting one or more parameters for the ER layer to obtain a target release profile, such as an in vitro release profile of the drug, from the ER layer. In some embodiments, the method includes selecting one or more parameters for the IR layer to obtain a target release profile of the drug from the IR layer, such as an in vitro release profile. In some embodiments, the one or more parameters are selected from the group consisting of: thickness, surface area, substrate erosion rate, drug mass fraction or drug concentration, and layer configuration.

In some embodiments, the method of designing an initial oral pharmaceutical dosage form described herein may be performed in whole or in part on a computer system. In some embodiments, the computer system includes a user interface. In some embodiments, the method comprises inputting one or more parameters of the oral pharmaceutical dosage form into a computer system. In some embodiments, the computer system is used to calculate parameters of an oral drug dosage form to provide a target drug release profile. In some embodiments, the computer system includes 3D drawing software. In some embodiments, the computer system is configured to create a 3D map of the initial oral drug dosage form based on predetermined parameters of the initial oral drug dosage form. In some embodiments, the computer system includes layered software. In some embodiments, the computer system is used to convert the three-dimensional map of the initial oral drug dosage form into a 3D printed code, e.g., a G-code. In some embodiments, the computer system executes the three-dimensional printing code to print the initial oral pharmaceutical dosage form.

Precursor dosage forms

In some aspects, the methods described herein comprise obtaining a PK profile for a precursor dosage form in a subject. In some embodiments, the methods described herein comprise designing and/or producing precursor dosage forms, such as IR precursor dosage forms comprising an IR layer and ER precursor dosage forms comprising an ER layer.

As used herein, "precursor dosage form" refers to a dosage form that mimics a portion of an oral pharmaceutical dosage form or dosage unit. In some embodiments, wherein the oral pharmaceutical dosage form or dosage unit comprises an IR portion and an ER portion, the IR precursor dosage form comprises an IR portion and the ER precursor dosage form comprises an ER portion. In some embodiments, wherein the oral pharmaceutical dosage form or dosage unit comprises an IR portion, an ER portion and a shell, the IR precursor dosage form comprises an IR portion and a shell and the ER precursor dosage form comprises an ER portion and a shell. In some embodiments, the components of the precursor dosage form, such as the IR portion, ER portion, intermediate portion, and shell, are the same as in the oral pharmaceutical dosage form or dosage unit. In some embodiments, the components of the precursor dosage form are positioned in the same manner as the positioning in the oral pharmaceutical dosage form or dosage unit.

In some embodiments, the method comprises obtaining (such as producing and/or 3D printing) a precursor dosage form, wherein the precursor dosage form is based on a dosage unit or oral pharmaceutical dosage form described herein. In some embodiments, the precursor dosage form is designed to mimic and detect the contribution of a component of the dosage form or oral pharmaceutical dosage form (e.g., ER layer, IR layer, or intermediate layer) to the pharmacokinetics of the dosage form or oral pharmaceutical dosage form. In some embodiments, the precursor dosage form comprises a dosage unit or a component of an oral pharmaceutical dosage form, such as a monolayer, e.g., an ER layer, an IR layer, or an intermediate layer. In some embodiments, the precursor dosage form further comprises a shell. In some embodiments, the components of the precursor dosage form are positioned in the precursor dosage form as they will be positioned in the dosage unit or oral pharmaceutical dosage form. In some embodiments, the component is a single component of a dosage unit or oral pharmaceutical dosage form. In some embodiments, the component is one or more components of a dosage unit or oral pharmaceutical dosage form. In some embodiments, components of the precursor dosage form are not present in the dosage form or oral pharmaceutical dosage form, e.g., the design of the dosage form or oral pharmaceutical dosage form is simulated using the components. In some embodiments, a component of a precursor dosage form is present to control an exposed surface of another component (such as exposure to gastrointestinal fluids after administration to an individual), for example, where the component is an intermediate layer. In some embodiments, multiple different precursor dosage forms may be obtained from a single dosage unit or a single oral pharmaceutical dosage form.

In some embodiments, the precursor dosage form comprises an IR layer. In some embodiments, the precursor dosage form comprises an IR layer and a shell. In some embodiments, the precursor dosage form comprises an IR layer and an intermediate layer. In some embodiments, the precursor dosage form comprises an IR layer, an intermediate layer, and a shell. In some embodiments, the precursor dosage form further comprises another component of the dosage form or oral pharmaceutical dosage form, such as a second IR layer, ER layer, intermediate layer, or shell.

In some embodiments, the precursor dosage form comprises an ER layer. In some embodiments, the precursor dosage form comprises an ER layer and a shell. In some embodiments, the precursor dosage form comprises an ER layer and an intermediate layer. In some embodiments, the precursor dosage form comprises an ER layer, an intermediate layer, and a shell. In some embodiments, the precursor dosage form further comprises another component of the dosage form or oral pharmaceutical dosage form, such as a second IR layer, ER layer, intermediate layer, or shell.

In some embodiments, wherein the dosage unit comprises an IR layer stacked over an ER layer, the first precursor dosage form comprises an IR layer optionally stacked over a first intermediate layer, and the second precursor dosage form comprises an ER layer optionally stacked over a second intermediate layer. In some embodiments, the first intermediate layer is based on properties of the ER layer, e.g., dissolution rate. In some embodiments, the second intermediate layer is based on properties of the IR layer, e.g., dissolution rate.

In some embodiments, wherein the dosage unit comprises an ER layer stacked over an IR layer, the first precursor dosage form comprises an ER layer optionally stacked over a first intermediate layer, and the second precursor dosage form comprises an IR layer optionally stacked over a second intermediate layer. In some embodiments, the first intermediate layer is based on properties of the IR layer, e.g., dissolution rate. In some embodiments, the second intermediate layer is based on properties of the ER layer, e.g., dissolution rate.

In some embodiments, wherein the dosage unit comprises an IR layer stacked over an ER layer, wherein the IR layer and the ER layer are partially surrounded by a shell, and wherein the shell is in direct contact with both the IR layer and the ER layer and exposes only an upper surface of the IR layer, the first precursor dosage form comprises an IR layer partially surrounded by a first shell, wherein the first shell is in direct contact with the IR layer and exposes an upper surface of the IR layer, and the second precursor dosage form comprises an ER layer partially surrounded by a second shell. In some embodiments, the second shell exposes an upper surface of the ER layer. In some embodiments, the second precursor dosage form further comprises an intermediate layer stacked over the ER layer, wherein the shell exposes an upper surface of the intermediate layer.

In some embodiments, wherein the dosage unit comprises an IR layer and an ER layer disposed side-by-side to each other, wherein the shell exposes the upper surfaces of the IR layer and the ER layer, the first precursor dosage form comprises the IR layer, and optionally, a first intermediate layer is side-by-side to the IR layer, and the first shell exposes the upper surface of the IR layer, the second precursor dosage form comprises the ER layer, and optionally, a second intermediate layer is side-by-side to the ER layer, and the second shell exposes the upper surface of the IR layer.

In some embodiments, wherein the IR layer is stacked over the ER layer, wherein the shell exposes an upper surface of the IR layer and a lower surface of the ER layer, the first precursor dosage form comprises the IR layer, and optionally, an intermediate layer stacked on the bottom of the IR layer, wherein the first shell exposes an upper surface of the IR layer and a lower surface of the intermediate layer, and the second precursor dosage form comprises the ER layer, and optionally, the intermediate layer stacked over the ER layer, wherein the second shell exposes a lower surface of the ER layer and an upper surface of the intermediate layer.

In some embodiments, the method comprises obtaining a PK profile for a precursor dosage form of the dosage unit in a subject. In some embodiments, the method comprises obtaining an ER PK profile for an ER precursor dosage form comprising an ER layer in the subject. In some embodiments, the method comprises: obtaining an IR PK profile for an IR precursor dosage form comprising an IR layer in a subject; and obtaining an ER PK profile for the ER precursor dosage form including the ER layer in the subject.

In some embodiments of the methods described herein, PK profiles are obtained for a plurality of ER precursor dosage forms and one or more ER precursor dosage forms are selected for oral pharmaceutical dosage forms or dosage units.

Obtaining PK curves

In some aspects, the methods described herein comprise obtaining, e.g., determining or measuring a PK profile for a drug in an individual. In some embodiments, the method comprises obtaining an IR PK profile for an IR precursor dosage form comprising an IR layer in a subject. In some embodiments, the method comprises obtaining an ER PK profile for an ER precursor dosage form comprising an ER layer in the subject. In some embodiments, the method comprises: obtaining an IR PK profile for an IR precursor dosage form comprising an IR layer in a subject; and obtaining an ER PK profile for the ER precursor dosage form including the ER layer in the subject. In some embodiments, the method comprises obtaining a PK profile for a dosage unit or oral pharmaceutical dosage form described herein. In some embodiments, the method comprises obtaining a PK profile for a reference oral pharmaceutical dosage form or dosing regimen thereof.

Techniques for obtaining drug PK profiles are known in the art, such as from the dosage units or oral pharmaceutical dosage forms described herein, or reference oral pharmaceutical dosage forms or dosing regimens thereof. See, e.g., Heller et al, Annu Rev Anal Chem,11,2018; and Ghand from mouth-Sattari et al, J Amino Acids, Article ID 346237, Volume 2010. In some embodiments, the PK profile of a drug in an individual is measured in a blood, plasma or serum sample of the individual. In some embodiments, the PK profile of the drug in the individual is measured using mass spectrometry techniques, such as LC-MS/MS.

In some embodiments, a PK profile for a drug of at least about 3 half-lives of the drug (such as at least about any of 4 half-lives of the drug, 5 half-lives of the drug, 6 half-lives of the drug, 7 half-lives of the drug, 8 half-lives of the drug, 9 half-lives of the drug, or 10 half-lives of the drug) is obtained after administration of the drug to the subject. In some embodiments, a drug PK profile is obtained for at least about 6 hours (such as at least any one of about 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 36 hours, or 48 hours) after administration of the dosage unit to the individual. In some embodiments, C can be obtained from PK curves_max、t_maxAnd AUC. In some embodiments, the AUC is limited by a time factor after administration of the drug to the subject, e.g., the AUC_{0 to 6 hours}(AUC from 0-6 hours post-administration). In some embodiments, pharmacokinetic parameters from PK profiles are evaluated using a non-compartmental modelAnd (4) counting.

In some embodiments, the PK profile of the drug is measured in an individual different from the individual for which the composite target PK profile is designed, e.g., the PK profile is measured in a dog and the composite target PK profile is designed for a human.

In some embodiments, more than one PK profile is obtained. For example, in some embodiments, at least 2, such as at least any one of 3, 4,5, 10, or 15, of IR precursor dosage forms and/or ER precursor dosage forms are obtained.

In some embodiments, PK profiles are obtained for a plurality of ER precursor dosage forms, wherein at least two of the plurality of ER precursor dosage forms have different configurations, such as different parameters selected from layer surface area, thickness, and erosion rate.

In some embodiments, two or more PK profiles are combined to obtain a composite PK profile. In some embodiments, the two or more PK profiles comprise PK profiles of at least two different dosage forms, e.g., a PK profile of an IR precursor dosage form and a PK profile of an ER precursor dosage form. In some embodiments, two or more PK profiles are obtained from the same individual. In some embodiments, two or more PK profiles are obtained from at least two different individuals.

Determining the relative amount of drug in a portion of an oral pharmaceutical dosage form

The methods described herein include determining the relative amounts of drugs in the MR1 and MR2 fractions based on PK profiles. In some embodiments, the method comprises: determining the relative amounts of the drug in the IR layer and the ER layer based on an IR PK profile in the subject for an IR precursor dosage form comprising the IR layer, and an ER PK profile in the subject for an ER precursor dosage form comprising the ER layer, such that the IR layer and the ER layer, when combined together, form a dosage unit or oral pharmaceutical dosage form that produces a composite target PK profile. In some embodiments, the method comprises determining the relative amount of drug in the IR layer and the ER layer based on an ER PK profile of an ER precursor dosage form comprising the ER layer in the subject.

In some embodiments, determining the relative amounts of drug in the IR layer and the ER layer of a dosage unit is based on theoretical PK simulations of exemplary oral drug dosage forms having different IR to ER drug ratio rates, wherein the theoretical simulations are based on PK profiles or PK profiles of an IR precursor dosage form and an ER precursor dosage form.

In some embodiments, the amount of drug in the IR layer and the ER layer is determined based on drug in vivo dynamic information, such as in vivo/in vitro correlation (IVIVC). In some embodiments, ivivivc is based on characterizing in vitro release and in vivo performance of a drug obtained using deconvolution based on PK data (such as PK data obtained from one or more PK profiles). In some embodiments, the amount of drug in the IR layer and the ER layer is determined based on a point-to-point relationship of the in vitro dissolution rate and in vivo dissolution rate (infusion rate) of the drug. In some embodiments, each point of the point-to-point relationship is based on a time after the time point of administration. In some embodiments, the point-to-point relationship is calculated to determine the in vitro release endpoint of the dose unit corresponding to the in vivo release end or sustained release portion of the oral pharmaceutical dosage form (such as the ER layer), and therefore, the dose unit or immediate release portion of the oral pharmaceutical dosage form (such as the IR layer) may be added to evaluate the composite PK information.

In some embodiments, the deconvolution method is suitable for IVIVC calculation of PK curves in animals (such as dogs and rodents, and humans). In some embodiments, the PK profile for a drug obtained from a human is more complex than the PK profile for a drug obtained from an animal (such as a dog or rodent). In some embodiments, ivivivc curves for in vitro and in vivo dissolution can be obtained based on a physiological pharmacokinetic (PBPK) model.

In some embodiments, the methods described herein comprise adjusting a parameter of a layer of the dosage unit or oral pharmaceutical dosage form, such as an IR layer or an ER layer. In some embodiments, the parameter is selected from the group consisting of layer surface area, thickness, erosion rate. In some embodiments, the adjustment of the parameters of the layer is performed to adjust the drug release profile of the layer.

Exemplary methods of designing oral pharmaceutical dosage forms described herein

In some embodiments, provided herein is a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) portion comprising the drug, the IR portion having an immediate release profile; and an Extended Release (ER) portion comprising the drug, the ER portion having an extended release profile, the method comprising: determining the relative amounts of the drug in the IR moiety and the ER moiety based on an IR PK profile in the subject for an IR precursor dosage form comprising the IR moiety and an ER PK profile in the subject for an ER precursor dosage form comprising the ER moiety, such that the IR moiety and the ER moiety, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the method further comprises obtaining an ER PK profile for the ER precursor dosage form in the subject, the ER precursor dosage form comprising the ER moiety. In some embodiments, the method further comprises obtaining an IR PK profile for said IR precursor dosage form in a subject, said IR precursor dosage form comprising said IR moiety.

In some embodiments, provided herein is a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) layer comprising a drug, the IR layer having an immediate release profile; and a sustained release (ER) layer comprising a drug, the ER layer having a sustained release profile, wherein the IR layer and the ER layer are stacked on one another, wherein the IR layer and the ER layer are partially surrounded by a shell, wherein the shell has a slower dissolution rate than the ER layer, wherein the IR layer has an upper surface and a lower surface, wherein the ER layer has an upper surface and a lower surface, and wherein the shell is in direct contact with both the IR layer and the ER layer and leaves only the upper surface of the IR layer exposed, the method comprising: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form comprising said IR layer; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER layer; and (c) determining the relative amount of the drug in the IR layer and the ER layer from the IR PK profile and the ER PK profile such that the IR layer and the ER layer when combined together make a composite target PK profile, thereby designing an oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the individual is a human. In some embodiments, the drug has linear pharmacokinetics. In some embodiments, the drug has linear pharmacokinetics for the concentration of the drug administered to the individual. In some embodiments, the dosage unit further comprises a second IR layer, wherein the second IR layer has an upper surface and a lower surface, wherein the ER layer is stacked over the second IR layer, and wherein the shell leaves only the upper surface of the IR layer exposed. In some embodiments, the dosage unit further comprises an intermediate layer located between the IR layer and the ER layer and/or the second IR layer and the ER layer.

In some embodiments, provided herein is a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) layer comprising a drug, the IR layer having an immediate release profile; and a sustained release (ER) layer comprising a drug, the ER layer having a sustained release profile, wherein the IR layer and the ER layer are stacked on one another, wherein the IR layer and the ER layer are partially surrounded by a shell, wherein the shell has a slower dissolution rate than the ER layer, wherein the IR layer has an upper surface and a lower surface, wherein the ER layer has an upper surface and a lower surface, and wherein the shell is in direct contact with both the IR layer and the ER layer and leaves only the upper surface of the ER layer exposed, the method comprising: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form comprising said IR layer; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER layer; and (c) determining the relative amount of the drug in the IR layer and the ER layer from the IR PK profile and the ER PK profile such that the IR layer and the ER layer when combined together make a composite target PK profile, thereby designing an oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the individual is a human. In some embodiments, the drug has linear pharmacokinetics. In some embodiments, the drug has linear pharmacokinetics for the concentration of the drug administered to the individual.

In some embodiments, provided herein is a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) layer comprising a drug, the IR layer having an immediate release profile; and a sustained release (ER) layer comprising a drug, the ER layer having a sustained release profile, wherein the IR layer and the ER layer are stacked on one another, wherein the IR layer and the ER layer are partially surrounded by a shell, wherein the shell has a slower dissolution rate than the ER layer, wherein the IR layer has an upper surface and a lower surface, wherein the ER layer has an upper surface and a lower surface, and wherein the shell is in direct contact with both the IR layer and the ER layer and leaves the upper surface of the IR layer and the lower surface of the ER layer exposed, the method comprising: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form comprising said IR layer; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER layer; and (c) determining the relative amount of the drug in the IR layer and the ER layer from the IR PK profile and the ER PK profile such that the IR layer and the ER layer when combined together make a composite target PK profile, thereby designing an oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the individual is a human. In some embodiments, the drug has linear pharmacokinetics. In some embodiments, the drug has linear pharmacokinetics for the concentration of the drug administered to the individual. In some embodiments, the dosage unit further comprises an intermediate layer located between the IR layer and the ER layer.

In some embodiments, provided herein is a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) layer comprising a drug, the IR layer having an immediate release profile; and a sustained release (ER) layer comprising a drug, the ER layer having a sustained release profile, the IR layer and the ER layer being positioned alongside one another, wherein the IR layer and the ER layer are partially surrounded by a shell, wherein the shell has a slower dissolution rate than the ER layer, wherein the IR layer has an upper surface and a lower surface, wherein the ER layer has an upper surface and a lower surface, and wherein the shell is in direct contact with both the IR layer and the ER layer and leaves the upper surfaces of the IR layer and the ER layer exposed, the method comprising: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form comprising said IR layer; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER layer; and (c) determining the relative amount of the drug in the IR layer and the ER layer from the IR PK profile and the ER PK profile such that the IR layer and the ER layer when combined together make a composite target PK profile, thereby designing an oral pharmaceutical dosage form having a composite target PK profile in the subject. In some embodiments, the individual is a human. In some embodiments, the drug has linear pharmacokinetics. In some embodiments, the drug has linear pharmacokinetics for the concentration of the drug administered to the individual. In some embodiments, the dosage unit further comprises an intermediate layer located between the IR layer and the ER layer.

In some embodiments, provided herein is a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) layer comprising the drug, the IR layer having an immediate release profile; and a sustained release (ER) layer comprising the drug, the ER layer having a sustained release profile, wherein the IR layer and the ER layer are stacked on top of each other, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER moiety; and (c) determining the relative amount of the drug in the IR layer and the ER layer from the IR PK profile and the ER PK profile such that the IR layer and the ER layer when combined together make the oral pharmaceutical dosage form having a composite target PK profile in the subject.

In some embodiments, provided herein is a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in humans, wherein the oral pharmaceutical dosage form comprises a dosage unit comprising: an Immediate Release (IR) layer comprising the drug, the IR portion having an immediate release profile; and a sustained release (ER) layer comprising the drug, the ER portion having a sustained release profile, wherein the IR layer and the ER layer are stacked on top of each other, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining an IR PK profile in a human for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a human for an ER precursor dosage form comprising said ER moiety; and (c) determining the relative amount of the drug in the IR layer and the ER layer from the IR PK profile and the ER PK profile such that the IR layer and the ER layer when combined together make the oral pharmaceutical dosage form having a composite target PK profile in humans.

In some embodiments, provided herein is a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) layer comprising the drug, the IR layer having an immediate release profile; and a sustained release (ER) layer comprising the drug, the ER layer having a sustained release profile, wherein the IR layer and the ER layer are stacked on top of each other, and wherein the drug has linear pharmacokinetics at a fixed amount of the drug, the method comprising: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER moiety; and (c) determining the relative amount of the drug in the IR layer and the ER layer from the IR PK profile and the ER PK profile such that the IR layer and the ER layer when combined together make the oral pharmaceutical dosage form having a composite target PK profile in the subject, wherein the time ranges of the composite target PK profile, IR PK profile and ER PK profile are each between 0 hour and 24 hours.

In some embodiments, provided herein is a method of designing an oral pharmaceutical dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an Immediate Release (IR) layer comprising the drug, the IR layer having an immediate release profile; and an Extended Release (ER) layer comprising the drug, the ER layer having an extended release profile, wherein the IR layer and the ER layer are stacked on top of each other, and wherein the composite target PK profile has an area under the curve (AUC), C, according to an acceptable threshold of a reference PK profile for the drug_maxAnd t_maxDetermining, the method comprises: (a) obtaining an IR PK profile in a subject for an IR precursor dosage form, said IR precursor dosage form comprising said IR moiety; (b) obtaining an ER PK profile in a subject for an ER precursor dosage form comprising the ER moiety; and (c) determining the relative amount of the drug in the IR layer and the ER layer from the IR PK profile and the ER PK profile such that the IR layer and the ER layer when combined together make the oral pharmaceutical dosage form having a composite target PK profile in the subject.

In some embodiments, provided herein is a method of determining the relative amount of a drug in an Immediate Release (IR) portion and a sustained release (ER) portion of an oral pharmaceutical dosage form having a fixed amount of drug and having a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an IR portion comprising the drug, the IR portion having an immediate release profile; and an ER portion comprising the drug, the ER portion having a sustained release profile, the method comprising: determining the relative amounts of the drug in the IR moiety and the ER moiety based on an IR PK profile in the subject for an IR precursor dosage form comprising the IR moiety and an ER PK profile in the subject for an ER precursor dosage form comprising the ER moiety, such that the IR moiety and the ER moiety, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject.

In some embodiments, provided herein is a method of making an oral pharmaceutical dosage form having a fixed amount of a drug and a composite target Pharmacokinetic (PK) profile in a subject, wherein the oral pharmaceutical dosage form comprises dosage units comprising: an IR portion comprising the drug, the IR portion having an immediate release profile; and an ER portion comprising the drug, the ER portion having a sustained release profile, the method comprising: determining the relative amounts of the drug in the IR moiety and the ER moiety based on an IR PK profile in the subject for an IR precursor dosage form comprising the IR moiety and an ER PK profile in the subject for an ER precursor dosage form comprising the ER moiety, such that the IR moiety and the ER moiety, when combined together, produce the oral pharmaceutical dosage form having a composite target PK profile in the subject.

In some embodiments, the methods described herein further comprise determining the IR PK profile and the ER PK profile, and correcting the relative amounts of drug in the IR and ER fractions. In some embodiments, the methods described herein further comprise determining a composite PK profile for said oral pharmaceutical dosage form. In some embodiments, the methods described herein further comprise correcting the relative amount of drug in the IR layer and the ER layer according to a comparison of the composite PK profile to the composite target PK profile.

In some embodiments, the methods described herein further comprise formulating the oral pharmaceutical dosage form. In some embodiments, the oral pharmaceutical dosage form is made by three-dimensional printing. In some embodiments, the three-dimensional printing is by Fused Deposition Modeling (FDM).

Three-dimensional printing method

In some aspects, the present invention provides methods of printing (such as three-dimensional (3D) printing) an oral pharmaceutical dosage form or component (such as a dosage unit or precursor thereof) having a composite target Pharmacokinetic (PK) profile.

In some embodiments, the method comprises 3D printing a dosage unit described herein. In some embodiments, the method comprises 3D printing a component of an oral pharmaceutical dosage form described herein, such as a dosage unit or a component thereof, e.g., an IR layer, an ER layer, an intermediate layer, or a shell. In some embodiments, the method comprises 3D printing a precursor dosage form, such as an IR precursor dosage form or an ER precursor dosage form.

As used herein, "printing," "three-dimensional printing," "3D printing," "additive manufacturing," or equivalents thereof, refers to a process of making a three-dimensional object, such as a pharmaceutical dosage form, layer-by-layer using a digital design. The basic process of three-dimensional printing is described in U.S. Pat. nos. 5,204,055; 5,260,009, respectively; 5,340,656, respectively; 5,387,380, respectively; 5,503,785; and 5,633,021. Other U.S. patents and patent applications related to three-dimensional printing include: U.S. patent nos. 5,490,962; 5,518,690, respectively; 5,869,170, respectively; 6,530,958, respectively; 6,280,771, respectively; 6,514,518, respectively; 6,471,992, respectively; 8,828,411, respectively; U.S. publication No. 2002/0015728; 2002/0106412, respectively; 2003/0143268, respectively; 2003/0198677, respectively; 2004/0005360. The contents of the above-mentioned U.S. patents and patent applications are incorporated herein by reference in their entirety.

In some embodiments, additive manufacturing techniques are used to make the pharmaceutical dosage forms described herein. In some embodiments, the pharmaceutical dosage forms described herein are made using a layer-by-layer technique.

Different 3D printing methods for the production of pharmaceutical dosage forms have been developed in terms of raw materials, equipment and curing. These 3D Printing methods include binder deposition (see Gibson et al, Additive Manufacturing Technologies:3D Printing, Rapid Engineering, and Direct Digital Manufacturing,2ed. Springer, New York, 2015; Katstra et al, Oral document for textile by needle Digital Printing, J Control Release,66,2000; Katstra et al, weaving of composite organic for textile by needle Printing, dispensing Materials and Engineering, Mass of Engineering of Technology, 2001; Lipson et al, Fasted: thermal Engineering, J Printing of raw Materials and Engineering, Johnology of Engineering, Johnson et al, J Printing of raw Materials, Johnology, Johnson et al 3D Printing, J Printing of raw Printing, Johnology, J Printing Technologies, J Printing of raw Printing, J Printing, P Printing, P.D.D.D.3 D.D., additive Manufacturing Technologies 3D Printing, Rapid Manufacturing, and Direct Digital Manufacturing. 2. Springer, New York,2015), and photopolymerization (see Melches et al, A review on stereolithography and matters application in biological engineering. biomaterials,31,2010).

In some embodiments, the oral pharmaceutical dosage forms described herein are 3D printed using an extrusion process. In some embodiments, the method of 3D printing comprises using a twin screw extrusion process. In the extrusion process, the material is extruded through the print nozzle of a mechanical print head. Unlike binder deposition, which requires a powder bed, the extrusion process can print on any substrate. A variety of materials can be extruded for three-dimensional printing, including the thermoplastic materials, pastes and colloidal suspensions, silicones, and other semisolids disclosed herein. One common type of extrusion printing is fused deposition modeling, which uses solid polymer filaments for printing. In fused deposition modeling, a gear system drives a filament into a heated nozzle assembly for extrusion (see Gibson et al, Additive Manufacturing Technologies:3D Printing, Rapid modeling, and Direct Digital Manufacturing,2ed Springer, New York, 2015).

In some embodiments, the 3D printing methods described herein comprise a continuous feed method.

In some embodiments, the 3D printing methods described herein comprise a fed-batch method.

In some embodiments, the 3D printing is performed by Fused Deposition Modeling (FDM). In some implementationsIn a mode, the 3D printing is performed by non-wire FDM. In some embodiments, the 3D printing is performed by Melt Extrusion Deposition (MED). In some embodiments, the 3D printing is performed by inkjet printing. In some embodiments, the 3D printing is performed by Selective Laser Sintering (SLS). In some embodiments, the 3D printing is performed by stereolithography (SLA or SL). In some embodiments, the 3D Printing is performed by Polyjet, Multi-Jet Printing System (MPP), Perfactry, Solid Object Ultraviolet-Laser Printer, Bioplotter, 3D Bioprinting, Rapid Freeze Programming, Benchtop System, Selective Deposition Printing (SDL), coated Objet Printing (LOM), Ultrasonic Printing, Colorjet Printing (CJP), EOSINT Systems, Lashing Engineered Net Printing (LENS) and Aerosol Printing System, Electron Beam Printing (EBM), LaserSelective Laser Messing (SLM), Phenix PXTM Series, MicroInterding, Digital Part Materialization (DPM), or VX System execution.

In some embodiments, three-dimensional printing is performed by hot melt extrusion in combination with 3D printing techniques such as FDM. In some embodiments, the three-dimensional printing is performed by Melt Extrusion Deposition (MED).

In some embodiments, the method for making the oral pharmaceutical dosage form described herein comprises a 3D printing technique, such as a combination of 3D printing and another method, e.g., a combination of injection molding and 3D printing. In some embodiments, the shell is made using injection molding and the one or more modified release portions are made using 3D printing techniques.

The method descriptions disclosed herein for 3D printing pharmaceutical dosage forms may be generated in a variety of ways, including direct encoding, derivation from a solid-state CAD model, or other ways specific to the computer interface and application software of the 3D printer. These specifications may include information about the number and spatial location of drops and general 3D printing parameters, such as drop spacing in each linear dimension (X, Y, Z) and fluid volume or mass per drop. For a given set of materials, these parameters can be adjusted to improve the quality of the created structure. The overall resolution of the created structures is a function of powder particle size, droplet size, printing parameters, and material properties.

Because 3D printing allows for the selection of a variety of drug materials and control of composition and structure, 3D printing is well suited for manufacturing oral drug dosage forms having complex geometries and compositions in accordance with the present invention.

In some embodiments, wherein the oral pharmaceutical dosage form comprises more than one dosage unit, each dosage unit is separately printed and subsequently assembled to form the oral pharmaceutical dosage form. In some embodiments, wherein the oral pharmaceutical dosage form comprises more than one dosage unit, the more than one dosage unit is printed as the formed oral pharmaceutical dosage form.

The oral pharmaceutical dosage forms and components thereof described in this application can be printed on a commercial scale. For example, in some embodiments, the methods disclosed herein can be used for 3D printing of 10,000 to 100,000 units of an oral pharmaceutical dosage form per hour. In some embodiments, the methods disclosed herein can be used for 3D printing of 10,000 to 100,000 oral pharmaceutical dosage forms per hour. In some embodiments, the methods disclosed herein may be used for 3D printing of 10,000 to 100,000 units of dosage units per hour. In some embodiments, the methods disclosed herein may be used for 3D printing of 10,000 to 100,000 dosage units per hour.

The use of 3D printing methods to produce pharmaceutical dosage forms also contributes to personalized medicine. Personalized medicine refers to the stratification of a patient population according to biomarkers to aid in treatment decisions and personalized dosage form design. It is easier to modify a digital design than to modify a physical device. Moreover, the operating costs of automated small-size three-dimensional printing are negligible. Thus, 3D printing may make individualized production of multiple small batches economically feasible and enable individualized dosage forms to improve patient compliance.

Personalized pharmaceutical dosage forms can adjust the amount of drug delivered according to the weight and metabolism of the patient. The 3D printed dosage form may ensure accurate administration in growing children and allow for personalized, highly effective administration of drugs. The personalized dosage form may also combine all patients' medications into a single daily dose, thereby improving patient compliance with medications and treatment compliance.

In some embodiments, the method comprises: the IR material is dispensed to make an IR layer comprising the drug. In some embodiments, multiple layers of IR material are dispensed to make the IR layer. In some embodiments, the IR layer has a predetermined surface area, thickness, and drug mass fraction. In some embodiments, the method comprises: an ER material is dispensed to make an ER layer comprising the drug. In some embodiments, multiple layers of ER material are dispensed to make the ER layer. In some embodiments, the ER layer has a predetermined surface area, thickness, and drug mass fraction. In some embodiments, the method comprises: dispensing an intermediate material to form an intermediate layer comprising the drug. In some embodiments, multiple layers of intermediate material are dispensed to make the intermediate layer. In some embodiments, the intermediate layer has a predetermined surface area and thickness. In some embodiments, the method comprises: dispensing the shell material to form a shell comprising the drug. In some embodiments, multiple layers of shell material are dispensed to make the shell. In some embodiments, the shell has a predetermined surface area and thickness.

In some embodiments, the method comprises: dispensing a shell material to make a shell or a portion thereof; dispensing an ER material comprising a drug over the shell or a portion thereof to make an ER layer; an IR material comprising a drug is dispensed over the ER layer to make an IR layer to print an oral pharmaceutical dosage form or dosage unit. In some embodiments, the method further comprises dispensing an intermediate material to make an intermediate layer, wherein the intermediate layer is positioned as described herein.

In some embodiments, the method comprises: printing a shell material to make a shell or a portion thereof; printing an IR material comprising a drug over the shell or a portion thereof to make an IR layer; an ER material comprising a drug is printed over the IR layer to make an ER layer, thereby printing an oral pharmaceutical dosage form or dosage unit. In some embodiments, the method further comprises printing an IR material comprising a drug over the ER layer to make a second IR layer. In some embodiments, the method further comprises printing an intermediate material to make an intermediate layer, wherein the intermediate layer is positioned as described herein.

In some embodiments, the method comprises: printing a shell material to make a shell or a portion thereof; printing an IR material comprising a drug over the shell or a portion thereof to make an IR layer; printing an ER material comprising a drug over the shell or a portion thereof to make an ER layer, thereby printing an oral pharmaceutical dosage form or dosage unit, wherein the IR layer and the ER layer are placed side by side. In some embodiments, the method further comprises printing an intermediate material to make an intermediate layer, wherein the intermediate layer is positioned as described herein.

In some embodiments, the materials or components thereof used to print the oral pharmaceutical dosage form and dosage form, e.g., the precursor dosage form, are each printed by a different print head. For example, in some embodiments, the IR material and the ER material, and optionally if present, the intermediate material and the shell material are each printed by different print heads.

The 3D printing methods described herein include printing materials in any order that allows for the production of oral pharmaceutical dosage forms and dosage units disclosed herein or components thereof (e.g., precursor dosage forms).

In some embodiments, a method for 3D printing includes designing, in whole or in part, an oral pharmaceutical dosage form or dosage unit or a component thereof, e.g., a precursor dosage form, on a computer system. In some embodiments, the method comprises inputting the target drug release profile and/or parameters of the oral pharmaceutical dosage form and/or dosage unit and/or precursor dosage form into a computer system. In some embodiments, the method includes providing one or more parameters to be printed, such as layer surface area, thickness, drug mass fraction, erosion rate. In some embodiments, the method comprises providing a target drug release profile. In some embodiments, the method includes creating a virtual image of the article to be printed. In some embodiments, the method includes creating a computer model containing predetermined parameters. In some embodiments, the method includes feeding predetermined parameters to a 3D printer and printing the article according to these predetermined parameters. In some embodiments, the method includes creating a 3D map of the item to be printed based on predetermined parameters, wherein the 3D map is created on a computer system. In some embodiments, the method includes converting, for example, a layered 3D drawing into 3D printed code, for example, G-code. In some embodiments, the method includes executing the 3D printing code using a computer system to print according to the methods described herein.

Those skilled in the art will recognize that several implementations are possible within the scope and spirit of the present disclosure. The present invention is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the particular processes described therein.

Examples of the invention

The following example demonstrates that the 3D print formulation is derived from designDesign of an exemplary oral drug dosage form having a fixed amount of drug and a composite target Pharmacokinetic (PK) profile in a subject (e.g., figures 4A-4E, figure 2E).

Example 1

An initial oral pharmaceutical dosage form is designed that includes a fixed amount of drug, an Immediate Release (IR) portion and a sustained release (ER) portion. See, for example, FIGS. 4A and 4D (showing exploded views of an oral pharmaceutical dosage form), and FIG. 4B (showing assembled views of an oral pharmaceutical dosage form; ER portion and IR portion stacked and disposed in the space formed by the shell).

To obtain an Immediate Release (IR) Pharmacokinetic (PK) profile to measure drug plasma concentrations attributable to the IR portion of the oral pharmaceutical dosage form, a corresponding IR precursor dosage form comprising a designed IR portion and a shell (excluding the ER portion of the oral pharmaceutical dosage form) was printed by 3D printing. Table 1 and table 2 provide the materials and dimensions of the IR precursor dosage form. The dimensions provided are the outer boundaries. The IR portion of the IR precursor dosage form was prepared to contain 50mg of drug. The PK profile for the IR precursor dosage form and the PK profile for an immediate release reference drug dosage form having the same amount of drug as the IR precursor dosage form (IR reference drug dosage form) were obtained according to the methods described herein.

Table 1 composition of components of IR precursor dosage forms.

Table 2 dimensions of components of the IR precursor dosage form.

Module	Radius (mm)	Inner length (mm)	Thickness (mm)
				Quick release portion	3	13	0.6
Shell	3.6	13	1.4

To obtain a sustained release (ER) Pharmacokinetic (PK) profile to measure drug plasma concentrations attributable to the IR portion of the oral pharmaceutical dosage form, a corresponding ER precursor dosage form comprising a designed ER portion and a shell (excluding the IR portion of the oral pharmaceutical dosage form) was printed by 3D printing. Table 3 and table 4 provide the materials and dimensions of the ER precursor dosage forms. The ER portion of the ER prodrug dosage form was made to contain 87.5mg of drug. The PK profile for the ER precursor dosage form and the PK profile for a sustained release reference drug dosage form (ER reference) having the same drug amount as the IR precursor dosage form were obtained according to the methods described herein.

Table 3 composition of components of ER precursor dosage forms.

Table 4 dimensions of components of ER precursor dosage forms.

Module	Radius (mm)	Inner length (mm)	Thickness (mm)
				Sustained release portion	3	12.5	3
Shell	3.6	12.5	3.8

In vivo pharmacokinetic studies were performed in fasted male beagle dogs. After oral administration of each precursor dosage form or the reference drug dosage form, blood samples were collected from the jugular vein at predetermined times and plasma concentrations of the drugs were determined by LC-MS/MS analysis.

The 3D printed IR precursor dosage forms had similar in vivo PK profiles as the IR reference drug dosage forms, demonstrating bioequivalence (fig. 5).

3D printed ER precursor dosage forms to C_maxThe ER PK profile was then shown with a slowly decreasing plateau (fig. 6). The in vitro dissolution of the 3D printed ER precursor dosage form was measured at-16 hours (data not shown).

Example 2

Using the PK Profile information for the precursor dosage forms obtained in example 1, as described hereinThe approach determines the relative amounts of drug in the IR and ER fractions necessary to achieve a composite target PK profile for an oral drug dosage form. In order to obtain a composite target PK profile (i.e. a target rapid initial pulse followed by an extended drug delivery phase), different IR and ER moieties are theoretically combined in a variable manner and different drug ratios so that the IR and ER moieties can be assembled together to obtain a designed oral pharmaceutical dosage form comprising an IR and ER moiety. Theoretical pharmacokinetic profiles of oral drug dosage forms were simulated based on the predetermined pharmacokinetic profiles of the components and a prescription with good results was selected for 3D printing and further study in vivo. Based onIn this way, it was determined that the target theoretical PK profile for a composite oral pharmaceutical dosage form could be achieved using an IR to ER drug ratio of 1: 7. Simulated drug plasma concentration-time curves for different IR: ER drug ratios compared to a reference ER drug dosage form with the same dose of drug are shown in fig. 7.

Example 3

Based on the simulated theoretical pharmacokinetics of the oral pharmaceutical dosage form described in embodiment 2, oral pharmaceutical dosage forms with a drug ratio of 1:7 in the IR portion and the ER portion were printed by 3D printing according to the composition and dimensions shown as shown in tables 5 and 6.

TABLE 5 composition of components of oral pharmaceutical dosage forms.

TABLE 6 dimensions of components of oral pharmaceutical dosage forms.

Module	Radius (mm)	Inner length (mm)	Thickness (mm)
				Quick release portion	3	12.5	0.2
Sustained release portion	3	12.5	3.0
				Shell	3.6	12.5	4.0

In vivo pharmacokinetic studies were performed in fasted male beagle dogs. After oral administration of the oral drug dosage form or the reference drug dosage form, blood samples were collected from the jugular vein at predetermined times and plasma concentrations of the drugs were determined by LC-MS/MS analysis.

As shown in FIG. 8, the 3D printed oral drug dosage forms had a smaller AUC and T approximately 2 hours earlier than the ER reference drug dosage form with the same dose of drug (100mg)_max。

Example 4

Pharmacokinetic optimization of 3D printed oral drug dosage forms was performed. Dissolution of in vitro 3D printed oral drug formulations and ER reference drug formulations. As shown in fig. 9, the in vitro dissolution rate of the 3D printed oral drug dosage form was about 16 hours, whereas the in vitro dissolution rate of the ER reference drug dosage form was much faster (about 8 hours). To obtain a 3D printed oral pharmaceutical dosage form with an ER portion with an in vitro dissolution rate close to that of the ER reference drug, the surface area and thickness of the ER portion are adjusted while maintaining the same drug dose. The second ER precursor dosage form was printed according to the composition and dimensions shown in table 3 and table 7. To improve dissolution, the 3D printed ER precursor dosage forms were designed to have larger surface area and smaller thickness (compare table 4 and table 7) than the 3D printed ER precursor dosage form in example 1, but with the same amount of drug (87.5mg drug).

Table 7 dimensions of components of ER precursor dosage forms.

Module	Radius (mm)	Inner length (mm)	Thickness (mm)
				Sustained release portion	3.1	13	2.4
Shell	3.7	13	3.2

The 3D printed ER precursor dosage forms with larger surface area and smaller thickness had an in vitro dissolution rate of 12 hours (data not shown) that was faster (-16 hours) than the in vitro dissolution rate of the 3D printed ER precursor dosage form of example 1.

In vivo pharmacokinetic studies were performed in fasted male beagle dogs using an optimized ER precursor dosage formulation. Following oral administration of the 3D printed ER precursor dosage form and the reference drug dosage form, blood samples were collected from the jugular vein at predetermined times and plasma concentrations of the drugs were determined by LC-MS/MS analysis. As can be seen from a comparison of fig. 6 and fig. 10, the AUC of the optimized ER precursor dosage form (fig. 10) is greater than the AUC of the ER precursor dosage form of example 1 (fig. 6), indicating that the optimized ER precursor dosage form having an in vitro dissolution rate of 12 hours is more suitable for use in an oral pharmaceutical dosage form.

3D printing of another ER precursor dosage form was performed 3D printing using 100mg of drug using the same percentage of drug and the same surface area in the ER material in order to directly compare the 3D printed ER precursor dosage form with the ER reference dose (100mg of drug). The 100mg ER precursor dosage forms were printed according to the compositions and dimensions shown in table 8 and table 9. In vivo pharmacokinetic studies were performed in fasted male beagle dogs using 100mg ER precursor dosage forms and 100mg ER reference pharmaceutical dosage forms. After oral administration of the 3D printed ER precursor dosage form and ER reference dosage form, blood samples were collected from the jugular vein at predetermined times and plasma concentrations of the drug were determined by LC-MS/MS analysis.

TABLE 8.100 composition of the components of the ER precursor dosage form.

Table 9 dimensions of components of ER precursor dosage forms.

Module	Radius (mm)	Inner length (mm)	Thickness (mm)
				Sustained release portion	3.1	13	2.75
Shell	3.7	13	3.55

As shown in fig. 11, the repetitions of the in vivo pharmacokinetic profiles of the 3D printed 100mg ER precursor dosage form and 100mg ER reference dosage form are very similar, indicating overall similarity. The 3D printed 100mg ER precursor dosage form had an in vitro dissolution of about 12 hours (data not shown).

Example 5

According to the embodiment of example 2, the following,the theoretical pharmacokinetics of oral pharmaceutical dosage forms comprising an optimized ER portion were simulated according to the PK profile of the 3D printed IR precursor dosage form of example 1 and the 87.5mg drug optimized 3D printed ER precursor dosage form of example 4. The pharmacokinetics of oral pharmaceutical dosage forms with an IR to ER drug ratio of 1 to 7 are highly similar to the predicted pharmacokinetic profile. Optimized 3D printed oral pharmaceutical dosage forms have a greater AUC, higher C than ER reference dosage forms with the same drug dose_maxEarlier T_maxAnd like C_maxFollowed by a slowly descending platform.

Using the optimized size of the ER precursor dosage form (87.5mg of drug in the ER portion), an oral drug dosage form with an IR: ER drug ratio of 1:7 was printed according to the compositions and sizes shown in table 10 and table 11.

In vivo pharmacokinetic studies were performed in fasted male beagle dogs. Following oral administration of the 3D printed oral drug dosage form and the ER and IR reference drug dosage forms, blood samples were collected from the jugular vein at predetermined times and plasma concentrations of the drugs were determined by LC-MS/MS analysis.

Table 10 composition of components of oral pharmaceutical dosage form (IR: ER ═ 1:7, total 100mg drug).

Table 11 dimensions of components of optimized oral pharmaceutical dosage forms (IR: ER ═ 1: 7).

Module	Radius (mm)	Inner length (mm)	Thickness (mm)
				Quick release portion	3.1	14.8	0.15
Sustained release portion	3.1	14.8	2.4
				Shell	3.7	14.8	3.35

As shown in fig. 12, the pharmacokinetics of the optimized 3D printed oral pharmaceutical dosage form were similar to the simulated theoretical pharmacokinetics of the oral pharmaceutical dosage form. PK curves for the IR reference drug dosage form (50mg) and the ER reference drug dosage form (100mg) were also plotted as references. The optimized 3D printed oral pharmaceutical dosage forms showed a greater AUC, higher C than the ER reference pharmaceutical dosage form at the same dose (100mg)_maxEarlier T_maxAnd the like C_maxThen slowly descending the platform; optimized 3D printed oral drug dosage form C_maxC lower than IR reference pharmaceutical dosage form_max。

Accordingly, as described hereinThe approach can provide a customized, easily adjusted and optimized 3D printed oral drug dosage form with a target PK profile, no significant fluctuation in plasma levels of the drug, faster drug effective plasma concentrations, longer and more stable duration of effective drug plasma concentrations,this will reduce side effects due to peak plasma levels of the drug when taken at high doses and provide an easier administration regimen, e.g. once daily.

Example 6

The BCS class I drug (model drug) is incorporated into the drug-containing portion of an oral pharmaceutical dosage form, which comprises an IR portion and an ER portion disposed side-by-side and separated by a shell that leaves the upper surfaces of the IR portion and the ER portion exposed to fluid for simultaneous release. Fig. 13A shows an exploded view of an oral drug dosage form 1400, which includes: the ER portion comprising model drug 1405, the IR portion comprising model drug 1410, and shell 1415.

IR precursor dosage forms and ER precursor dosage forms were produced using a proprietary FDM pharmaceutical 3D printer using designed oral pharmaceutical dosage forms. In vivo pharmacokinetic studies were performed in male beagle dogs on a low fat diet to measure the PK profile of the precursor dosage forms. After oral administration of the 3D printed IR precursor dosage form, the 3D printed ER precursor dosage form or the reference drug dosage form, blood samples were collected from the jugular vein at predetermined times and plasma concentrations LC-MS/MS analysis of the model drug was determined by the following method. Fig. 13B shows plasma concentrations following administration of 3D printed IR precursor dosage forms and 3D printed ER precursor dosage forms.

Using as described hereinIn this way, the theoretical pharmacokinetics of oral pharmaceutical dosage forms with different IR: ER drug ratios were simulated (fig. 13C). Oral drug dosage forms having an IR to ER drug ratio of 1:1 were selected to obtain a composite target pharmacokinetic profile and the corresponding oral drug dosage forms were 3D printed.

In vivo pharmacokinetic studies were performed in fasted male beagle dogs to measure PK profiles of 3D-printed oral drug dosage forms. Following oral administration of the 3D printed oral drug dosage form, blood samples were collected from the jugular vein at predetermined times and plasma concentrations of the drug were determined by LC-MS/MS analysis. As shown in fig. 13D, the PK profile for the oral drug dosage form printed in 3D depicts a modified release profile with a rapid initial peak followed by a smooth decline in plasma concentration, similar to the simulated theoretical pharmacokinetic profile.