阅读说明：本技术 快速崩解大麻素片剂 (Rapidly disintegrating cannabinoid tablets ) 是由 海迪·齐格勒·布鲁恩 多特·沙克尔·伯森 布鲁诺·普罗夫斯特高·涅尔森 于 2020-04-17 设计创作，主要内容包括：本发明在第一方面涉及快速崩解大麻素片剂,所述片剂包含糖醇组合物,所述糖醇组合物以片剂的至少20重量％的量包含一种或更多种糖醇颗粒；大麻素组合物,所述大麻素组合物包含一种或更多种大麻素；以及崩解剂组合物,所述崩解剂组合物包含可操作地使片剂在与口腔唾液接触的2分钟或更短的时间内崩解的一种或更多种崩解剂。在第二方面,本发明涉及模块化片剂,其中该片剂包含在组成方面不同的另外的片剂模块。(The present invention relates in a first aspect to a rapidly disintegrating cannabinoid tablet comprising a sugar alcohol composition comprising one or more sugar alcohol particles in an amount of at least 20% by weight of the tablet; a cannabinoid composition comprising one or more cannabinoids; and a disintegrant composition comprising one or more disintegrants operable to cause the tablet to disintegrate within 2 minutes or less of contact with the oral saliva. In a second aspect, the present invention relates to a modular tablet, wherein the tablet comprises further tablet modules that differ in composition.)

1. A rapidly disintegrating cannabinoid tablet, comprising:

a sugar alcohol composition comprising one or more sugar alcohol particles in an amount of at least 20 wt% of the tablet,

cannabinoid compositions comprising one or more cannabinoids, and

a disintegrant composition comprising one or more disintegrants operable to cause the tablet to disintegrate within 2 minutes or less of contact with oral saliva.

2. The tablet of claim 1, wherein the one or more disintegrants are operable to disintegrate the tablet within 1.5 minutes or less of contact with oral saliva.

3. The tablet of claim 1 or 2, wherein the one or more disintegrants are operable to disintegrate the tablet within 1 minute or less of contact with oral saliva.

4. The tablet of any one of the preceding claims, wherein the one or more disintegrants are present in an amount of 0.5 to 25% by weight of the tablet.

5. The tablet of any one of the preceding claims, wherein the one or more disintegrants are present in an amount of 2 to 15% by weight of the tablet.

6. The tablet of any one of the preceding claims, wherein the one or more disintegrants are swellable upon contact with oral saliva.

7. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise starch.

8. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise microcrystalline cellulose.

9. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise low substituted hydroxypropyl cellulose (LHPC).

10. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise a super disintegrant.

11. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise a super disintegrant in an amount of 2 to 15% by weight of the tablet.

12. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise a super disintegrant of cross-linked polymer.

13. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise a super disintegrant selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and combinations thereof.

14. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise cross-linked polyvinylpyrrolidone.

15. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise cross-linked polyvinylpyrrolidone, and wherein at least 50 wt% of the cross-linked polyvinylpyrrolidone has a particle size below 50 microns.

16. The tablet of any one of the preceding claims, wherein the one or more disintegrants comprise cross-linked polyvinylpyrrolidone, and wherein at least 25 wt% of the cross-linked polyvinylpyrrolidone has a particle size below 15 microns.

17. The tablet of any one of the preceding claims, wherein the one or more sugar alcohol particles are present in an amount of at least 30% by weight of the tablet.

18. The tablet of any one of the preceding claims, wherein the one or more sugar alcohol particles are present in an amount of at least 40% by weight of the tablet.

19. The tablet of any one of the preceding claims, wherein the one or more sugar alcohol particles are present in an amount of at least 50% by weight of the tablet.

20. The tablet of any one of the preceding claims, wherein the one or more sugar alcohol particles are present in an amount of at least 60% by weight of the tablet.

21. The tablet according to any one of the preceding claims, wherein the one or more sugar alcohol particles are selected from the group consisting of xylitol, lactitol, sorbitol, maltitol, erythritol, isomalt and mannitol, and mixtures and combinations thereof.

22. The tablet of any one of the preceding claims, wherein at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles.

23. The tablet of any one of the preceding claims, wherein at least a portion of the one or more cannabinoids are reversibly associated with 1:10 to 1:4 by weight of the one or more sugar alcohol particles.

24. The tablet of any one of the preceding claims, wherein at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by way of agglomeration.

25. The tablet of any one of the preceding claims, wherein at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by means of a plurality of particles having a volume weighted mean diameter of from 10 μ ι η to 400 μ ι η.

26. The tablet of any one of the preceding claims, wherein at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by means of a plurality of particles having a volume weighted mean diameter of from 50 μ ι η to 300 μ ι η.

27. The tablet of any one of the preceding claims, wherein at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by way of a pre-mix.

28. The tablet of any one of the preceding claims, wherein at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by way of adsorption in a premix.

29. The tablet of any one of the preceding claims, wherein at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by means of adsorption, and wherein the one or more cannabinoids are applied by spraying.

30. The tablet of any one of the preceding claims, wherein the tablet is compressed at a pressure greater than 10 kN.

31. The tablet of any one of the preceding claims, wherein the tablet is compressed at a pressure greater than 15 kN.

32. The tablet of any one of the preceding claims, wherein the tablet is compressed at a pressure of less than 30 kN.

33. The tablet of any one of the preceding claims, wherein at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles, thereby reducing the compressibility of the composition compared to a composition in which the one or more cannabinoids are not reversibly associated with at least a portion of the one or more sugar alcohol particles.

34. The tablet of any one of the preceding claims, wherein the tablet in contact with saliva has a disintegration curve that varies by less than 10% at a compression pressure of 10kN to 30 kN.

35. The tablet of any one of the preceding claims, wherein the tablet in contact with saliva has a disintegration curve that varies by less than 5% at a compression pressure of 10kN to 30 kN.

36. The tablet of any one of the preceding claims, wherein the weight ratio of the one or more cannabinoids to the one or more sugar alcohol particles is from 1:30 to 1: 1.

37. The tablet of any one of the preceding claims, wherein the weight ratio of the one or more cannabinoids relative to the one or more sugar alcohol particles is from 1:20 to 1: 10.

38. The tablet of any one of the preceding claims, further comprising a binder, such as a dry binder or a wet binder.

39. The tablet of any one of the preceding claims, further comprising at least one dissolution modifying agent selected from: acacia, agar, alginic acid or a salt thereof, carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone, cyclodextrin, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hypromellose, inulin, methylcellulose, pectin, polycarbophil or a salt thereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, pullulan, starch, tragacanth, trehalose, xanthan gum, and mixtures thereof.

40. The tablet according to any one of the preceding claims, further comprising at least one dissolution modifying agent selected from alginic acid or a salt thereof, polycarbophil or a salt thereof, xanthan gum, and mixtures thereof.

41. The tablet according to any one of the preceding claims, further comprising at least one dissolution modifying agent selected from the group consisting of sodium alginate, calcium polycarbophil, xanthan gum, and mixtures thereof.

42. The tablet of any one of the preceding claims, further comprising at least one viscosifier which forms a gel having a positive surface charge when hydrated and at least one viscosifier which forms a gel having a negative surface charge when hydrated.

43. The tablet according to any one of the preceding claims, further comprising at least one basic buffer selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate, and mixtures thereof.

44. The tablet of any one of the preceding claims, further comprising at least one excipient selected from a high intensity sweetener, a flavoring agent, a chelating agent, a glidant, or a coloring agent.

45. The tablet of any one of the preceding claims, wherein the tablet has a unit weight of about 50mg to about 250 mg.

46. The tablet of any one of the preceding claims, wherein the tablet has a unit weight of about 75mg to about 150 mg.

47. The tablet of any one of the preceding claims, wherein the sugar alcohol composition has an average particle size of less than 350 microns.

48. The tablet of any one of the preceding claims, wherein the sugar alcohol composition has an average particle size of less than 250 microns.

49. The tablet of any one of the preceding claims, wherein the sugar alcohol composition has an average particle size of at least 100 microns.

50. The tablet of any one of the preceding claims, wherein the one or more cannabinoids are present in an amount of from 0.5mg to 100 mg.

51. The tablet of any one of the preceding claims, wherein the one or more cannabinoids are present in an amount of from 1mg to 80 mg.

52. The tablet of any one of the preceding claims, wherein the one or more cannabinoids include Cannabidiol (CBD), cannabidiolic acid (CBDA), Cannabidivarin (CBDV), salts and derivatives thereof.

53. The tablet of any one of the preceding claims, wherein the one or more cannabinoids comprise Tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), Tetrahydrocannabivarin (THCV), salts and derivatives thereof.

54. The tablet of any one of the preceding claims, wherein the one or more cannabinoids comprise Cannabidiol (CBD).

55. The tablet of any one of the preceding claims, wherein the one or more cannabinoids are selected from Cannabidiol (CBD), cannabidiolic acid (CBDA), Tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), Cannabigerol (CBG), cannabicycloterpene phenol (CBC), Cannabinol (CBN), Cannabigerol (CBE), iso-tetrahydrocannabinol (iso-THC), Cannabicyclophenol (CBL), Cannabidicarbone (CBT), Cannabigerol (CBV), Tetrahydrocannabigerol (THCV), Cannabidivarin (CBDV), cannabigerol (CBCV), Cannabigerol (CBGV), cannabigerol monomethylether (CBGM), salts thereof, derivatives thereof, and mixtures of cannabinoids.

56. The tablet of any one of the preceding claims, wherein the one or more cannabinoids form part of a complex with a cyclodextrin.

57. The tablet of any one of the preceding claims, wherein the one or more cannabinoids comprise at least one phytocannabinoid that forms part of an extract.

58. The tablet of any one of the preceding claims, wherein the one or more cannabinoids comprise at least one isolated cannabinoid.

59. The tablet according to any one of the preceding claims, wherein the one or more cannabinoids are located in a protein carrier, such as a pea protein carrier.

60. The tablet of any one of the preceding claims, wherein the one or more cannabinoids are located in a polymeric carrier.

61. The tablet of any one of the preceding claims, wherein the one or more cannabinoids are located in an amphiphilic polymer carrier.

62. The tablet according to any one of the preceding claims, wherein the one or more cannabinoids comprise at least one endocannabinoid or endocannabinoid compound, such as Palmitoylethanolamide (PEA).

63. The tablet of any one of the preceding claims, wherein the one or more cannabinoids comprise at least one water soluble cannabinoid.

64. The tablet of any one of the preceding claims, wherein the tablet comprises a self-emulsifying agent.

65. The tablet of any one of the preceding claims, wherein the tablet comprises a lipophilic association between the one or more cannabinoids and a fatty acid, such as oleic acid.

66. The tablet of any one of the preceding claims, wherein the tablet comprises a lipid carrier for the one or more cannabinoids.

67. The tablet of any one of the preceding claims, wherein the lipid carrier of one or more cannabinoids comprises one or more terpenes.

68. The tablet of any one of the preceding claims, wherein the lipid carrier of one or more cannabinoids comprises one or more terpenes selected from: bisabolol, borneol, caryophyllene, carene, camphene, eucalyptol, citronella, cineole, geraniol, guaiol, luprene, isopropyltoluene, isopulegol, linalool, limonene, menthol, myrcene, nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpinolene, thymol, salts thereof, derivatives thereof, and mixtures of terpenes.

69. The tablet of any one of the preceding claims, for use in treating or alleviating a medical condition.

70. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition.

71. The tablet of any one of the preceding claims, wherein the tablet comprises further tablet modules that differ in composition and comprise one or more cannabinoids according to any one of the preceding claims.

72. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and disintegrate within 3 minutes or more of contact with oral saliva.

73. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and disintegrate within 4 minutes or more of contact with oral saliva.

74. The tablet according to any one of the preceding claims, wherein the tablet comprises further tablet modules that differ in composition and comprise the sugar alcohol composition according to any one of the preceding claims.

75. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and comprise a sugar alcohol composition having a larger average particle size.

76. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and constitute at least 50% by weight of the total tablet.

77. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and constitute at least 60% by weight of the total tablet.

78. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and constitute at least 70% by weight of the total tablet.

79. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and constitute from 50 to 90% by weight of the total tablet.

80. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and constitute from 60 to 90% by weight of the total tablet.

81. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and constitute from 70 to 90% by weight of the total tablet.

82. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and have a unit weight of from about 250mg to about 950 mg.

83. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and have a unit weight of from about 400mg to about 900 mg.

84. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and have a unit weight of from about 400mg to about 900 mg.

85. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and comprise a gum base polymer.

86. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and do not comprise a gum base polymer.

87. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and are compressed together with the tablet of any one of claims 1 to 69 to form an integrated two-layer tablet.

88. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and are tableted in a separate step prior to tableting the tablet of any one of claims 1-69.

89. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and are compressed in a separate step at a higher pressure prior to compressing the tablet of any one of claims 1 to 69.

90. The tablet of any one of the preceding claims, wherein the tablet comprises additional tablet modules that differ in composition and comprise any one of a binder, dissolution agent, excipient, viscosifier, or alkaline buffer of any one of claims 1 to 69.

Technical Field

The present invention relates to the field of oral delivery vehicles for alleviating or treating conditions with one or more cannabinoids. In particular, the present invention relates to rapidly disintegrating tablets for oral administration of one or more cannabinoids.

Background

Cannabinoids are a group of chemicals found in Cannabis sativa (Cannabis sativa), Cannabis indica (Cannabis indica), Cannabis sativa (Cannabis ruderalis), Cannabis sativa plants (Marijuana plant) and related plant species. Cannabinoids are known to activate cannabinoid receptors (CB1 and CB 2). These chemicals are also produced endogenously in humans and other animals. Cannabinoids are cyclic molecules: it exhibits particular properties such as being lipophilic, having the ability to readily cross the blood brain barrier, and having low toxicity.

Cannabis contains more than 400 chemicals and about 120 cannabinoids, and the active ingredients of cannabis include Tetrahydrocannabinol (THC), Cannabidiol (CBD), Cannabinol (CBN), Tetrahydrocannabivarin (THCV) and Cannabigerol (CBG). Pharmacologically, the major psychoactive ingredient of cannabis is Tetrahydrocannabinol (THC) which is used in the treatment of a wide range of medical conditions including glaucoma, AIDS wasting, neuropathic pain, treatment of spasticity associated with multiple sclerosis, fibromyalgia and chemotherapy-induced nausea. THC is also effective in the treatment of allergy, inflammation, infection, depression, migraine, bipolar disorder, anxiety disorder, drug dependence and withdrawal syndrome.

In recent years, cannabinoid delivery methods have received increasing attention. Pulmonary delivery is most commonly achieved by the inhalation of cannabis. However, this mode of administration presents health concerns. Cannabis smoke carries even more tar and other particulate matter than tobacco. In addition, many patients find the act of smoking unattractive and often unhealthy.

Attempts have been made to overcome some of the problems associated with smoking both cannabis and tobacco by providing various smokeless inhalable aerosol formulations for pulmonary delivery. These formulations were found to have different effectiveness in delivering active agents to the lungs, and compliance was an issue even with appropriate practice for use of the inhalation device.

In formulating tablets, various challenges are associated with obtaining a homogeneous mixture in which variations are avoided and safe and convenient delivery can be obtained. Furthermore, the general formulation of tablets to provide convenience to the user need not be compromised, as is often the case if conventional delivery means are employed.

One of the challenges of tablets as a delivery vehicle for cannabinoids is that cannabinoids tend to be associated with abnormal characteristics during administration due to the specific physiochemical properties of the compound. The taste masking challenge is even more profound when higher cannabinoid release is expected in tablets for oral administration. Convenience may be affected if abnormal features are the primary sensation during administration, and even more critically, cannabinoid delivery may also be affected. Saliva production may be inhibited and the delivery vehicle may not be properly handled.

Furthermore, it is important that the formulation is provided such that it may also contribute to obtaining a release profile of the cannabinoid that provides improved convenience and effectiveness. Generally, there is less attention given in the prior art regarding the impact of tablet formulations on the organoleptic properties of oral cannabinoid delivery. Here, important organoleptic properties include friability, hardness, texture, flavor perception, sweetness perception, and cannabinoid-related abnormal characteristics. These properties are relevant from the point of view of the convenience of the tablet for oral administration, but of course also in order to support the proper delivery of the cannabinoid from the tablet and to avoid the adverse side effects of the cannabinoid.

Accordingly, there is a need in the art for improved tablet formulations that address the above-mentioned challenges and problems of the prior art. In particular, there is a need in the art for new tablets that support a suitably rapid delivery of cannabinoids combined with beneficial organoleptic properties.

Disclosure of Invention

Accordingly, in one aspect of the invention, there is provided a rapidly disintegrating cannabinoid tablet comprising: a sugar alcohol composition comprising one or more sugar alcohol particles in an amount of at least 20% by weight of the tablet; a cannabinoid composition comprising one or more cannabinoids; and a disintegrant composition comprising one or more disintegrants operable to cause the tablet to disintegrate within 2 minutes or less of contact with the oral saliva.

Providing a rapidly disintegrating cannabinoid tablet according to the invention may solve various problems of the prior art and aim to create a formulation: which combines cannabinoid beneficial delivery properties in combination with advantageous sensory properties.

Generally, the tablets according to the invention disintegrate in a relatively short time without significantly causing abnormal characteristics from the cannabinoids released during use of the tablet. The tablets are intended to disintegrate in the mouth without chewing, mainly by providing saliva already present in the mouth or produced during use of the tablet. Thus, the tablet is neither chewed nor swallowed, but is held in place in the mouth or moved back and forth in the mouth in the same manner as cleaning systems for the oral cavity.

One of the features of the present invention is the unexpected recognition that: tablets can be provided which have fast disintegration properties while ensuring beneficial organoleptic properties, including insignificant or insignificant off-flavors from the cannabinoids employed. The inventors of the present application did not expect that a rapid release of cannabinoids is possible without compromising the sensory parameters of the tablet. The specific properties of cannabinoids such as CBD are not believed to allow such rapid disintegration and release of the active ingredient. Cannabinoids are considered as a diverse group of active ingredients, often prejudiced by the art with respect to taste characteristics in oral tablet formulations. Furthermore, the properties of cannabinoids, e.g. lipophilic properties, as a diverse group of active ingredients would not be expected to work properly in such rapidly disintegrating tablets. In particular, it includes CBD and CBDA. More particularly, it includes extracts of cannabinoids, such as CBD and CBDA. Thus, in the field of cannabinoids, a person skilled in the art would not have expected that a rapidly disintegrating tablet according to the invention would be feasible.

In particular, the content of disintegrant greatly facilitates the disintegration of the tablets according to the invention. However, while disintegrants have been used previously in tablet formulation science, the particular combination of a disintegrant with a cannabinoid according to the present application may be considered problematic in view of the particular properties of the cannabinoid, such as CBD. The inventors of the present application suspect various problems such as sensory defects and concentration problems of high loading of active ingredients.

With respect to release profile, the present invention can provide improved cannabinoid release profiles as compared to conventional lozenge formulations. In particular, the particular tablets of the present invention may be used to provide improved cannabinoid release profiles as compared to conventional lozenge formulation platforms used in combination with cannabinoids. The improved release in combination with the lipophilic properties of cannabinoids such as CBD would be expected to be contradictory. However, the present inventors have recognized that the delivery of cannabinoids is unexpectedly beneficial.

Furthermore, the present invention can be used to provide a fast and controlled release of cannabinoids, such that the tablet formulation is tailored to deliver an effective amount of cannabinoids over time and at the same time avoid the adverse effects, e.g. abnormal characteristics, of cannabinoids.

A very important aspect of the present invention is to provide beneficial organoleptic properties. Here, important organoleptic properties include friability, texture, flavor perception, sweetness perception, and cannabinoid-related abnormal features. These properties are relevant from the point of view of convenience of the tablet, but of course also in order to support proper delivery of the cannabinoid from the formulation (e.g. improved release profile) and to avoid adverse side effects of the cannabinoid.

The inventors have shown very unexpected results of particular combinations of features of the invention in terms of these organoleptic properties. An unexpected result is that the present invention may both contribute to an improved release profile, e.g. a fast release of cannabinoids, and at the same time provide very beneficial sensory properties, which in terms of it may also support the proper delivery of cannabinoids from orally ingested tablets and avoid the adverse side effects of cannabinoids.

One of the particularly advantageous organoleptic properties is the friability of the tablets. Balancing the friability is critical both to ensure the desired release of cannabinoids and to improve the perception of the consumer. Furthermore, the texture of the tablet formulation during use is critical for the release of the cannabinoid as well as the experience and convenience during use. These characteristics can be improved by the present invention, which the inventors of the present invention have not expected.

Advantageously, the compositions of the present invention can be formulated in much smaller tablets than traditional cannabinoid-containing lozenges and thus can have reduced dissolution time in the oral cavity while still achieving significant cannabinoid plasma levels and achieving cannabinoid pharmacokinetic profiles comparable to traditional lozenges. Patient compliance may also be improved by reducing dissolution time and improving the rate of cannabinoid absorption.

In one embodiment of the invention, the one or more disintegrants are operable to cause the tablet to disintegrate within 1.5 minutes or less of contact with the oral saliva.

In one embodiment of the invention, the one or more disintegrants are operable to disintegrate the tablet within 1 minute or less of contact with the oral saliva.

In one embodiment of the invention, the one or more disintegrants are operable to cause the tablet to disintegrate within 0.5 minutes or less of contact with saliva in the oral cavity.

In this context, "operable" or "operably cause" to disintegrate "is intended to mean that the tablet, upon administration, is capable of passively disintegrating through saliva interaction and does not need to be chewed or otherwise forced to disintegrate. In other embodiments, the tablet disintegrates in contact with oral saliva in 1.5 minutes or less. In other embodiments, the tablet disintegrates within 1 minute or less of contact with oral saliva. In other embodiments, the tablet disintegrates in contact with oral saliva in 0.5 minutes or less.

In the present context, "disintegrating" or "disintegration" is intended to mean that the tablet is no longer considered to be a tablet, but that the tablet has been reduced and/or dispersed in saliva.

In the present context, a tablet is intended to mean a "fast disintegrating tablet" or similar expressions such as "orally disintegrating tablet". If not stated otherwise, if the tablet according to the invention is made as one module, as opposed to two or more modules, the tablet is intended as an FDT tablet. If, on the other hand, the tablets are made of more than one module, for example two modules, such further modules are intended as "lozenge" modules, which provide a longer disintegration time compared to the FDT module according to the invention. The combination of "FDT" and "lozenge" modules is discussed later in this application and contributes to another aspect of the invention. The "lozenge" module according to the invention may also contain elements from the "FDT" module but is usually different in composition, providing an extended disintegration time.

Importantly, the improved organoleptic properties of the tablet formulation of the present invention also accommodate the improved rate of cannabinoid release. The reason may be due to the fact that: this will encourage the user to use the product effectively if the user's initial impression is improved and the tablet texture is also improved. Furthermore, once the product formulation is improved, saliva production may be increased, which in turn may accommodate further increased cannabinoid release. However, the exact mechanism is not well understood.

It was found that the formulation of the tablets according to the invention provides a beneficial disintegration compared to conventional tablet formulations known in the art. Surprisingly, it was found that disintegration times of less than 30 seconds are possible without impairing the properties of the tablets according to the invention. The organoleptic properties are influenced only insignificantly or only to a lesser extent by such short disintegration times. The rapidly disintegrating tablets according to the invention may then provide potentially relatively fast relief or treatment response times.

In some embodiments of the invention, the composition contacted with saliva has a disintegration curve that varies by less than 10% at a compression pressure of 10kN to 30 kN. In the present context, a "disintegration curve" is intended to mean that the total loss in weight percent of material from the tablet varies by less than 10% for a given time during use at a tabletting force of from 10kN to 30 kN. This measurement is typically measured when the tablet does not "disintegrate" completely. Measurements when the tablets are contacted with saliva are considered in vivo measurements according to the measurements outlined in the examples of the present invention.

In one embodiment of the invention, the one or more disintegrants are present in an amount of 0.5 to 25% by weight of the tablet.

In some embodiments of the invention, the one or more disintegrants are present in an amount of 0.5 to 20% by weight of the tablet. In some embodiments of the invention, the one or more disintegrants are present in an amount of 0.5 to 15% by weight of the tablet. In some embodiments of the invention, the one or more disintegrants are present in an amount of 1 to 25% by weight of the tablet. In some embodiments of the invention, the one or more disintegrants are present in an amount of 1 to 20% by weight of the tablet.

In one embodiment of the invention, the one or more disintegrants are present in an amount of 2 to 15 wt% of the tablet.

In some embodiments of the invention, the one or more disintegrants are present in an amount of 2 to 10% by weight of the tablet. In some embodiments of the invention, the one or more disintegrants are present in an amount of 3 to 15% by weight of the tablet. In some embodiments of the invention, the one or more disintegrants are present in an amount of 4 to 15% by weight of the tablet. In some embodiments of the invention, the one or more disintegrants are present in an amount of 5 to 15% by weight of the tablet.

In one embodiment of the invention, the one or more disintegrants may swell in contact with the oral saliva. This means that the tablet breaks into smaller pieces upon contact with saliva.

In one embodiment of the invention, the one or more disintegrants comprise starch. This may be the case in particular when a ready-to-use disintegrant system is used, for example Pearlitol Flash which contains a certain amount of starch.

In one embodiment of the invention, the one or more disintegrants comprise microcrystalline cellulose.

In one embodiment of the invention, the one or more disintegrants comprise low-substituted hydroxypropyl cellulose (LHPC).

In one embodiment of the invention, the one or more disintegrants comprise super disintegrants. By "super disintegrant" is meant a disintegrant that provides superior disintegration compared to more traditional disintegrants used in the manufacture of tablets.

In one embodiment of the invention, the one or more disintegrants comprise a super disintegrant in an amount of 2 to 15% by weight of the tablet.

In some embodiments of the invention, the one or more super disintegrants are present in an amount of 2 to 10% by weight of the tablet. In some embodiments of the invention, the one or more super disintegrants are present in an amount of 3 to 15% by weight of the tablet. In some embodiments of the invention, the one or more super disintegrants are present in an amount of 4 to 15% by weight of the tablet. In some embodiments of the invention, the one or more superdisintegrants are present in an amount of from 5 wt% to 15 wt% of the tablet.

In one embodiment of the invention, the one or more disintegrants comprise a super disintegrant of a cross-linked polymer.

In one embodiment of the invention, the one or more disintegrants comprise a super disintegrant selected from croscarmellose sodium, crospovidone, sodium starch glycolate (sodium starch glycolate), and combinations thereof.

In one embodiment of the invention, the one or more disintegrants comprise cross-linked polyvinylpyrrolidone.

In one embodiment of the invention, the one or more disintegrants comprise cross-linked polyvinylpyrrolidone, and wherein at least 50 wt% of the cross-linked polyvinylpyrrolidone has a particle size below 50 microns.

In one embodiment of the invention, the one or more disintegrants comprise cross-linked polyvinylpyrrolidone, and wherein at least 25 wt% of the cross-linked polyvinylpyrrolidone has a particle size below 15 microns.

In one embodiment of the invention, the one or more solid particles are water insoluble.

In one embodiment of the invention, the plurality of solid particles is selected from the group consisting of silicon dioxide, microcrystalline cellulose, silicified microcrystalline cellulose, clay, talc, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, magnesium carbonate, magnesium-aluminum-metasilicate, ultra-porous silicon dioxide, and mixtures thereof. In some embodiments of the invention, silica is less preferred in the masterbatch particle (granules) component. In some embodiments of the invention, silica is to be avoided in the masterbatch particle component.

In one embodiment of the invention, the plurality of solid particles comprises microcrystalline cellulose.

In one embodiment of the invention, the one or more solid particles are water soluble.

In one embodiment of the invention, the plurality of solid particles comprises one or more sugar alcohols. In one embodiment of the invention, the solid particles comprise a Directly Compressible (DC) sugar alcohol. In one embodiment of the invention, the solid particles comprise a non-direct compressible (non-DC) sugar alcohol.

In one embodiment of the invention, the one or more solid particles are selected from the group consisting of xylitol, lactitol, sorbitol, maltitol, erythritol, isomalt and mannitol, and mixtures and combinations thereof.

In one embodiment of the invention, the one or more sugar alcohol particles are present in an amount of at least 30% by weight of the tablet. In one embodiment of the invention, the one or more sugar alcohol particles are present in an amount of at least 40% by weight of the tablet. In one embodiment of the invention, the one or more sugar alcohol particles are present in an amount of at least 50% by weight of the tablet. In one embodiment of the invention, the one or more sugar alcohol particles are present in an amount of at least 60% by weight of the tablet.

In one embodiment of the invention, the one or more sugar alcohol particles are selected from the group consisting of xylitol, lactitol, sorbitol, maltitol, erythritol, isomalt and mannitol, and mixtures and combinations thereof. In one embodiment of the invention, the one or more sugar alcohols are in free form.

In some embodiments of the invention, the sugar alcohol in the composition is present in an amount greater than 70% by weight of the composition, for example greater than 80% by weight of the composition.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more solid materials, such as microcrystalline cellulose.

In addition to the aforementioned benefits, the solid component can also be used to obtain a more homogeneous mixture of cannabinoids. However, due to the nature of the material, such as friability characteristics, it may be advantageous in some embodiments that the material is only present in an amount less than the amount of free sugar alcohol particles. In another aspect, it may be advantageous to have an amount of material in combination with the cannabinoid to ensure a homogeneous mixture of the tablet.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with 1:10 to 1:4 by weight of the one or more sugar alcohol particles. In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with 1:30 to 1:2 by weight of the one or more sugar alcohol particles. In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with 1:20 to 1:3 by weight of the one or more sugar alcohol particles.

In some embodiments of the invention, at least a portion of the one or more cannabinoids are reversibly associated with 1:15 to 1:3 by weight of the one or more sugar alcohol particles. In some embodiments of the invention, at least a portion of the one or more cannabinoids are reversibly associated with 1:20 to 1:2 by weight of the one or more sugar alcohol particles.

In the present context, the phrase "cannabinoid is reversibly associated with one or more solid particles" or "cannabinoid is reversibly associated with one or more sugar alcohol particles" or similar phrases are intended to mean that one or more cannabinoids are in contact with one or more solid particles and are not loosely distributed within the material. During storage of the tablet composition and during storage of the tablet, the one or more cannabinoids are typically associated with one or more solid particles. This may be in the form of: physical attachment, encapsulation, incorporation, solution, chemical interaction, and the like. However, during use in the oral cavity in contact with saliva, the aim is that the cannabinoid can be separated or released from the one or more solid particles, such that the one or more cannabinoids can be targeted to the mucosal surface. Thus, the meaning of "reversible" is intended to mean that the one or more solid particles serve as a means to carry the one or more cannabinoids prior to use and to ensure delivery of the one or more cannabinoids. Furthermore, one or more solid particles may be used to ensure that a more stable microenvironment of the composition may be provided. Furthermore, the one or more solid particles may ensure that the one or more cannabinoids are targeted to the site of their action, i.e. the mucosa.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by way of agglomeration. In one embodiment of the invention, the agglomeration is obtained by wet granulation. In one embodiment of the invention, the agglomeration is obtained by dry granulation.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by means of a plurality of particles having a volume weighted mean diameter of from 10 μm to 400 μm.

In some embodiments, particles are preferred. Because saliva is continuously secreted in the oral cavity, a general problem associated with transmucosal administration via the oral route is swallowing. For optimal drug delivery, the tablet formulation may preferably remain in contact with the oral mucosa for a time sufficient to allow absorption of the one or more cannabinoids. More specifically, if oral absorption is the target, the tablet formulation may preferably not be flushed away by saliva into the gastrointestinal tract. However, the rate of disintegration or dissolution of the tablet formulation may preferably not be so slow as to cause discomfort or inconvenience to the user. Additionally, suitable tablet formulations may preferably be of small size and designed such that the shape avoids discomfort to the patient during use. Most importantly, the formulation may preferably be designed such that the cannabinoids are in solution, which optimizes the transmucosal permeation of the cannabinoids. These considerations may be obtained with the premixes of the invention.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by means of a plurality of particles having a volume weighted mean diameter of from 50 μm to 300 μm.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more solid particles by way of a pre-mix.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by way of a pre-mix.

In the present context, "premix" or similar expressions are intended to mean that the one or more cannabinoids have been mixed with one or more solid particles, such as solid sugar alcohol particles, before being applied in a tablet formulation together with the sugar alcohol formulation.

In this context, the premix is used in part to properly distribute the one or more cannabinoids to the manufacturing process and to ensure that homogeneity is not compromised and that the cannabinoids are properly distributed into the mixture. Preferably, the cannabinoids are provided as a premix with one or more sugar alcohols. To the inventors' surprise, it is important to have a premix in order to distribute the cannabinoid properly during the manufacturing process and in order to finally obtain a product with a consistent homogeneity.

In one embodiment of the invention, at least a portion of the one or more cannabinoids and at least a portion of the one or more sugar alcohol particles are reversibly associated by way of adsorption in the premix.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles by means of adsorption, and wherein the one or more cannabinoids are applied by spraying.

In one embodiment of the invention, the particles comprise one or more cannabinoid solvents, such as glycols, alcohols, or alkyl solvents, or mixtures thereof, that solvate one or more cannabinoids. This may for example be the case when isolated cannabinoids, e.g. solid isolated cannabinoids, are applied.

In one embodiment of the invention, the one or more cannabinoid solvents are selected from polyethylene glycol, ethanol, substituted polyethylene glycol, diethylene glycol monoethyl ether, propylene glycol, propylene carbonate, or mixtures thereof.

In one embodiment of the invention, the tablet is compressed at a pressure of greater than 10 kN. In one embodiment of the invention, the tablet is compressed at a pressure of more than 15 kN. In one embodiment of the invention, the tablet is compressed at a pressure of less than 30 kN.

In one embodiment of the invention, at least a portion of the one or more cannabinoids are reversibly associated with at least a portion of the one or more sugar alcohol particles, decreasing the compressibility of the composition compared to a composition in which the one or more cannabinoids are not reversibly associated with at least a portion of the one or more sugar alcohol particles.

In one embodiment of the invention, the tablets contacted with saliva have a disintegration curve which varies by less than 10% at a compression pressure of 10kN to 30 kN.

In one embodiment of the invention, the tablets contacted with saliva have a disintegration curve which varies by less than 5% at a compression pressure of 10kN to 30 kN.

In some embodiments of the invention, the composition contacted with saliva has substantially the same disintegration curve at a compression pressure of 10kN to 30 kN.

One of the observations of the present invention that has a large effect is that the compression force does not generally have a large effect on the disintegration time of the tablet or even on the dissolution time of the tablet. It is a common understanding in the art of tablets that compression force has a great influence on the disintegration time and dissolution time of a tablet. The present inventors have found that the cannabinoid formulations of the present invention are highly advantageous in this regard.

In one embodiment of the invention, the weight ratio of the one or more cannabinoids to the one or more sugar alcohol particles is from 1:30 to 1: 1. In one embodiment of the invention, the weight ratio of the one or more cannabinoids to the one or more sugar alcohol particles is from 1:20 to 1: 10.

In one embodiment of the invention, the tablet further comprises a binder, such as a dry binder or a wet binder.

In one embodiment of the invention, the tablet further comprises at least one dissolution modifying agent selected from: acacia, agar, alginic acid or a salt thereof, carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone, cyclodextrin, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hypromellose, inulin, methylcellulose, pectin, polycarbophil or a salt thereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, pullulan, starch, tragacanth, trehalose, xanthan gum, and mixtures thereof.

According to one embodiment of the invention, the tablet further comprises at least one dissolution modifying agent selected from alginic acid or a salt thereof, polycarbophil or a salt thereof, xanthan gum, and mixtures thereof.

In one embodiment of the invention, the tablet further comprises at least one dissolution modifying agent selected from the group consisting of sodium alginate, calcium polycarbophil, xanthan gum, and mixtures thereof.

In one embodiment of the invention, the tablet further comprises at least one viscosifying agent (viscolizing agent) which forms a gel with a positive surface charge when hydrated and at least one viscosifying agent which forms a gel with a negative surface charge when hydrated.

In one embodiment of the invention, the tablet further comprises at least one alkaline buffer selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate and potassium bicarbonate, and mixtures thereof.

In one embodiment of the invention, the tablet further comprises at least one excipient selected from the group consisting of high intensity sweeteners, flavoring agents, chelating agents, glidants, or coloring agents.

In one embodiment of the invention, the unit weight of the tablet is from about 50mg to about 500 mg. In one embodiment of the invention, the unit weight of the tablet is from about 200mg to about 400 mg. This is particularly the case when tablets of only one module are made and a relatively high load of cannabinoids is applied, for example when the tablet is a rapidly disintegrating tablet without any lozenge module.

In one embodiment of the invention, the unit weight of the tablet is from about 50mg to about 250 mg. In one embodiment of the invention, the unit weight of the tablet is from about 75mg to about 150 mg. This is particularly the case when tablets of only one module are made and a relatively low load of cannabinoids is applied, for example when the tablet is a rapidly disintegrating tablet without any lozenge module.

In one embodiment of the invention, the sugar alcohol composition has an average particle size of less than 350 microns. In one embodiment of the invention, the sugar alcohol composition has an average particle size of less than 250 microns. In one embodiment of the invention, the sugar alcohol composition has an average particle size of at least 100 microns.

In one embodiment of the invention, the one or more cannabinoids are present in an amount of from 0.5mg to 100 mg.

In one embodiment of the invention, the one or more cannabinoids are present in an amount of from 1mg to 80 mg. In one embodiment of the invention, the one or more cannabinoids are present in an amount of from 5mg to 50 mg. In one embodiment of the invention, the one or more cannabinoids are present in an amount of from 5mg to 30 mg. In one embodiment of the invention, the one or more cannabinoids are present in an amount of from 5mg to 20 mg.

In some embodiments of the invention, the tablet composition has a unit weight of about 50mg to about 2000 mg. In some embodiments of the invention, the tablet composition has a unit weight of about 50mg to about 1000 mg. In some embodiments of the invention, the tablet composition has a unit weight of about 50mg to about 750 mg. In some embodiments of the invention, the tablet composition has a unit weight of about 100mg to about 750 mg. This is particularly the case when tablets of two or more modules are made, for example when the tablets comprise a fast disintegrating module and a lozenge module.

In some embodiments of the invention, the one or more cannabinoids are present in an amount of from 0.1mg to 400 mg. In some embodiments of the invention, the one or more cannabinoids are present in an amount of from 10mg to 100 mg.

In one embodiment of the invention, the one or more cannabinoids are present in an amount of from 0.1mg to 200 mg. In some further embodiments of the invention, the one or more cannabinoids are present in an amount of from 0.1mg to 100 mg. In some further embodiments of the invention, the one or more cannabinoids are present in an amount of from 0.1mg to 50 mg. In one embodiment of the invention, the tablet comprises the cannabinoid in an amount of from 0.1mg to 30mg, such as from 1mg to 20mg, such as from 5mg to 15 mg.

In one embodiment of the invention, the one or more cannabinoids include Cannabidiol (CBD), cannabidiolic acid (CBDA), Cannabidivarin (CBDV), salts and derivatives thereof.

In one embodiment of the invention, the one or more cannabinoids include Tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), Tetrahydrocannabivarin (THCV), salts and derivatives thereof.

In one embodiment of the invention, the one or more cannabinoids comprise Cannabidiol (CBD).

In one embodiment of the invention, the one or more cannabinoids are selected from Cannabidiol (CBD), cannabidiolic acid (CBDA), Tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), Cannabigerol (CBG), cannabichromene (CBC), Cannabinol (CBN), Cannabigerol (CBE), iso-tetrahydrocannabinol (iso-THC), Cannabicyclol (CBL), cannabidithane (cannabihexacycloalkane, CBT), Cannabidivarin (CBV), Tetrahydrocannabivarin (THCV), Cannabidivarin (CBDV), cannabichromene (CBCV), cannabigerol (cbb igervarin, CBGV), cannabigerol (monomenthyl), cannabinoyl monomenthyl, salts thereof, derivatives thereof, and mixtures thereof.

In one embodiment of the invention, the one or more cannabinoids include Cannabidiol (CBD), cannabidiolic acid (CBDA), Cannabidivarin (CBDV), salts and derivatives thereof. In one embodiment of the invention, the one or more cannabinoids include CBD, salts and derivatives thereof, including analogues and homologues. In one embodiment of the invention, the one or more cannabinoids comprise CBD. In one embodiment of the invention, the one or more cannabinoids is CBD.

In one embodiment of the invention, the one or more cannabinoids include Tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), Tetrahydrocannabivarin (THCV), salts and derivatives thereof. In one embodiment of the invention, the one or more cannabinoids comprise Tetrahydrocannabinol (THC). Preferably, THC is intended to mean (-) -trans- Δ⁹-tetrahydrocannabinol, i.e. (6aR,10aR) - δ -9-tetrahydrocannabinol). In one embodiment of the invention, the one or more cannabinoids is THC.

In one embodiment of the invention, the one or more cannabinoids comprise at least two cannabinoids. In one embodiment of the invention, the one or more cannabinoids include a combination of several cannabinoids, for example THC and CBD. In one embodiment of the invention, the one or more cannabinoids is a combination of THC and CBD.

In one embodiment of the invention, the tablet formulation comprises a flavoring agent in an amount of 0.01 to 10% by weight of the tablet formulation, for example in an amount of 0.01 to 5% by weight of the tablet formulation.

In one embodiment of the invention, the tablet formulation comprises a high intensity sweetener.

In one embodiment of the invention, the one or more cannabinoids are present in solid form. In one embodiment of the invention, the one or more cannabinoids are present in liquid or semi-liquid form.

In one embodiment of the invention, the one or more cannabinoids form part of a complex with the cyclodextrin. In one embodiment of the invention, the one or more cannabinoids form part of a complex with the cyclodextrin. The complex may enhance the release of cannabinoids according to the invention. In addition, the complex may enhance delivery of one or more cannabinoids to the oral mucosa.

In one embodiment of the invention, the one or more cannabinoids include at least one phytocannabinoid that forms part of the extract. In some embodiments of the invention, it was observed that cannabinoids as part of the extract may enhance the release of cannabinoids.

In one embodiment of the invention, the one or more cannabinoids comprise at least one isolated cannabinoid.

In one embodiment of the invention, the one or more cannabinoids are located in a protein carrier, such as a pea protein carrier.

In one embodiment of the invention, the one or more cannabinoids are located in a polymeric carrier.

In one embodiment of the invention, the one or more cannabinoids are located in an amphiphilic polymer carrier.

In one embodiment of the invention, the one or more cannabinoids include at least one endocannabinoid or endocannabinoid compound, such as Palmitoyl Ethanolamide (PEA).

In one embodiment of the invention, the one or more cannabinoids include at least one water soluble cannabinoid.

In one embodiment of the invention, the tablet comprises a self-emulsifying agent.

In one embodiment of the invention, the tablet comprises a lipophilic association between one or more cannabinoids and a fatty acid, for example oleic acid.

In one embodiment of the invention, the tablet comprises a lipid carrier for one or more cannabinoids.

In one embodiment of the invention, the lipid carrier of one or more cannabinoids comprises one or more terpenes.

In one embodiment of the invention, the lipid carrier of one or more cannabinoids comprises one or more terpenes selected from the group consisting of: bisabolol, borneol, caryophyllene, carene, camphene, cineole, citronella, eucalyptol, geraniol, guaiol, luprene, isopropyl toluene, isopulegol, linalool, limonene, menthol, myrcene, nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpinolene, thymol, salts thereof, derivatives thereof, and mixtures of terpenes.

In one embodiment of the invention, the tablet is used to treat or alleviate a medical condition.

In certain embodiments of the invention, the tablet formulation of the invention may be used to treat or alleviate a medical condition selected from the group consisting of: pain, epilepsy, cancer, nausea, inflammation, congenital disorders, neurological disorders, oral infections, dental pain, sleep apnea, psychiatric disorders, gastrointestinal disorders, inflammatory bowel disease, anorexia, diabetes and fibromyalgia.

In another aspect of the invention, the tablet comprises additional tablet modules that differ in composition.

If not otherwise stated, if a tablet according to the invention is made as one module, as opposed to two or more modules, the tablet is intended to be an FDT tablet. If on the other hand the tablets are made of more than one module, e.g. two modules, such further modules are intended to be "lozenge" modules, which provide a longer disintegration time compared to the FDT module according to the invention. The combination of "FDT" and "lozenge" modules is discussed in the following section and contributes to another aspect of the invention. The "lozenge" module according to the invention may also comprise elements from the "FDT" module described in the previous section, but typically differ in composition, thereby providing an extended disintegration time.

In one embodiment of the invention, the tablet comprises additional tablet modules that differ in composition and comprise one or more cannabinoids as previously described with respect to the FDT element.

In one embodiment of the invention, the tablets comprise additional tablet modules that differ in composition and disintegrate within 3 minutes or more of contact with oral saliva.

In one embodiment of the invention, the tablets comprise additional tablet modules that differ in composition and disintegrate within 4 minutes or more of contact with oral saliva.

In one embodiment of the invention, the tablets comprise further tablet modules that differ in composition and comprise the previously described sugar alcohol composition according to FDT elements.

In one embodiment of the invention, the tablets comprise further tablet modules that differ in composition and comprise a sugar alcohol composition having a larger average particle size.

In one embodiment of the invention, the tablet comprises further tablet modules which differ in composition and constitute at least 50 wt% of the total tablet.

In one embodiment of the invention, the tablet comprises further tablet modules which differ in composition and constitute at least 60 wt.% of the total tablet.

In one embodiment of the invention, the tablet comprises further tablet modules which differ in composition and constitute at least 70 wt% of the total tablet.

In one embodiment of the invention, the tablets comprise further tablet modules which differ in composition and constitute from 50 to 90% by weight of the total tablet.

In one embodiment of the invention, the tablets comprise further tablet modules which differ in composition and constitute from 60 to 90% by weight of the total tablet.

In one embodiment of the invention, the tablets comprise further tablet modules which differ in composition and constitute from 70 to 90% by weight of the total tablet.

In one embodiment of the invention, the tablet comprises additional tablet modules that differ in composition and have a unit weight of from about 250mg to about 950 mg.

In one embodiment of the invention, the tablet comprises further tablet modules that differ in composition and have a unit weight of about 400mg to about 900 mg.

In one embodiment of the invention, the tablet comprises further tablet modules that differ in composition and have a unit weight of about 400mg to about 900 mg.

In one embodiment of the invention, the tablet comprises further tablet modules that differ in composition and have a unit weight of about 200mg to about 500 mg.

In one embodiment of the invention, the tablets comprise further tablet modules which differ in composition and comprise a gum base polymer.

In one embodiment of the invention, the tablets comprise further tablet modules which differ in composition and which do not comprise a gum base polymer.

In one embodiment of the invention, the tablet comprises such further tablet modules: which differ in composition and are compressed together with the FDT tablets previously described according to the FDT element to form an integrated two-layer tablet.

In one embodiment of the invention, the tablet comprises such further tablet modules: which differ in composition and are compressed in a separate step before compressing the FDT tablets previously described according to the FDT elements.

In one embodiment of the invention, the tablet comprises such further tablet modules: which differ in composition and are compressed in a separate step at a higher pressure before compressing the FDT tablets previously described according to the FDT factor.

In one embodiment of the invention, the tablet comprises such further tablet modules: which differ in composition and comprise any of the binders, dissolution agents, excipients, viscosifiers, or alkaline buffers previously described according to the FDT elements.

Detailed Description

The present invention will now be described in more detail with respect to certain aspects and embodiments thereof. These aspects and embodiments are intended to be understood in conjunction with the remainder of the specification, including the summary and examples of the invention.

As used herein, the term "about" or "approximately" in reference to a number is generally considered to include numbers that fall within a range of 5%, 10%, 15%, or 20% of the number in either direction (greater than or less than) unless otherwise indicated or otherwise evident from the context (unless such numbers are less than 0% or more than 100% of the possible values).

As used herein, the term "disintegrate" refers to reducing an object into components, fragments, or granules. The disintegration time can be measured in vitro or in vivo. Unless otherwise indicated, in vitro measurements were made according to the European pharmacopoeia 9.0, section 2.9.1, "Disintegration of tablets and capsules" (European Pharmacopeia 9.0, section 2.9.1, resolution of tablets and capsules).

As used herein, the term "dissolution" is the process of the solid substance entering a solvent (oral saliva) to produce a solution. Unless otherwise stated, dissolution means complete dissolution of the compound in question.

As used herein, the term "disintegrant" refers to an ingredient that promotes the disintegration of the FDT module when the FDT module is contacted with saliva. Disintegrants that may be used within the scope of the invention may include starch, pregelatinized starch, modified starches (including potato starch, corn starch, starch 1500, sodium starch glycolate, and starch derivatives), cellulose, microcrystalline cellulose, alginates, ion exchange resins, and super-disintegrants such as cross-linked cellulose (e.g., sodium carboxymethyl cellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starch, cross-linked alginic acid, natural super-disintegrants, and calcium silicate. Disintegrants are generally considered as measures that facilitate breaking up of the module into smaller pieces upon administration to facilitate nicotine release and eventual absorption. Crospovidone may include various grades, such as Kollidon CL-F or Kollidon CL-SF, available from BASF.

The term "disintegrant composition" is intended to mean a number of substances comprising one or more disintegrants. The disintegrant composition may comprise other excipients in addition to the disintegrant. The disintegrant composition may constitute a disintegrant. The disintegrant composition may constitute one type of disintegrant. The disintegrant composition may constitute two types of disintegrants. The disintegrant composition may constitute two or more types of disintegrants. Preferably, the disintegrant composition comprises "a portion of a granule". Preferably, the disintegrant composition is "part of a granule".

The term "particle size" relates to the ability of a particle to move through or be retained by a particular size of sieve opening. Unless specifically mentioned otherwise, the term "particle size" as used herein refers to the average particle size as determined according to the european pharmacopoeia 9.1 at the particle size distribution evaluation by analytical sieving (particle size distribution evaluation) using test method 2.9.38 ".

The term "plurality of particles" is intended to encompass a "population of particles" in the sense that the term "plurality" encompasses the sum of the population.

The term "a portion of a particle" or similar phrases is intended to mean a plurality of particles that collectively may include one or more populations of particles.

The term "granule" or similar is intended to mean a single discrete composition of a solid substance, such as a particle or individual elements in powder form, having a certain size which may deviate significantly.

The term "DC sugar alcohol particles" or similar expressions refer to particles of Directly Compressible (DC) sugar alcohols. The DC sugar alcohol particles may be obtained, for example, as particles of sugar alcohols naturally having DC grades, such as sorbitol, or by granulating non-DC sugar alcohols with, for example, other sugar alcohols or binders for the purpose of obtaining so-called directly compressible particles (DC). In addition, granulation of a non-DC sugar alcohol with water as a binder is believed to produce "DC sugar alcohol particles" in this context. This is in contrast to the term "non-DC sugar alcohol particles", which refers to particles of a directly incompressible (non-DC) sugar alcohol. In the present context, non-DC sugar alcohol particles refer to particles which have not been pre-treated by granulation with e.g. other sugar alcohols or binders for the purpose of obtaining so-called directly compressible particles (DC). Thus, a non-DC sugar alcohol particle is considered to be a particle consisting of a non-DC sugar alcohol.

The term "sugar alcohol composition" is intended to mean a number of substances comprising one or more sugar alcohols. The disintegrant composition may comprise other excipients besides sugar alcohols. The sugar alcohol composition may constitute a sugar alcohol. The sugar alcohol composition may constitute one type of sugar alcohol. The sugar alcohol composition may constitute two types of sugar alcohols. The sugar alcohol composition may constitute two or more types of sugar alcohols. Preferably, the sugar alcohol composition comprises "a portion of a granule". Preferably, the sugar alcohol composition is "part of a granule".

The term "compressed" or "tablet" or "compressed" is intended to mean that the tablet composition is compressed in a tabletting equipment and consists essentially of a particulate material. Although these terms imply process steps, in the present context, these terms are intended to mean the resulting tablets obtained when compressing a portion of the granulate. Note that reference to a tablet or a compressed composition ultimately comprising granules is to be understood as a granule that has been compressed together in a compression step.

In one aspect of the invention, "tablet" is intended to mean "rapidly disintegrating tablet" ("FDT") or similar expressions, such as "orally disintegrating tablet" ("ODT"). If not stated otherwise, a tablet according to the invention is intended to be an FDT tablet if it is made as one module, as opposed to two or more modules. If on the other hand the tablets are made of more than one module, e.g. two modules, such further modules are intended to be "lozenge" modules, which provide a longer disintegration time compared to the FDT module according to the invention. The combination of the "FDT" module and "lozenge" module contributes to another aspect of the invention. The "lozenge" module according to the invention may also contain elements from the "FDT" module, but typically differ in composition to provide an extended disintegration time.

The term "lozenge" is intended to encompass "lozenge compositions" that have been "compressed" into "lozenge modules". In this context, "lozenge module" or similar phrases are intended to mean that the module is intended to be sucked or licked during use in the oral cavity. The term "lozenge" gives a general meaning in the art of lozenges. The goal is that the lozenge module may not be chewed. The aim is also to not chew the FDT module. Generally, the "lozenge modules" of the present invention may disintegrate within minutes when sucked or licked, as opposed to seconds for tablets that are Orally Disintegrating Tablets (ODT) or rapidly disintegrating tablets (FDT). Thus, if a tablet is made as a combination of two modules, the objective is a "lozenge module" for delivering one or more cannabinoids over a longer period of time than an FDT module.

The term "module" is generally intended to be composed of a composition of matter having substantially the same characteristics throughout the module. Thus, if there are two modules, the two modules differ in composition and typically have two different characteristics throughout the respective modules. In this context, a module is considered to be an FDT tablet if there is only one module. On the other hand, if there are two modules, the tablet is composed of an FDT tablet module or FDT tablet fused with a lozenge tablet or pastille module. The term "fusing" is intended to mean that the tablets are brought together by a compressive force. Typically, if there are two modules, the lozenge module is made as a first module and the FDT module is made as a second module. A tablet may be composed of more than two modules. Lozenge modules may be replaced by gum base modules in certain embodiments. In this context, the present invention provides an attractive biphasic masked delivery, even if the delivery of nicotine is "monophasic".

The phrase "additional tablet modules that differ in composition" or similar phrases are intended to mean that the additional modules differ from the FDT module in the sense that the composition of the module is substantially different from the FDT module (e.g., with respect to disintegration time).

The term "cannabinoid composition" is intended to mean a number of substances comprising one or more cannabinoids. Cannabinoid compositions may comprise other components in addition to cannabinoids. Cannabinoid compositions may constitute cannabinoids. Cannabinoid compositions may constitute one type of cannabinoid. Cannabinoid compositions can constitute two types of cannabinoids. Cannabinoid compositions may constitute two or more types of cannabinoids.

The term "weight of the tablet composition" or similar wording having the same meaning is defined in this context as the weight of the tablet composition excluding the weight of an outer coating, e.g. hard coating, soft coating, etc.

The phrase "texture" means a qualitative measure of the characteristics of the tablet composition or tablet and the overall mouthfeel experienced by the user during use. Thus, the term "texture" encompasses measurable quantities, such as hardness, as well as more subjective parameters related to the sensation experienced by the user.

The term "in vivo use" is intended to mean the use of the tablet composition system by a human subject in a laboratory setting of trained test personnel according to statistical principles, and to mean that the saliva of the human subject is subjected to a measurement or that the tablet composition is subjected to a measurement.

The term "in vivo release" or "in vivo release test" or similar phrases are intended to mean testing of the tablet composition as outlined in the examples.

The term "in vitro release" or "in vitro release test" or similar expressions are intended to mean that the tablet composition is tested according to the examples.

The term "release" in this context is intended to mean under "in vitro" conditions, unless otherwise indicated. In particular, the "release rate" during a particular time period is intended to mean the amount in percent of the cannabinoid that is released over that time period.

The term "sustained release" or "extended release" is intended herein to mean extended release over time. The term "rapid release" or "fast release" or "high release" is intended herein to mean that a higher level is released over a given period of time. The term "controlled release" is intended to mean the release of a substance from a tablet composition by active use of the tablet composition in the oral cavity of a subject, thereby actively using the amount of the substance that is released.

The term "delivery to the oral mucosa" or similar expressions are intended to mean testing of the tablet composition according to the examples.

As used herein, the terms "buffering agent" and "buffer" are used interchangeably and refer to the reagents used to obtain a buffered solution. The buffer includes an acidic buffer (i.e., for obtaining a buffer solution having an acidic pH) and an alkaline buffer (i.e., for obtaining a buffer solution having an alkaline pH).

"self-emulsifying agent" is an agent that when presented in alternating phases will form an emulsion with minimal energy requirements. In contrast, emulsifiers are emulsifiers that require additional energy to form an emulsion, as opposed to self-emulsifiers.

In one embodiment of the invention, the tablet composition comprises additional tablet composition ingredients selected from the group consisting of: flavoring agents, dry binders, tableting aids, anti-caking agents, emulsifiers, antioxidants, enhancers, muco-film adsorbents, absorption enhancers, high intensity sweeteners, softeners, pigments, active ingredients, water-soluble indigestible polysaccharides, water-insoluble polysaccharides, or any combination thereof.

In embodiments where the lozenge contains a filler, different fillers may be used. In some embodiments of the invention, microcrystalline cellulose may be used as a filler. Examples of useful fillers include: magnesium and calcium carbonate, sodium sulfate, ground limestone, silicate compounds (e.g., magnesium and aluminum silicate, kaolin and clay), alumina, silica, talc, titanium oxide, monocalcium phosphate, dicalcium phosphate and tricalcium phosphate, cellulosic polymers (e.g., wood), starch polymers, fibers, and combinations thereof.

Examples of useful disintegrants include: starches, pregelatinized starches, modified starches (including potato starch, corn starch, starch 1500, sodium starch glycolate, and starch derivatives), celluloses, microcrystalline celluloses, alginates, ion exchange resins, and super-disintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate, cross-linked celluloses (e.g., sodium carboxymethylcellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starches, cross-linked alginic acid, natural super-disintegrants, and calcium silicate, and combinations thereof.

Useful high intensity sweeteners include, but are not limited to, sucralose, aspartame, salts of acesulfame (e.g., acesulfame potassium), alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside, and the like, alone or in combination.

Useful flavoring agents include: almond, almond wine (almond amaretto), apple, Bavarian cream (Bavarian cream), black cherry, black sesame seed, blueberry, brown sugar, bubble gum (bubblegum), butterscotch (butterscotch), cappuccino (cappuccino), caramel cappuccino, cake of cheese (whole wheat husk), red cinnamon (cinammon redhot), marshmallow, round marshmallow, clove, coconut, coffee, sake, double chocolate, energy cow (energy cow) biscuit, whole wheat biscuit, grape juice, green apple, hawaibin (Hawaiian punch), honey, Jamaican (jamai wine), tartary boy (jamai), kiwi, cool sugar (olakoda), lemon (lemon lim), tobacco, maple syrup, marquis (margari), cotton (cherry), honey, cherry (honey, etc.), kiwi, honey, chocolate, honey, chocolate, honey, chocolate, peanut butter, pecan, mint, raspberry, banana, ripe banana, root beer (root beer), RY 4, spearmint, strawberry, sweet cream, sweet pie (sweet start), sweetener, toasted almond, tobacco mix, vanilla bean ice cream, vanilla cupcake, vanilla sunrise (swirl), vanillin, waffle, belgium, watermelon, whipped cream (whipped cream), white chocolate, wintergreen, almond wine (amaretto), banana cream, black walnut, blackberry, butter, cream rum (butter rum), cherry chocolate, cinnamon roll, cola, mint wine (creme de menthe), egg wine (egg), hazelnut taffy, tomato, lemon water, licorice, maple (maple), mint flakes, orange cream, peach, ice cream (pineapple), pineapple juice (pineapple), apple juice (pineapple juice, apple juice (apple juice), apple juice, apple juice, apple, etc., black walnut, and apple, black walnut, and apple, black walnut (black walnut, and black walnut, black bean, and black walnut, black bean, and black bean, strawberry, and black bean, strawberry, and black plum, strawberry, and black bean, strawberry, and black bean, strawberry, and black bean, and black plum, and black bean, and black plum, and black bean, and black plum, pomegranate, praline and cream, red licorice, taffy, strawberry banana, strawberry kiwi, tropical cocktail (tropical punch), fruit set (tutti), vanilla, or any combination thereof.

Useful buffers include alkali metal carbonates (including monocarbonates, bicarbonates, and sesquicarbonates), glycerates, phosphates, glycerophosphates, acetates, gluconates, or citrates, ammonium, tris buffers, amino acids, and mixtures thereof. Encapsulation buffers such as Effersoda may also be used.

In some embodiments, the buffer comprises sodium carbonate and sodium bicarbonate, for example, in a weight ratio of 5:1 to 2.5:1, preferably in a weight ratio of 4.1:1 to 3.5: 1.

Silicon dioxide may be used as a glidant. Other glidants that may be used in the formulation may also be used within the scope of the present invention. Magnesium stearate and/or sodium stearyl fumarate (sodium stearyl fumarate) may be used as a lubricant. Other lubricants useful in the formulation may also be used within the scope of the present invention.

It is within the scope of the invention to use a ready-to-use system. Typically, such ready-to-use systems may replace fillers, disintegrants, glidants or the like, for example, with a single powder mixture. Suitable ready-to-use systems for this purpose include, but are not limited to: pearlitol Flash (Roquette), Pharmaburst 500(SPI Pharma), Ludflash (BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-melt (Fuji chemical), SmartEx50, or SmartEx100(Shin Etsu/Harke Pharma). The use of a ready-to-use system comprising a disintegrant may be particularly advantageous.

In particular, the inclusion of a disintegrant can significantly affect the disintegration time, depending on the overall composition of the second module. In addition, by varying the amount and type of disintegrant, the disintegration time can be further adjusted. For example, if a second layer with a shorter disintegration time is desired, the percentage content of disintegrant may be increased and/or the type of disintegrant may be at least partially exchanged for a more effective disintegrant.

In addition, reducing the particle size of the disintegrant tends to reduce disintegration time, possibly due to the increased surface area to volume ratio.

Furthermore, the compression force used to compress the second module is significantly related to the stiffness of the obtained second module, such that a high compression force typically increases the stiffness of the obtained second module. By adjusting the hardness of the second module, the disintegration time can also be influenced, so that a reduced hardness typically gives a shorter disintegration time. It is observed here that for many compositions, by applying the right compression force, disintegration times of less than 60 seconds upon oral administration can be achieved, whereas too high a compression force may result in longer disintegration times of more than 60 seconds. In this regard, it is noted that the threshold compressive force may vary significantly depending on other parameters (e.g., overall composition, content and type of disintegrant, etc.). When, for example, a certain setting results in disintegration too slowly, an additional mode of adjustment may be to replace the conventional disintegrant with a super disintegrant (i.e., which promotes disintegration in a more efficient manner).

Typically, the formulation of the FDT module may comprise ingredients selected from the group consisting of: bulk sweeteners, fillers, ready-to-use systems, flavoring agents, dry binders, disintegrants, super disintegrants, below, tableting aids, anti-caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffers, high intensity sweeteners, pigments, glidants, lubricants, or any combination thereof. The absorption enhancer may include, for example, pH adjusting agents such as buffering agents and mucoadhesive adsorbents.

Mannitol may be used as the sugar alcohol in the lozenge module and the FDT module. Particularly preferred grades of mannitol include mannitol 100SD, mannitol 150SD or mannitol 200SD with different average particle sizes available from Roquette. Other useful sugar alcohols for use in the lozenge module may include sorbitol, erythritol, xylitol, maltitol, lactitol and isomalt. Among them, isomalt, erythritol and sorbitol are particularly preferable. Other useful sugar alcohols for use in the FDT module may include sorbitol, erythritol, xylitol, maltitol, lactitol, and isomalt. The disintegrant in the FDT module may for example be a starch-based disintegrant. In embodiments of the invention, the disintegrant may be supplied as part of a ready-to-use system (e.g., Pearlitol Flash from Roquette, a mannitol-based product containing about 17% by weight of disintegrant). Examples of other ready-to-use systems that can be used include, for example, Pharmaburst 500(SPI Pharma), Ludflash (BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-melt (Fuji chemical), SmartEx50, or SmartEx100(Shin Etsu/Harke Pharma).

The Pearlitol Flash used contained about 17% by weight of starch disintegrant. Examples of other ready-to-use systems that can be used include, for example, Pharmaburst 500(SPI Pharma), Ludflash (BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-melt (Fuji chemical), SmartEx50, or SmartEx100(Shin Etsu/Harke Pharma).

Preferred High Intensity Sweeteners (HIS) may be, for example, sucralose, acesulfame potassium, and mixtures thereof. Other high intensity sweeteners, such as aspartame, salts of acesulfame (e.g., acesulfame potassium), alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside, alone or in combination, may also be used within the scope of the present invention.

Menthol, peppermint, and mixtures thereof may be used in the above formulations as a flavoring agent. Other flavoring agents may also be used within the scope of the present invention.

Sodium carbonate may be used as a buffer. Additional useful buffers include other carbonates of alkali metals (including monocarbonates, bicarbonates, and sesquicarbonates), glycerates, phosphates, glycerophosphates, acetates, gluconates, or citrates, ammonium, tris buffers, amino acids, and mixtures thereof.

In the above, MgSt (magnesium stearate) was used as a lubricant. Other lubricants such as sodium stearyl fumarate may also be used within the scope of the present invention.

According to an embodiment of the invention, the emulsifier may be selected from sucrose fatty acid esters (e.g. sucrose monostearate), polyethylene glycol esters or ethers (PEG) (e.g. caprylocaproyl macrogol-8 glyceride and lauroyl macrogol-32-glyceride), mono-and diglycerides of fatty acids (e.g. glycerol monostearate, glycerol monolaurate, glycerol behenate), acetates (Acetem) of mono-and diglycerides of fatty acids, polyoxyethylene alkyl ethers, diacetyl tartaric acid esters of monoglycerides, lactylated monoglycerides, glycerophospholipids (e.g. lecithin), poloxamers (non-ionic block copolymers of ethylene oxide and propylene oxide), cyclodextrins, fatty acid esters of sorbitol (e.g. sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, Polysorbate ester). The self-emulsifying emulsifier can be phospholipid (lecithin), polysorbate (polysorbate 80).

The SEDDS (self-emulsifying drug delivery system) may consist of a hard or soft capsule filled with a liquid or gel consisting of a self-emulsifying agent, one or more cannabinoids, an oil (for dissolving the cannabinoids) and a surfactant. The SEDDS may comprise a blend or mixture of a self-emulsifying agent, one or more cannabinoids, an oil (for dissolving the cannabinoids) and a surfactant. The SEDDS may comprise particles containing a self-emulsifying agent, one or more cannabinoids, an oil (for dissolving cannabinoids), one or more surfactants, a solvent and a co-solvent. Upon contact with gastric juice, the SEDDS spontaneously emulsifies due to the presence of the surfactant. However, many surfactants are lipid-based and interact with lipases in the GIT (gastrointestinal tract). This may result in a reduced ability of the lipid-based surfactant to emulsify the one or more cannabinoids as well as the oil carrier, both of which reduce bioavailability.

In the present context, a SEDDS is a solid or liquid dosage form comprising an oil phase, a surfactant and optionally a co-surfactant, characterized mainly in that the dosage form can spontaneously form an oil-in-water emulsion in the oral cavity or under mild agitation at ambient temperature (usually body temperature, i.e. 37 ℃). When the SEDDS enters the oral cavity, it initially self-emulsifies into emulsion droplets and rapidly disperses throughout the oral cavity and thus reduces irritation caused by direct contact of the drug with the mucosa of the oral cavity. In the mouth, the structure of the emulsion particles will be altered or destroyed. The generated micro-or nano-particles can penetrate into the mucosa of the oral cavity, and the digested oil drops enter the blood circulation, thereby significantly improving the bioavailability of the drug.

In particular, for SEDDS, the formulations of the invention may provide some significant benefits, both allowing for higher loading of cannabinoids and at the same time providing improved organoleptic properties of the formulation during use. Other advantages also exist. The combination of one or more cannabinoid-associated components and the composition comprising one or more sugar alcohol particles is believed to provide the benefits of the present invention with respect to both loading of cannabinoids and improved sensory properties (e.g., less aberrant characteristics) compared to prior art formulations.

In one embodiment of the invention, the one or more self-emulsifying agents are selected from: PEG-35 castor oil, PEG-6 oleoyl glyceride, PEG-6 linoleoyl glyceride, PEG-8 caprylic/capric glyceride, sorbitan monolaurate, sorbitan monooleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (60) sorbitan monostearate, polyoxyethylene (80) sorbitan monooleate, lauroyl polyoxy-32 glyceride, stearoyl polyoxy-32 glyceride, polyoxy-32 stearate, propylene glycol monolaurate, propylene glycol dilaurate, and mixtures and combinations thereof.

According to an embodiment of the invention, the flavouring agent may be selected from coconut, coffee, chocolate, vanilla, grapefruit, orange, lemon, menthol, licorice, caramel essence, honey essence, peanut, walnut, cashew, hazelnut, almond, pineapple, strawberry, raspberry, tropical fruit, cherry, cinnamon, peppermint, wintergreen, spearmint, eucalyptus, and mint, fruit essences (e.g. from apple, pear, peach, strawberry, apricot, raspberry, cherry, pineapple, and plum). The essential oils include peppermint, spearmint, menthol, eucalyptus, clove oil, bay oil, anise, thyme, cedar leaf oil, nutmeg and oils of the above fruits.

The petroleum wax aids in the solidification and improves the pot life and texture of the final tablet composition made from the tablet composition. Wax crystal size affects flavor release. Those waxes that are high in isoalkanes have a smaller crystal size than those waxes that are high in n-alkanes, especially those having n-alkanes with a carbon number less than 30. Smaller crystal sizes allow for slower release of flavor because there is more impediment to flavor escaping from the wax relative to waxes with larger crystal sizes.

Petroleum waxes (refined and microcrystalline) and paraffins are composed primarily of straight chain normal and branched chain isoalkanes. The ratio of normal to iso-alkanes is different.

Microcrystalline cellulose may be applied in various grades, such as Avicel PH-101, Avicel PH-102, or Avicel PH-105 available from FMC.

Antioxidants prolong the pot life and storage of the tablet composition, the final tablet composition, or components thereof, including fats and flavor oils.

Antioxidants suitable for use in the tablet composition include Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), beta carotene, tocopherols, acidulants such as vitamin C (ascorbic acid or a corresponding salt (ascorbate)), propyl gallate, catechins, other synthetic and natural types, or mixtures thereof.

Further tablet composition ingredients that may be comprised in the tablet composition according to the present invention comprise surfactants and/or solubilizers. As examples of the type of surfactant used as solubilizer in the tablet composition according to the invention, reference is made to h.p. fiedler, Lexikon der hilfstoffee fur pharmace, Kosmetik und angrenzene Gebiete, pages 63 to 64 (1981) and the list of food emulsifiers approved by each country. Anionic, cationic, amphoteric or nonionic solubilizers may be used. Suitable solubilizers include lecithin, polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid esters, fatty acid salts, monoacetyl and diacetyl tartaric acid esters of mono-and diglycerides of edible fatty acids, citric acid esters of mono-and diglycerides of edible fatty acids, sucrose esters of fatty acids, polyglycerol esters of transesterified castor oil acid (E476), sodium stearoyl lactylate, sodium lauryl sulfate and sorbitan esters of fatty acids and polyoxyethylated hydrogenated castor oil (such as the product sold under the trade name CREMOPHOR), block copolymers of ethylene oxide and propylene oxide (such as the products sold under the trade names PLURONIC and POLOXAMER), polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, sorbitan esters of fatty acids and polyoxyethylene stearates.

Particularly suitable solubilizers are polyoxyethylene stearates (such as polyoxyethylene (8) stearate and polyoxyethylene (40) stearate), polyoxyethylene sorbitan fatty acid esters sold under the trade name TWEEN (such as TWEEN 20 (monolaurate), TWEEN 80 (monooleate), TWEEN40 (monopalmitate), TWEEN 60 (monostearate) or TWEEN 65 (tristearate)), monoacetyl and diacetyl tartaric acid esters of mono-and diglycerides of edible fatty acids, citric acid esters of mono-and diglycerides of edible fatty acids, sodium stearoyl lactylate, sodium lauryl sulfate, polyoxyethylated hydrogenated castor oil, block copolymers of ethylene oxide and propylene oxide and polyoxyethylene fatty alcohol ethers. The solubilizer may be a single compound or a combination of several compounds. The tablet composition may also preferably comprise a carrier known in the art of tablet compositions and active ingredients in the presence of an active ingredient, such as the one or more cannabinoids comprised. Poloxamer F68 is another very suitable solubilizer.

High intensity artificial sweeteners may also be used according to preferred embodiments of the present invention. Preferred high intensity sweeteners include, but are not limited to, sucralose, aspartame, salts of acesulfame, alitame, neotame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, luo han guo extract, edvandula (an), stevioside, and the like, alone or in combination.

In order to provide longer lasting sweetness and taste perception, it may be desirable to encapsulate or otherwise control the release of at least a portion of the artificial sweetener.

Techniques such as wet granulation, wax granulation, spray drying, spray cooling, fluid bed coating, preservation, encapsulation in yeast cells, and fiber extrusion may be used to achieve the desired release profile. Additional tablet composition components such as resin compounds may also be used to provide encapsulation of the sweetener.

The level of high intensity sweetener used will vary widely and will depend on factors such as the potency of the sweetener, the rate of release, the desired sweetness of the product, the level and type of flavoring used, and cost considerations. Thus, the active level of the artificial sweetener may vary from about 0.001% to about 8% (preferably from about 0.02% to about 8%) by weight. When carriers are included for encapsulation, the usage levels of encapsulated high intensity sweeteners will be proportionately higher.

If desired, the tablet and/or lozenge compositions may contain one or more fillers/modifiers including, by way of example, magnesium and calcium carbonate, sodium sulfate, ground limestone, silicate compounds (e.g., magnesium and aluminum silicate, kaolin and clay), alumina, silica, talc, titanium oxide, monocalcium phosphate, dicalcium phosphate and tricalcium phosphate, cellulosic polymers (e.g., wood), and combinations thereof. According to one embodiment of the invention, a preferred filler/conditioning agent is calcium carbonate.

Many tablet composition components known in the art may be employed within the scope of the present invention. Such components include, but are not limited to, waxes, fats, softeners, fillers, bulk sweeteners, flavoring agents, antioxidants, emulsifiers, colorants, binders, and acidulants.

In one embodiment of the invention, the water soluble component comprises at least one sugar alcohol. The at least one sugar alcohol may be selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, isomalt, erythritol, lactitol, maltodextrin, hydrogenated starch hydrolysates, and combinations thereof.

In one aspect of the invention, the sugar alcohol of the invention may be replaced with one or more sugars, for example selected from dextrose, sucrose, maltose, fructose, lactose, and combinations thereof.

Sugar sweeteners generally include, but are not limited to, sugar-containing components such as sucrose, dextrose, maltose, sucrose, lactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, fructose, levulose, galactose, corn syrup solids, glucose syrup, hydrogenated glucose syrup, and the like, alone or in combination. These sugar sweeteners may also be included as humectants.

Tablets according to the invention are manufactured by applying pressure to the contents of the granules by a suitable compression means. The granules or powder are then compressed into a dense, cohesive tablet. The particles may for example comprise so-called primary particles or aggregated primary particles. When these granules are compressed, a bond is established between the granules or particles, giving the compressed tablet some mechanical strength.

It should be noted that the terms powder, primary particles and aggregated primary particles introduced above may be somewhat misleading in the sense that the difference between primary particles and aggregated primary particles may often be viewed differently depending on the context of the user. Some people may, for example, consider sweeteners such as sorbitol as primary particles despite the fact that sorbitol should be considered as some sort of aggregated primary particles due to the typical pre-treatment of sorbitol when delivered to a customer. The definition used in the description of the invention is that aggregated primary particles refer to macroscopic particles comprising more or less pretreated primary particles.

When pressure is applied to the particles, the total volume (bulk volume) decreases and the amount of air decreases. Energy is consumed during this process. As the particles become closer to each other during the volume reduction process, a bond may be established between the particles or grains. As energy is released, bond formation is associated with a reduction in the energy of the system. The volume reduction occurs by a variety of mechanisms and depending on the applied pressure and the nature of the particles or grains, different types of bonds may be established between the particles or grains. The first thing that occurs when pressing powders is that the particles rearrange under low compaction pressure to form a more tightly packed structure. Particles with regular shapes appear to rearrange more easily than particles with irregular shapes. With increasing pressure, further rearrangement is prevented, followed by a volume reduction obtained by plastic and elastic deformation and/or breaking of the tablet particles. Brittle particles tend to undergo fracture, i.e., the original particles break into smaller units. Plastic deformation is an irreversible process such that the particle shape is permanently altered, while the particle recovers its original shape after elastic deformation. Obviously, both plastic and elastic deformation can occur when compressing the tablet composition.

By the process of the invention, one-layer tablets or multi-layer tablets, for example two-layer tablets or three-layer tablets, can be formed.

Several studies have been carried out over the years on the type of binding in compressed tablets, typically in the context of pharmaceuticals, and several techniques have been provided for obtaining compressed tablets based on available powders. Such studies are of great interest in what happens when a volume reduction is made and how the final product can be optimized for a given purpose. In order to obtain sufficient strength of the final compressed tablet while maintaining acceptable properties, e.g. with respect to release, several improvements have been made with respect to compressed tablets, e.g. with respect to the addition of binders to the tablet raw materials.

According to the present invention, a tableted tablet composition according to the present invention may comprise from about 0.1% to about 75% by weight of an outer coating applied to the center of the tablet composition. Thus, suitable coating types include: hard, film, and soft coatings of any composition including those currently used in the coating of tableted tablet compositions.

One presently preferred type of outer coating is a hard coating, which term is used in its conventional sense and includes both sugar coatings and sugar-free (or sugar-free) coatings and combinations thereof. The purpose of the hard coating is to obtain a sweet, crunchy layer that is preferred by consumers, and it can protect the tablet composition center for various reasons. In a typical process for providing a protective sugar coating for a center of a tablet composition, the center of the tablet composition is subjected to a continuous process with an aqueous solution of a crystallizable sugar (e.g., sucrose or dextrose) in a suitable coating apparatus, which may contain other functional ingredients, such as fillers, binders, colorants, and the like, depending on the coating stage achieved. In this context, the sugar coating may comprise further functional or active compounds, including flavor compounds and/or active compounds.

In a typical hard coating process, as will be described in detail below, a suspension comprising a crystallizable sugar and/or polyol is applied to the center of the tablet composition and the water it contains is evaporated by purging with air. This cycle must be repeated several times, typically 3 to 80 times, to achieve the desired expansion. The term "swelling" refers to an increase in the weight or thickness of the product as considered at the end of the coating operation compared to the start and related to the final weight or thickness of the coated product. According to the present invention, the coating layer constitutes from about 0.1% to about 75% by weight, such as from about 10% to about 60% by weight, including from about 15% to about 50% by weight, of the elements of the final tablet composition.

In other useful embodiments, the outer coating of the tablet composition element of the present invention is an element that: which is subjected to a film coating process and which therefore comprises one or more film-forming polymeric agents and optionally one or more auxiliary compounds such as plasticizers, pigments and opacifiers. A film coating is a thin polymer-based coating applied to the center of a tablet composition of any of the above forms. The thickness of such a coating is typically 20 μm to 100 μm.

Typically, the film coating is obtained by: the tablet composition center is passed through a spray zone with atomized droplets of coating material in a suitable aqueous or organic solvent carrier, after which the material adhered to the tablet composition center is dried before receiving the next portion of the coating. This cycle is repeated until the coating is complete.

In this context, suitable film coating polymers include edible cellulose derivatives such as cellulose ethers including Methylcellulose (MC), Hydroxyethylcellulose (HEC), Hydroxypropylcellulose (HPC) and Hydroxypropylmethylcellulose (HPMC). Further useful film coating agents are acrylic polymers and copolymers, for example amino methacrylate copolymers or mixtures of cellulose derivatives and acrylic polymers. A particular group of film coating polymers (also referred to as functional polymers) are polymers that: in addition to its film-forming properties, it also confers improved release properties with respect to the active ingredient of the tablet composition formulation. Such release modifying polymers include methacrylate ester copolymers, Ethylcellulose (EC), and enteric polymers designed to withstand the acidic gastric environment. The latter group of polymers includes: cellulose Acetate Phthalate (CAP), polyvinyl acetate phthalate (PVAP), shellac, methacrylic acid copolymers, Cellulose Acetate Trimellitate (CAT) and HPMC. It is to be understood that the outer film coating according to the present invention may comprise any combination of the above film coating polymers.

According to the present invention, the one or more cannabinoids may be selected from a variety of cannabinoids.

"cannabinoids" are a group of compounds including endocannabinoids, phytocannabinoids and those that are neither endocannabinoids nor phytocannabinoids (hereinafter referred to as "synthetic cannabinoids").

An "endocannabinoid" is an endocannabinoid that may have a high affinity ligand for the CB1 receptor and the CB2 receptor.

"phytocannabinoids" are cannabinoids that are naturally derived and may be found in cannabis plants. The phytocannabinoids may be present in isolated or synthetically reproduced extracts (including botanical drug substances).

"synthetic cannabinoids" are those compounds which are capable of interacting with cannabinoid receptors (CB1 and/or CB2) but which are not found endogenously or in cannabis plants. Examples include WIN 55212 and rimonabant (rimonabant).

An "isolated phytocannabinoid" is a phytocannabinoid that is extracted from cannabis plants and purified to the extent that additional components such as secondary and secondary cannabinoids as well as non-cannabinoid moieties are substantially removed.

"synthetic cannabinoids" are cannabinoids produced by chemical synthesis. The term includes modifications thereof, for example, by forming pharmaceutically acceptable salts of the isolated phyto-cannabinoids.

"substantially pure" cannabinoids are defined as cannabinoids present in greater than 95% (w/w) purity. More preferably more than 96% (w/w) to 97% (w/w) to 98% (w/w) to 99% (w/w) and more.

"highly purified" cannabinoids are defined as cannabinoids: other cannabinoid and non-cannabinoid components that have been extracted from cannabis plants and purified to the extent that they are co-extracted with cannabinoids have been substantially removed such that the highly purified cannabinoids are greater than or equal to 95% (w/w) pure.

"plant material" is defined as a plant or plant parts (e.g., bark, wood, leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof) and secretions, and includes material within the definition of "plant raw materials" that falls within the U.S. Department of Health and public Services Food and Drug Administration Drug discovery and Research Center, Draft (Draft) 8/2000, Botanical Drug New Drug discovery guide (guide for Industry pharmaceutical Products, August 2000, US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research).

In the context of the present application, the terms "cannabinoid extract" or "extract of cannabinoids" are used interchangeably to include "botanical drug substances" derived from cannabis plant material. The botanical drug substance is defined in the U.S. department of health and public service food and drug administration drug evaluation and research center, the "guide for research on botanical drug substances" (draft) in month 8, 2000 as: "pharmaceutical substance derived from one or more plants, algae or macroscopic bacteria. It is prepared from plant raw materials by one or more of the following methods: grinding, decocting, squeezing, aqueous extracting, ethanol extracting or other similar method. "botanical drug substances do not include highly purified or chemically modified substances derived from natural sources. Thus, in the case of cannabis, the "botanical drug substance" derived from cannabis plants does not include highly purified pharmacopoeia-grade cannabinoids.

The term "Cannabis plant" includes wild-type Cannabis sativa as well as variants thereof, including chemically modified Cannabis sativa (cannabibis chemovers), Cannabis indica subspecies (Cannabis sativa subspecies indica) (including variants var. indica and var. kafiristanaica), Cannabis indica, Cannabis ruderalis and plants which are the result of genetic crosses, selfs or hybrids thereof (hybrids). The term "cannabis plant material" should accordingly be construed to include plant material derived from one or more cannabis plants. For the avoidance of doubt, it is stated herein that "cannabis plant material" comprises dried cannabis biomass.

Preferably, the one or more cannabinoids are selected from: cannabichromenic acid (CBC), cannabidiol (CBCV), Cannabidiol (CBD), cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabigerol (CBG), cannabigerol propyl variant (CBGV), Cannabigerol (CBL), Cannabinol (CBN), cannabigerol propyl variant (CBNV), dihydrocannabinol (CBO), Tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), Tetrahydrocannabivarinol (THCV) and Tetrahydrocannabidivarin (THCVA). More preferably, the one or more cannabinoids are CBD or THC. This list is not exhaustive, but only the cannabinoids identified in the present application are detailed for reference.

To date, more than 120 different phytocannabinoids have been identified within the scope of the present invention.

Cannabinoids can be divided into different groups as follows: phyto-cannabinoids; (ii) an endocannabinoid; and synthetic cannabinoids.

For purposes of the present invention and whether or not so specifically named herein, cannabinoid receptors can be activated by three major groups of agonist ligands that are lipophilic in nature and classified as follows: endocannabinoids (produced endogenously by mammalian cells); phytocannabinoids (e.g., cannabidiol produced by cannabis); and synthetic cannabinoids (e.g. HU-210).

Phyto-cannabinoids may exist as neutral carboxylic acids or as decarboxylated forms, depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form results in decarboxylation of a majority of the carboxylic acid form.

Phytocannabinoids may also occur as pentyl (5 carbon atoms) or propyl (3 carbon atoms) variants. For example, the phytocannabinoid THC is known to be a CB1 receptor agonist, whereas the propyl variant THCV has been found to be a CB1 receptor antagonist, meaning that it has almost opposite effects.

According to the present invention, examples of phytocannabinoids may be cannabichromene (CBC), cannabichromene acid (CBCV), Cannabidiol (CBD), cannabidiolic acid (CBDA), Cannabidiol (CBDV), Cannabigerol (CBG), cannabigerol propyl variant (CBGV), Cannabichromene (CBL), Cannabinol (CBN), cannabinol propyl variant (CBNV), dihydroxycannabinol (CBO), Tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), Tetrahydrocannabigerol (THCV) and tetrahydrocannabinolic acid (THCVA). More preferably, the one or more cannabinoids are CBD or THC.

The formulation according to the invention may also comprise at least one cannabinoid selected from those disclosed in a. douglas Kinghorn et al, phytonanbindoids, volume 103, chapter 1, pages 1 to 30.

An example of an endocannabinoid is a molecule that activates a cannabinoid receptor in vivo. Examples include 2-arachidonic acid glycerol (2-arachidonyl glycerol, 2AG), 2-arachidonic acid glycerol ether (2-arachidonyl glycerol ether, 2AGE), arachidonic acid dopamine and arachidonic acid ethanolamide (arachidonic acid ethanolamine, anandamide). Structurally related endogenous molecules have been determined to share similar structural features but exhibit little or no activity at the cannabinoid receptor, but are also referred to as endocannabinoids. Examples of these endocannabinoid lipids include 2-acylglycerols, alkyl or alkenyl glycerol ethers, acyl dopamine and N-acyl ethanolamides containing alternative fatty acid or alcohol moieties, as well as other fatty acid amides containing different head groups. These include N-acyl serines as well as many other N-acylated amino acids. Examples of cannabinoid receptor agonists are neuromodulatory substances and influence short-term memory, appetite, stress response, anxiety, immune function and analgesia.

In one embodiment, the cannabinoid is Palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the class of nuclear factor agonists.

Synthetic cannabinoids include a variety of different chemical classes: (ii) a cannabinoid that is structurally related to THC; THC independent cannabinoids, e.g. (cannabinoids), including aminoalkyl indoles, 1, 5-diaryl pyrazoles, quinolines and aryl sulfonamides; and the dodecanoic acid analogues associated with endocannabinoids. All or any of these cannabinoids may be used in the present invention.

Preferably, the formulation comprises one or two primary cannabinoids, preferably selected from Cannabidiol (CBD) or Cannabidivarin (CBDV), Tetrahydrocannabinol (THC), Tetrahydrocannabivarin (THCV), tetrahydrocannabinolic acid (THCA), Cannabigerol (CBG) and cannabidiolic acid (CBDA) or a combination thereof. Preferably the formulation comprises cannabidiol and/or tetrahydrocannabinol.

Preferably, the tablet composition of the present invention may be used for the treatment or alleviation of pain, epilepsy, cancer, nausea, inflammation, congenital disorders, neurological disorders, oral infections, dental pain, sleep apnea, psychiatric disorders, gastrointestinal disorders, inflammatory bowel disease, appetite reduction, diabetes and fibromyalgia.

In another aspect of the invention, the oral cannabinoid formulation is useful for treating a condition requiring administration of a neuroprotective agent or an anticonvulsant drug.

The oral cannabinoid formulation can be used to treat seizures.

The oral cannabinoid formulations can be used to treat delaviru syndrome (Dravet syndrome), Lennox Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome (West syndrome), infantile spasms, refractory infantile spasms, tuberous sclerosis complex, brain tumors, neuropathic pain, cannabis use disorders, post-traumatic stress disorders, anxiety, early psychosis, alzheimer's disease, and autism.

The following non-limiting examples illustrate different variations of the invention. These examples are intended to illustrate the inventive concept; the embodiments mentioned are therefore not to be understood as exhaustive for the invention. In particular, CBD is used as an exemplary compound, but may also be an additional cannabinoid.

Examples

Example 1

Has 50% of CBD extract

The CBD extract with a CBD content of 50% provided by CBDepot (lot No. CSFF2018/5) was preheated to about 60 ℃ for about 0.5 to 1 hour until the extract was in liquid form. In addition to cannabinoids, the extract also has a content of fatty acids, glycerol, waxes, terpenes and flavonoids. After the pre-heating process, the extract is applied as a thin layer on top of the one or more sugar alcohol particles. After mixing until the CBD is uniformly distributed in the one or more sugar alcohol particles, the mixture is sieved through a 1400 micron sieve.

Example 1A

CBD extract not premixed with sugar alcohol granules 50%

The CBD extract with a CBD content of 50% provided by CBDepot (lot No. CSFF2018/5) was preheated to about 60 ℃ for about 0.5 to 1 hour until the extract was in liquid form. In addition to cannabinoids, the extract also has a content of fatty acids, glycerol, waxes, terpenes and flavonoids. In this example, the extract was not applied as a premix with the sugar alcohol particles.

Example 2

Has 10% of CBD extract

CBD extract with CBD content of 10% (batch MH131B Gold) supplied by Medical hemap was preheated to about 60 ℃ for about 0.5 to 1 hour until the extract was in liquid form. In addition to cannabinoids, the extract also has a content of fatty acids, glycerol, waxes, terpenes and flavonoids. After the pre-heating process, the extract is applied as a thin layer on top of the one or more sugar alcohol particles. After mixing until the CBD is uniformly distributed in the one or more sugar alcohol particles, the mixture is sieved through a 1400 micron sieve.

Example 3

Compositions having CBD isolates with solvent

CBD isolate from cannabis plant tissue (phytocannabinoid) (batch MH18212) with a CBD content of 98.5% provided by Medical hemap was dissolved in 96% ethanol solution. The ratio of CBD isolate to ethanol was 1: 1. Once the CBD is dissolved in ethanol, the CBD isolate is applied as a premix with one or more sugar alcohol particles. After mixing until the CBD is uniformly distributed in the one or more sugar alcohol particles, the mixture is sieved through a 1400 micron sieve.

Example 4

Compositions with solvent-free CBD isolates

CBD isolate of cannabis plant tissue (phytocannabinoid) with a CBD content of 98.5% provided by Medical hemap (batch No. MH18212) was added as a free powder and mixed with one or more sugar alcohol particles. After mixing until the CBD is uniformly distributed in the one or more sugar alcohol particles, the mixture is sieved through a 1400 micron sieve.

Example 4A

CBD isolate free of solvent and not premixed with sugar alcohol particles

CBD isolate from cannabis plant tissue (phytocannabinoid) with a CBD content of 98.5% provided by Medical hemap (batch No. MH18212) was added as a free powder. In this example, the CBD powder was not applied as a premix with the sugar alcohol particles.

Example 4B

Water-soluble CBD not premixed with sugar alcohol particles

Water-soluble CBD, i.e. water-soluble carrier material loaded with 20% CBD (micro-encapsulation grade from hema & Me), was added as free powder. In this example, the CBD powder was not applied as a premix with the sugar alcohol particles.

Example 4C

Palmitoylethanolamide (PEA) not premixed with sugar alcohol granules

Palmitoylethanolamide (PEA) isolate with a PEA content of 98% (OptiPEA WSL from regreo APS) was added as a free powder. In this example, the cannabinoid powder was not applied as a premix with the sugar alcohol particles.

Example 5

Composition comprising microcrystalline cellulose

The CBD extract with a CBD content of 50% provided by CBDepot (lot No. CSFF2018/5) was preheated to about 60 ℃ for about 0.5 to 1 hour until the extract was in liquid form. In addition to cannabinoids, the extract also has a content of fatty acids, glycerol, waxes, terpenes and flavonoids. After the preheating process, the extract is applied as a thin layer on microcrystalline cellulose (MCC). Mixing was performed until the CBD was evenly distributed in the MCC. Optionally, the CBD-MCC pre-mix may be further mixed with one or more sugar alcohol particles. The mixture was sieved through a 1400 micron sieve.

Example 6

Components comprising silica support

The CBD extract with a CBD content of 50% provided by CBDepot (lot No. CSFF2018/5) was preheated to about 60 ℃ for about 0.5 to 1 hour until the extract was in liquid form. In addition to cannabinoids, the extract also has a content of fatty acids, glycerol, waxes, terpenes and flavonoids. After the preheating process, the extract is applied as a thin layer on silicon dioxide (SiO)₂) The above. Mixing was carried out until the CBD was uniformly distributed on the SiO₂In (1). Optionally, CBD-SiO may be incorporated₂The pre-mix is further mixed with one or more sugar alcohol particles. The mixture was sieved through a 1400 micron sieve.

Example 7

Composition comprising a magnesium-aluminium-metasilicate of ultra-porous silica

The CBD extract with a CBD content of 50% provided by CBDepot (lot No. CSFF2018/5) was preheated to about 60 ℃ for about 0.5 to 1 hour until the extract was in liquid form. In addition to cannabinoids, the extract also has a content of fatty acids, glycerol, waxes, terpenes and flavonoids. After the preheating process, the extract is applied as a thin layer on the nanoporous silica magnesium-aluminum-metasilicate. Mixing was performed until the CBD was uniformly distributed in the nanoporous silica magnesium-aluminum-metasilicate. Optionally, the CBD-nanoporous silica magnesium-aluminum-metasilicate pre-mixture may be further mixed with one or more sugar alcohol particles. The mixture was sieved through a 1400 micron sieve.

Example 8

Preparation of cannabinoid component with emulsifier and oil

The solutions of Labrafil M1944 CS and Maisine CC (1:1) were mixed. The CBD isolate from example 3 or CBD extract from example 1 was added to the solution using a Vortex mixer and dissolved in the solution to obtain a 33% CBD solution. The solution with CBD is applied as a premix with one or more sugar alcohols. After mixing until the CBD is uniformly distributed in the one or more sugar alcohols, the mixture is sieved through a 1400 micron sieve.

Example 9

Preparation of cannabinoid component with emulsifier, oil and co-solvent

Mix 60% Labrafac Lipophile WL1349 and a solution of 25% Labrasol and 15% propylene glycol. The CBD isolate from example 3 or CBD extract from example 1 was added to the solution using a Vortex mixer and dissolved in the solution to obtain a 33% CBD solution. The solution with CBD is applied as a premix with one or more sugar alcohols. After mixing until the CBD is uniformly distributed in the one or more sugar alcohols, the mixture is sieved through a 1400 micron sieve.

Example 10

Preparation of cannabinoid component with solid solubilizer

Gelucire 50/13 was melted at about 60 ℃ and the CBD isolate from example 3 or CBD extract from example 1 was added to and dissolved in the melted solution using a Vortex mixer to obtain a 50% CBD solution. The solution with CBD is applied as a premix with one or more sugar alcohols. After mixing until the CBD is uniformly distributed in the one or more sugar alcohols, the mixture is sieved through a 1400 micron sieve.

Example 11

Preparation of cannabinoid component with emulsifier and co-solvent

The CBD extract from example 1 was preheated at 60 ℃ until it was in liquid form, and then dissolved in propylene glycol. Labrasol ALF was then added using a Vortex mixer to obtain a 17% CBD solution. The solution with CBD is applied as a premix with one or more sugar alcohols. After mixing until the CBD is uniformly distributed in the one or more sugar alcohols, the mixture is sieved through a 1400 micron sieve.

Example 12

Preparation of cannabinoid component with amphiphilic Polymer Carrier

The CBD extract from example 1 was preheated at 60 ℃ until it was in liquid form. After the pre-heating process, the extract was applied as a premix with Soluplus (graft copolymer supplied by BASF) and mixed until the premix was homogeneous, to obtain a 12.5% CBD premix. The premix is then mixed with one or more sugar alcohols. After mixing until the CBD is uniformly distributed in the one or more sugar alcohols, the mixture is sieved through a 1400 micron sieve.

Example 13

Preparation of cannabinoid component with dextrin and emulsifier

The CBD isolate from example 3 was added to polysorbate 80 and dissolved in polysorbate 80 to obtain a 10% CBD solution. The 10% CBD solution was slowly added and mixed into the solution with 4% cyclodextrin to form CBD-cyclodextrin complexes. The water is removed and the complex is then applied as a premix with one or more sugar alcohols. After mixing until the CBD-cyclodextrin complex is uniformly distributed in the one or more sugar alcohols, the mixture is sieved through a 1400 micron sieve.

Example 14

A: preparation of rapidly disintegrating tablets (FDT) with one layer

The cannabinoid component and FDT component from any of examples 1 to 13 were blended and optionally loaded with processing aids in a mixing vessel at about 7 to 9rpm to improve the free-flowing properties of the granules and avoid stickiness.

In the first step, half of the FDT component is added to the mixing vessel. The High Intensity Sweetener (HIS), flavor and cannabinoid components are added to the container, followed by the addition of the other half of the FDT component. Optionally, a premix of cannabinoids is applied. The mixture was rolled at 7 to 9rpm for 10 minutes. The processing aid was added and the mixture was allowed to roll at 7 to 9rpm for an additional 2 minutes. Thereafter, the mixture is ready for tableting.

The FDT component comprises sugar alcohol granules, such as mannitol granules. The mannitol applied according to the examples was mannitol 200SD with different average particle sizes available from Roquette. Isomalt applied according to the examples is GalenIQ 720 available from Beneo. The microcrystalline cellulose applied according to the examples was Avicel PH-105 available from FMC. The FDT component also comprises one or more disintegrants. Herein, crospovidone is applied in a grade available as Kollidon CL-SF available from BASF.

The mixture was then sent to a standard tablet press (3090i, available from Fette GmbH, germany) comprising a metering device (P3200C, available from Fette GmbH) and compressed into FDT tablets. The tablets were compressed using a compression pressure of 15kN to 20 kN. There were 75 punches on the rotor and the rotor speed used was 11 rpm. The weight of an individual tablet is about 150 mg. Unless otherwise stated, the CBD content in the FDT tablets was 10 mg. Punch used (punch): 10.00mm, round, dimple, D tool (D tool).

B: preparation of tablets with two layers

A laminate sheet prepared in the same manner as in example 14A was taken as a first layer, after which the layer of example 14A (herein denoted as a second layer) was laminated on top of this first prepared layer. The ratio of the components is different in the first layer. The weight ratio of the two layers was 70 to 30 (first layer to second layer). Here, layer 1 is a lozenge layer and layer 2 is an FDT layer. The weight of the individual tablets was about 500mg, with layer 1 being 350mg and layer 2 being 150 mg. Unless otherwise stated, the CBD content in the tablets amounted to 10 mg. The punch used was: 10.00mm, round, dimple, D-tool. Layer 1 is then compressed under a compressive force of about 3kN, after which layer 2 is fused to layer 1 by the compressive force under a compressive force of 20 kN. The tablet press was adjusted by adjusting the fill depth and compression force such that the weight and hardness of the tablets met the acceptance criteria. A pre-compression force may be included to avoid capping.

Example 15

Compositions of cannabinoid tablets with different CBD sources

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet.

Table 1: ensuring that the CBD is completely mixed into the premix. CBD isolate has been added loosely to the premix-not dissolved in ethanol-according to the procedure in example 4 (deviating from the procedure in example 3).

Example 16

Compositions of cannabinoid tablets with premixes of different ratios

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet.

Table 2: ensuring that the CBD is completely mixed into the premix.

Example 17

Composition of cannabinoid tablets with different sugar alcohol particles

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet.

Table 3: ensuring that the CBD is completely mixed into the premix.

Example 18

Compositions of cannabinoid tablets with different disintegrants

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet.

Table 4: ensuring that the CBD is completely mixed into the premix.

Example 19

Composition of cannabinoid tablets with microcrystalline cellulose in premixture

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet.

Table 5: ensuring that the CBD is completely mixed into the premix. CBD isolate has been added loosely to the premix-not dissolved in ethanol-according to the procedure in example 4 (deviating from the procedure in example 3).

Example 20

Compositions of cannabinoid tablets with different carriers

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet.

Table 6: ensuring that the CBD is completely mixed into the premix. CBD isolate has been added loosely to the premix-not dissolved in ethanol-according to the procedure in example 4 (deviating from the procedure in example 3). Ultra-porous carrier magnesium-aluminum-metasilicate

Example 21

Compositions of cannabinoid tablets with varying levels of disintegrant

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet.

Table 7: ensuring that the CBD is completely mixed into the premix. CBD isolate has been added loosely to the premix-not dissolved in ethanol-according to the procedure in example 4 (deviating from the procedure in example 3).

Example 22

Compositions of cannabinoid tablets with different self-emulsifying drug delivery system (SEDDS) components

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet.

Table 8: ensuring that the CBD is completely mixed into the premix.

Example 23

Preparation of rapidly disintegrating tablets

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In these examples, the following conditions were applied. The punch used was: 7.00mm, round, dimple, type B tool. Tablet weight: 100.0 mg. In these examples, the amounts of the various ingredients are given as mg.

Table 9: a rapidly disintegrating tablet composition having CBD isolate. The amounts are given in mg. FDT ═ rapidly disintegrating tablets.

Example 24

Compositions of cannabinoids with ready-to-use disintegrants

Cannabinoid tablets were formulated based on the procedure in example 14A using the formulation outlined in the examples below. In these examples, the following conditions were applied. The punch used was: 7.00mm, round, dimple, type B tool. Tablet weight: 100.0 mg. In these examples, the amounts of the various ingredients are given as mg.

Another way to prepare fast disintegrating tablets would be to use a ready-to-use system. In this example, five cannabinoid-free rapidly disintegrating tablets (fdt (g) through fdt (k)) were prepared with a ready-to-use system in the formulation as outlined in table 10.

Table 10: rapidly disintegrating tablet compositions with different ready-to-use systems. The amounts are given in mg. FDT ═ rapidly disintegrating tablets.

Additionally, five rapidly disintegrating tablets with cannabinoid (fdt (l) through fdt (p)) were prepared with the ready-to-use system in the formulation as outlined in table 11.

Table 11: rapidly disintegrating tablet compositions with different ready-to-use systems and CBD isolates. The amounts are given in mg. FDT ═ rapidly disintegrating tablets.

As outlined in table 12, four additional rapidly disintegrating tablets with cannabinoid (FDT (1) to FDT (4)) were prepared with different amounts of MCC (microcrystalline cellulose) as filler.

	FDT(1)	FDT(2)	FDT(3)	FDT(4)
					CBD	10.0	10.0	10.0	10.0
Microcrystalline cellulose (MCC)	0.0	5.0	10.0	20.0
					Mannitol	77.7	72.7	67.7	57.7
Crospovidone	5.0	5.0	5.0	5.0
					Mint	4.4	4.4	4.4	4.4
Menthol	1.5	1.5	1.5	1.5
					Sucralose	0.4	0.4	0.4	0.4
Magnesium stearate	1.0	1.0	1.0	1.0
					Total of	100.0	100.0	100.0	100.0

Table 12: rapidly disintegrating tablet compositions with varying amounts of MCC and CBD as isolates. The amounts are given in mg. FDT ═ rapidly disintegrating tablets.

As summarized in table 13, four additional rapidly disintegrating tablets with cannabinoid (FDT (5) to FDT (8)) were prepared with different amounts of disintegrant.

	FDT(5)	FDT(6)	FDT(7)	FDT(8)
					CBD	10.0	10.0	10.0	10.0
Mannitol	39.7	37.2	39.7	29.7
					Microcrystalline cellulose (MCC)	43	43	43	43
Crospovidone	0.0	2.5	5.0	10.0
					Mint	4.4	4.4	4.4	4.4
Menthol	1.5	1.5	1.5	1.5
					Sucralose	0.4	0.4	0.4	0.4
Magnesium stearate	1.0	1.0	1.0	1.0
					Total of	100.0	100.0	100.0	100.0

Table 13: rapidly disintegrating tablet compositions with varying amounts of disintegrant and CBD isolate. The amounts are given in mg. FDT ═ rapidly disintegrating tablets.

As summarized in table 14, three rapidly disintegrating tablets with cannabinoid (FDT (9) to FDT (11)) were prepared with different types of lubricants.

	FDT(9)	FDT(10)	FDT(11)
				CBD	10.0	10.0	10.0
Microcrystalline cellulose (MCC)	5.0	5.0	5.0
				Mannitol	76.6	75.6	75.6
Crospovidone	5.0	5.0	5.0
				Eucalyptus hol flavoring agent	2.0	2.0	2.0
Sucralose	0.4	0.4	0.4
				Magnesium stearate	1.0	-	-
Stearyl fumarate sodium salt	-	2.0	-
				Compritol HD5	-	-	2.0
Total of	100.0	100.0	100.0

Table 14: rapidly disintegrating tablet compositions with different types of lubricants and CBD isolates. The amounts are given in mg. FDT ═ rapidly disintegrating tablets.

As summarized in table 15, three rapidly disintegrating tablets with cannabinoid FDT (12) to FDT (14) were prepared.

In this example, the following conditions were applied. The punch used was: 7.00mm, round, dimple, type B tool. Tablet weight: 75.0 mg.

	FDT(12)	FDT(13)	FDT(14)
				SmartEx QD 50	53.0	58.0	58.0
CBD	10.0	10.0	10.0
				Anhydrous sodium carbonate	5.0	0.0	5.0
Crospovidone	5.0	5.0	0.0
				Mint powder	0.4	0.4	0.4
Sucralose	0.4	0.4	0.4
				Silicon dioxide (Aerosil 200)	0.2	0.2	0.2
Magnesium stearate	1.0	1.0	1.0
				Total of	75.0	75.0	75.0

Table 15: a rapidly disintegrating tablet composition having CBD isolate. The amounts are given in mg. FDT ═ rapidly disintegrating tablets. FDT (13) was prepared similarly to FDT (12) but without buffer. FDT (14) is prepared similarly to FDT (12) but without a disintegrant.

FDT (12) to FDT (13) are pressed to a hardness of 15N to 20N. FDT (14) is pressed to a hardness of 25N to 35N.

Example 25

Disintegration of tablets

The in vitro disintegration of the rapidly disintegrating tablets of examples 15 to 24 was carried out according to the european pharmacopoeia 9.0, section 2.9.1, "disintegration of tablets and capsules". The results of example 23 are summarized in table 16. The minimum and maximum values of the measured disintegration are given and this is more or less a function of the hardness.

Table 16: in vitro disintegration, hardness, friability. Time is given in seconds.

The above table should be construed as described in the following examples. When observing for example fdt (a), a minimum mean disintegration time of 21 seconds corresponds to a tablet that is compressed just hard enough to obtain a cohesive tablet with a minimum mean hardness of 14N and a friability of 0.3%. Similarly, a maximum average disintegration time of 24 seconds corresponds to another tablet that is compressed to be harder so as to have a maximum average hardness of 63N. In this way, tablets with an average friability of fdt (a) of 0.0% correspond to tablets with an average hardness of 63N. In other words, in table 4 fdt (a) refers to two different tablets compressed at two different pressures, in relation to what is shown above. That is, each row corresponds to two different tablets, one with respect to the minimum of disintegration time and hardness and the maximum of friability, the other with respect to the maximum of disintegration time and hardness and the minimum of friability.

The results of example 24 are summarized in table 17.

Table 17: in vitro disintegration, hardness, friability. Time is given in seconds.

The above table should be interpreted as described in the examples below in table 16.

It can be seen that the in vitro disintegration can vary widely between the disclosed rapidly disintegrating tablets.

In vitro tests were also repeated for some of the ready-to-use systems in FDT (l) to FDT (p).

In vitro disintegration is a rapid method of determining the time and mechanism of tablet performance. More preferably, or in combination, in vivo disintegration is measured. The in vivo disintegration time is the value at which the tablet actually disintegrates under the tongue. Tables 18 and 19 highlight the results of in vivo disintegration.

Table 18: can be disintegrated in vivo. Time is given in seconds.

Table 19: can be disintegrated in vivo. Time is given in seconds.

Tables 18 to 19 above should be construed as described in the examples below in table 16.

In vivo tests were also repeated for some of the ready-to-use systems in FDT (l) to FDT (p).

Table 19A: can be disintegrated in vivo. Time is given in seconds.

The above table should be interpreted as described in the examples below in table 16.

As recognized for the in vitro disintegration results above, the rate of in vivo disintegration can vary between disclosed batches. The disintegration time should be completed within 60 seconds from the start of disintegration, or preferably faster.

Example 26

Composition of cannabinoid tablet having two layers

Cannabinoid tablets were formulated based on the procedure in example 14B using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet layer.

Table 20: ensuring that the CBD is completely mixed into the premix.

Example 27

Compositions of cannabinoid bilayer tablets with different levels of CBD

Cannabinoid tablets were formulated based on the procedure in example 14B using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet layer.

TABLE 21 compositions of the first and second layers.

Example 28

Compositions of cannabinoid bilayer tablets with different levels of superdisintegrant

Cannabinoid tablets were formulated based on the procedure in example 14B using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet layer.

Table 22: composition of the first layer and the second layer. The super disintegrant is crospovidone.

Example 29

Composition of cannabinoid two-layer tablet with ready-to-use disintegrant

Cannabinoid tablets were formulated based on the procedure in example 14B using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet layer.

Table 23: composition of the first layer and the second layer. The content of starch disintegrant was based on the content of starch in Pearlitol Flash.

Example 30

Composition of cannabinoid two-layer tablet having CBD in two layers

Cannabinoid tablets were formulated based on the procedure in example 14B using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet layer.

Table 24: composition of the first layer and the second layer.

Example 31A

Composition of cannabinoid bilayer tablet with different sugar alcohols

Cannabinoid tablets were formulated based on the procedure in example 14B using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet layer.

Table 25: composition of the first layer and the second layer.

Example 31B

Composition of cannabinoid bilayer tablet with different sugar alcohols

Cannabinoid tablets were formulated based on the procedure in example 14B using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet layer. Tablet numbers 41 to 42 are 400mg tablets each made with 300mg of the first layer and 100mg of the second layer. Tablet numbers 43 to 48 are 500mg tablets each made with 350mg of the first layer and 150mg of the second layer.

Table 26: composition of the first layer and the second layer.

Example 31C

Composition of two-layered tablets of cannabinoids with different cannabinoid sources

Cannabinoid tablets were formulated based on the procedure in example 14B using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet layer.

Table 27: composition of the first layer and the second layer. CBD is adsorbed on the carrier in a weight ratio of 1:2

Example 31D

Composition of two-layered tablets of cannabinoids with different active ingredients, terpenes and antioxidants

Cannabinoid tablets were formulated based on the procedure in example 14B using the formulation outlined in the examples below. In all tablet examples, the amounts of the various ingredients are given as weight% of the tablet layer.

Table 27A: ensuring that the active ingredient is uniformly distributed throughout the final formulation blend. Added according to the procedure in example 4B. Added according to the procedure in example 1. Added according to the procedure in example 4C. The dosage of PEA is 50mg PEA/tablet

Example 32

Evaluation of two-layer tablets-first layer of tablet numbers 43, 47 and 48

Tablet numbers 43, 47 and 48 were each made in three variants, in which the pressures applied for compressing the first layer were 10kN, 20kN and 30kN, respectively (single punch set with a punch diameter of 10.0 mm). For each of these variants, five tablets were made. For each of the variants of tablets 43, 47 and 48, the breaking point test, the friability test and the dissolution time measurement were carried out on the first layer. For the measurement of the breaking point, PTB 311 from Pharma Test was used.

The brittleness test involves evaluating the number of fractured layers produced. When all five are complete, a "pass" grade is assigned, and one or more breaker layers are shown by the number of breaker layers. Alternatively, friability may be used as a measure of friability.

To test dissolution time, the following method was used. 15mL of 0.02M potassium dihydrogen phosphate-buffer (pH adjusted to 7.4) was added to 50mL of water in a measuring tube with a screw cap. The tablets were inserted into the measuring tube and the screw cap was tightened. The measurement tube was fixed horizontally. The measurement tube was vibrated at about 110RPM so that the tablets could move back and forth in the measurement tube. The measuring tube is vibrated until the tablet in question or its module is completely dissolved and the vibration time is recorded as the dissolution time.

Table 28: the friability test indicates the number of tablets that broke during the test, or "pass" when no tablets broke.

As can be seen from table 28, the breaking point test reflects that tablet number 47 with a first layer based on sorbitol as sugar alcohol gives a higher breaking point than tablet number 43 with a first layer based on isomalt as sugar alcohol. Tablet number 43 shows that the variant compressed with 30kN actually has a lower breaking point than the variant compressed with 20kN, indicating that the 30kN compression force will be too high, and that the direct compressibility of the sugar alcohol (isomalt) is impaired.

Furthermore, it was observed that in the brittleness test all tested layers were evaluated as passing, meaning that five of the variants were not evaluated as brittle or broken during manufacturing.

Furthermore, the dissolution time test showed that sorbitol-based tablet number 47 generally dissolved faster than isomalt-based tablet number 43. In addition, higher compaction forces result in longer dissolution times.

Finally, tablet number 48 is compared to tablet number 43. Tablet number 48 is somewhat similar to tablet number 43, but additionally comprises xanthan gum. As seen from table 28, the addition of xanthan gum did not significantly affect the breaking point test or friability test, however, the dissolution time increased significantly from about 9 to 10 minutes for tablet No. 43 to about 12 to 16 minutes for tablet No. 48, indicating the effect of xanthan gum to retard dissolution and thus retard its constituent release such as sugar alcohols, flavors, nicotine (if any), and the like. While obtaining the above, no impairment of the masking effect of the first layer was observed.

Example 33

Evaluation of two-layer tablets-second layer of tablet No. 43 to 46

Each of tablet numbers 43 to 46 was manufactured in three variants, wherein the pressure applied for compressing the first layer was 10kN, 20kN and 30kN, respectively. For each of these variants, five tablets were made. For each variant of tablets 43 to 46, the breaking point test, the friability test and the dissolution time measurement were carried out on the second layer.

Table 29: the friability test indicates the number of tablets that broke during the test, or "pass" when no tablets broke.

First, looking at tablet numbers 43 to 45, table 29 shows that the breaking point of the second layer of the produced tablets generally increases as the compression force increases from 10kN to 30 kN.

However, tablets also show that friability can be a problem. Note that the performance of tablet number 43 was quite good, with only 1 tablet breaking during the test.

Table 29 also shows that there is a tradeoff between applying sufficient compressive force to obtain a non-brittle second layer, but increasing the compressive force also affects dissolution time.

Further, it was noted that the use of the disintegrant (tablet numbers 44 to 45) in the second layer leads to a reduction in dissolution time as compared to the absence of the disintegrant (tablet number 43) in the second layer, and also that increasing the amount of the disintegrant as in tablet number 45 leads to a further reduction in dissolution time as compared to tablet number 44.

Considering also tablet number 46, it is noted that the measured dissolution time is rather short while producing a very brittle second module. Note that when the particle size distributions of mannitol used in tablet nos. 43 to 44 and 46, Pearlitol Flash used in tablet nos. 44 to 45, and erythritol used in tablet No. 46 were evaluated, Pearlitol Flash exhibited the smallest particle size followed by mannitol, while the applied erythritol (non-DC grade erythritol) had significantly larger particles. The use of larger particles of non-DC grade erythritol allows for relatively fast dissolution times.

Example 34

Evaluation of two-layer tablets-tablet number 45 Whole tablet

Tablet number 45 was made with the compression force indicated in table 30.

Table 30: the whole two-layer tablet.

Table 30 shows that layer 1 can be compressed with a higher compression force than applied to layer 2, while still obtaining a less brittle tablet. It is noted, however, that decapping of layer 2 from layer 1 may be avoided if the compressive force applied to layer 1 is not too high. Furthermore, the measured dissolution time is entirely acceptable, in particular because the second layer dissolves in 1 minute, whereas the first layers both require more than 5 minutes to dissolve.

Example 35

In vivo Release test

The sample tablets were tested in a test panel of 8 test persons. At least 30 minutes before starting any test, the subject had no access to food and water. The human subject is a healthy person who is arranged on an objective basis according to specified requirements. The CBD content of the remaining tablet residue was measured after 0 min, 0.5 min, 1 min, 2 min, 3 min, 5 min and 10 min. For each of the 8 test persons, the tablets were subjected to 3 measurements, giving a total of 24 measurements for each sample. The average of 24 measurements was calculated and the wt% release was calculated based on the original content of CBD in the sample. If still present, the CBD content of the remaining tablet residue is measured.

The tablets were weighed and placed in the mouth between the tongue and the palate. Suck and invert the tablets every 0.5 minutes. Once the desired test time (0.5 min, 1 min, 2 min, 3 min, 5 min and 10 min) was reached, the tablets were removed and weighed directly in a measuring cup for analysis of API content. In vivo dissolution profiles were obtained by analyzing the API content in the tablets at different dissolution times.

Example 36

In vitro Release test

The sample tablets were tested. The CBD content of the remaining tablet residue was measured after 0 min, 0.5 min, 1 min, 2 min, 3 min, 5 min and 10 min. The tablets were subjected to three measurements. The average of the measurements was calculated and the wt% release was calculated based on the original content of CBD in the sample. If still present, the CBD content of the remaining tablet residue is measured.

The tablets were weighed. Then 25ml of phosphate buffer was added to a 50ml measuring tube with a screw cap. Tablets were added to the tube. The tube is fixed horizontally on a shaking table. After shaking, the tablets were analyzed for API content. An in vitro curve was obtained by analyzing the API content in the tablets at different dissolution times.

Example 37

CBD delivery to oral mucosa

In a test panel of 8 test persons, the samples were sucked for 1 minute. At least 30 minutes before starting any test, the subject had no access to food and water. The subject is not allowed to swallow during this step. The tablets were weighed and placed in the mouth between the tongue and the palate. Suck and invert the tablet every 10 seconds. After one minute, saliva is obtained from the test person and collected in a container for later analysis. In the 2 minute release test, the same procedure was followed up to 2 minutes, with the last sample collected and added to the same container for aggregation analysis. The human subject is a healthy person who is arranged on an objective basis according to specified requirements. The pooled saliva samples were collected after 2 minutes and the CBD content of the saliva was measured. The CBD content in the remaining residue was also measured. The residue (if still present) was placed in a flask, weighed and analyzed. For each of the 8 test persons, the residue (if still present) and saliva were subjected to 3 measurements, giving a total of 24 measurements for each sample. The average of 24 measurements was calculated and the wt% release was calculated. By comparing the amount of CBD in the residue with the amount of CBD in saliva, the amount of CBD delivered to the oral mucosa can be assessed.

Example 38

Sensory evaluation test set-up

In addition to in vivo or in vitro release tests, sensory tests were also performed to reveal very important features and characteristics of the tablets. These sensory parameters are important as indicators of the structure of the tablet composition. The structure is the basic guideline as to how a tablet is similar to the structure of a comparative tablet (which is set as a standard in the test series), i.e. tablets are compared to each other in a test series of preferably 5 samples. The test setup consisted of 8 human subjects in the test panel. All subjects were healthy individuals scheduled on an objective basis according to the specified requirements. Sensory analysis was performed according to ISO4121-2003 under test conditions in compliance with ISO 8589. The results are the average of the results for 8 individuals.

The test person gives a rating from "+" to "++++", where "+" is poor and "++++" is excellent, i.e. "+++++" means that the tablet is excellent compared to the standard, "+++++++" means that the tablet is comparable to the standard and "+" means that the tablet is very poor compared to the standard. "0" means not tested.

Four different parameters were tested in the test panel:

degree of friability

Flavor (I) and flavor (II)

Sweet taste

Abnormal features

"texture" -the overall impression of the tablet when placed in the mouth with respect to elements such as hardness, roughness and smoothness.

"friability" -the impression of a tablet when placed in the mouth and sucking begins. For example, very hard and sticky structures give very low grades, and very brittle structures also give very low grades.

"flavour" -the overall impression of the tablet as to flavour during sucking. For example, a very low flavour experience gives a very low rating, and a too high flavour experience, which is not commensurate with the standard, also gives a very low rating.

"sweetness" — the overall impression of the taste of a tablet with respect to sweetness during sucking. For example, if the sweetness drops rapidly, a very low grade is given, and if the sweetness is too high to give an uncomfortable feeling, a very low grade is also given.

"abnormal characteristic" -the overall impression of abnormal characteristics from one or more cannabinoids in a composition during sucking. For example, a low rating is given if an abnormal feature is experienced in the throat (grassy, bitter, throat irritation), and a low rating is given if other unpleasant sensations are experienced.

Example 39

Sensory evaluation of cannabinoid two-layer tablet according to example 14B

Tablet formulation	Texture of	Flavor (I) and flavor (II)	Sweet taste	Abnormal features
					41	+++	+++	++++	+++
42	+++	+++	++++	+++
					43	+++	++++	++++	++++
44	++	++++	++++	++++
					45	++	++	+++	++++
46	+++	+++	+++	++++
					47	++++	+++	++++	++++
48	++++	+++	+++	++++

Table 31: sensory test results according to the test setup of example 38.