阅读说明：本技术 一种帕博西林组合物及其制备方法 (Pabocillin composition and preparation method thereof ) 是由 张席妮 潘卡基˙莱克斯米坎特˙英格 熊志刚 陆乾 于 2017-04-21 设计创作，主要内容包括：本发明公开了一种提高了溶解度和生物利用度的帕博西林组合物,其制备方法以及使用该组合物治疗癌症的方法。(the present invention discloses a pabocillin composition with improved solubility and bioavailability, a preparation method thereof and a method for treating cancer using the composition.)

1. A palbocillin composition is characterized by comprising co-ground palbocillin and at least one hydrophilic auxiliary material.

2. the palbocillin composition of claim 1, wherein 85% or more of the palbocillin composition is soluble in 900ml of 0.1n hydrochloric acid within 30 minutes.

3. the palbocillin composition of claim 1, wherein the hydrophilic excipient is one or more of a monosaccharide, a polysaccharide, and a disaccharide.

4. The palbocillin composition of claim 1, wherein at least one of the hydrophilic excipients is starch.

5. The palbocillin composition of claim 1, wherein at least one of the hydrophilic excipients is pregelatinized starch.

6. the palbocillin composition of claim 1, wherein the hydrophilic excipient is one or more of starch, calcium carbonate, cellulose, mannitol, sorbitol, povidone, silicic acid, β -cyclodextrin, polyethylene glycol.

7. The palbocillin composition as claimed in claim 1, wherein the weight ratio of the palbocillin to the hydrophilic excipients is 1:10-10: 1.

8. The palbocillin composition as claimed in claim 1, wherein the weight ratio of the palbocillin to the hydrophilic excipients is 1:5-5: 1.

9. The palbocillin composition as claimed in claim 1, wherein the weight ratio of palbocillin to hydrophilic excipients is 1:3-1: 1.

10. The palbocillin composition of claim 1, wherein the weight ratio of palbocillin to hydrophilic excipients is 1: 2.

11. The palbocillin composition as claimed in claim 1, wherein the particle size of the palbocillin composition is: d (10) is less than or equal to 50 mu m, d (50) is less than or equal to 200 mu m, and d (90) is less than or equal to 400 mu m.

12. The palbocillin composition as claimed in claim 1, wherein the particle size of the palbocillin composition is: d (10) is less than or equal to 25 mu m, d (50) is less than or equal to 100 mu m, and d (90) is less than or equal to 200 mu m.

13. The palbocillin composition as claimed in claim 1, wherein the particle size of the palbocillin composition is: d (10) is less than or equal to 15 mu m, d (50) is less than or equal to 50 mu m, and d (90) is less than or equal to 100 mu m.

14. the palbocillin composition according to claim 1, wherein the particle size of the palbocillin composition is preferably: 1 < d (10) < 5 μm, 5 < d (50) < 10 μm, d (90) < 20 μm.

15. the palbocillin composition as claimed in claim 1, further comprising one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are binders, fillers, disintegrants or lubricants.

16. The palbocillin composition of claim 1, further comprising one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are povidone, microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium or magnesium stearate.

17. The palbocillin composition as claimed in claim 1, wherein the palbocillin composition is in the form of granules or powder.

18. The palbocillin composition as claimed in claim 1, further comprising an organic solvent for preparing the palbocillin dispersion, wherein the organic solvent is one or more selected from methanol, ethanol, isopropanol, ethyl acetone, dichloromethane and tetrahydrofuran.

19. The palbocillin composition according to claim 1, wherein the palbocillin composition has diffraction peaks at 2 Θ angles of 8.0 ± 0.2, 10.1 ± 0.2, 10.3 ± 0.2 and 11.5 ± 0.2 in the powder X-ray diffraction pattern.

20. The preparation method of the palbocillin composition is characterized by comprising the following steps:

1) Preparing a palbocillin free alkali solution: (a) dissolving palbocillin dihydrochloride in water; (b) adding the solution obtained in step (a) dropwise to a mixture of ammonium hydroxide, methanol and dichloromethane; (c) collecting the lower layer solution in layers for further processing;

2) Adding a hydrophilic auxiliary material into the palbocillin free alkali solution obtained in the step 1);

3) Removing part of the solvent from the solution of the free alkali of the panocillin treated in the step 2), drying, and then drying in vacuum to obtain a dry panocillin mixture containing at least one hydrophilic auxiliary material;

4) Grinding the dry palbocillin mixture obtained in the step 3) by a grinding device, wherein the grinding device is at least one of a jet mill, a rolling mill, a hammer mill, centrifugal impact type grinding, a pebble mill, a cutting mill, a flow mill, a mortar and a pestle;

5) The particle size of the palbocillin dry mixture after grinding in the step 4) is as follows:

1 μm < d (10) < 5 μm, 5 μm < d (50) < 10 μm, and d (90) < 20 μm.

21. A method for preparing a palbocillin composition, which is characterized by comprising the step of co-grinding the palbocillin and at least one hydrophilic auxiliary material to form the palbocillin composition.

22. The method of claim 21, wherein 85% or more of the resulting palbocillin composition is soluble in 900ml of 0.1n hydrochloric acid within 30 minutes.

23. the method of preparing a palbocillin composition as claimed in claim 21, wherein the co-milling is performed using a device selected from the group consisting of a jet mill, a rolling mill, a hammer mill, a centrifugal impact mill, a screen, a pebble mill, a chopper, a runner mill, a pulper, and a pestle.

24. the method of claim 21, wherein the hydrophilic excipient is one or more of a monosaccharide, a polysaccharide, and a disaccharide.

25. The method for preparing a palbocillin composition according to claim 21, wherein the weight ratio of the palbocillin to the hydrophilic excipients is 1:10 to 10: 1.

26. The method of preparing a palbocillin composition as claimed in claim 21, wherein the particle size of the formed palbocillin composition is: 1 μm < d (10) < 5 μm, 5 μm < d (50) < 10 μm, and d (90) < 20 μm.

27. The method of claim 21, further comprising a wet granulation or dry granulation process.

28. The method of preparing a palbocillin composition as claimed in claim 21, further comprising the step of wet granulation: (a) co-grinding pabocillin and a hydrophilic excipient by means of a grinding tool according to claim 23; (b) granulating by a wet method; (c) drying; (d) screening and sieving; (e) mixing with external adjuvants; (f) and (5) filling the mixture into capsules.

29. The method of preparing a palbocillin composition as claimed in claim 28, wherein the wet granulation comprises: (a) co-grinding the palbocillin and the hydrophilic auxiliary materials, dissolving the palbocillin and the hydrophilic auxiliary materials in ethanol through povidone, and granulating, or granulating by using ethanol, pure water or a hydrophilic solvent; (b) then drying at 50-60 ℃, and then screening the dried palbocillin composition particles through a 30-mesh sieve; (c) mixing additional adjuvants with the screened palbocillin composition granules in step (b); (d) blending the mixture of step (c) for use in a capsule filling process.

30. The method of preparing a palbocillin composition as claimed in claim 21, further comprising a dry granulation step: (a) co-grinding pabocillin and a hydrophilic excipient by means of a grinding tool according to claim 23; (b) dry granulation-direct compression and non-recompression; (c) adding additional granular auxiliary materials; (d) and (5) filling the mixture into capsules.

31. the method of preparing a palbocillin composition as claimed in claim 30, further comprising the steps of:

(a) Preparing particles of a pabocillin composition using the process of claim 20;

(b) Passing the particles of the palbocillin composition obtained in step (a) through a multi-mill with a 2.5mm screen and then sieving with a 1.5mm screen until all particles pass through a 20 mesh screen;

(c) Mixing the palbocillin composition granules subjected to the step (b) with external auxiliary materials;

(d) Mixing the mixture obtained in step (c) for use in a capsule filling process.

32. the method of preparing a palbocillin composition as claimed in claim 21, further comprising mixing the palbocillin composition formed by co-milling with an external excipient selected from one or more of sodium carboxymethylcellulose, sodium starch glycolate, colloidal silicon dioxide, crospovidone, microcrystalline cellulose and starch.

33. The method of preparing a palbocillin composition as claimed in claim 21, further comprising mixing the palbocillin composition formed by co-milling with an external excipient selected from one or more of the group consisting of gelatinized silica, magnesium trisilicate, cellulose powder, starch, and talc.

34. The method of preparing a palbocillin composition as claimed in claim 21, further comprising blending the palbocillin composition formed by co-milling with a lubricant selected from one or more of magnesium stearate, hydrogenated castor oil, mineral oil, polyethylene glycol, sodium stearyl fumarate and sodium lauryl sulfate.

35. The method of preparing a palbocillin composition as claimed in claim 21, further comprising encapsulating the palbocillin composition using a capsule, wherein the capsule is a hard gelatin capsule or a hydroxypropyl methylcellulose-based capsule.

36. The method of preparing a palbocillin composition as claimed in claim 21, further comprising encapsulating with a hard gelatin capsule.

37. a method of treating cancer comprising administering to a subject in need of such treatment an effective dose of a palbocillin composition of any one of claims 1 to 19.

38. the method of treating cancer according to claim 37, wherein said cancer is breast cancer.

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a Palbociclib composition with improved solubility and bioavailability, a preparation method thereof, and application of the composition in treating cancers.

background

The compound 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyridin-7-one, has the defined chemical structure:

Pabocillin is reported to be a yellow to orange crystalline powder belonging to the biopharmaceutical classification system BCSII class of compounds, which is slightly soluble in dimethyl sulfoxide and N, N-dimethylformamide, and very slightly soluble in methanol and water.

Palbocillin is a kinase inhibitor suitable for use in combination with letrozole for the treatment of Estrogen Receptor (ER) -positive, human epidermal growth factor receptor 2(HER2) -negative advanced or breast cancer postmenopausal women, and as an initial endocrine-based treatment for their metastatic disease; in combination with fulvestrant, for use in patients with advanced or metastatic breast cancer with HR +/HER 2-following endocrine drug therapy. Pabocillin is available under the trade name PeveristThe product is sold on the market and is provided with a plurality of groups of capsules,The capsule has dosage specifications of 125mg, 100mg and 75 mg. Inactive ingredients of IBRANCE are reported to be microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and hard gelatin capsule shells. Light orange, light orange/caramel and caramel opaque capsule shells comprise gelatin, red iron oxide, yellow iron oxide and titanium dioxide; the printing ink contains shellac, titanium dioxide, ammonium hydroxide, propylene glycol and dimethicone.

The palbocillin is extremely slightly dissolved in water, and when solid dose of palbocillin is orally taken, the medicine must be dissolved in gastrointestinal fluid in the stomach of a patient to exert curative effect. At pH 4 or below, palbocillin exhibits high solubility, and above pH 4, its solubility decreases significantly. A recurring problem with compressed solid oral dosage forms such as tablets, capsules and caplets (i.e., caplets) is that the rate of dissolution of the drug limits its bioavailability.

methods for increasing solubility by reducing particle size have been reported for water-insoluble drugs other than palbocillin. However, particle size reduction is not always sufficient to effectively increase the dissolution rate of a drug to a certain desired value, and many water-insoluble drugs have a strong tendency to aggregate during the manufacturing process of the dosage form, being larger particles with an overall reduction in the effective surface area. Remington: the present application, in conjunction with the article, more thoroughly investigated the concept of "effective surface area" and the effect of particle size on solubility, was carried out in 20 th edition of science and practice of pharmacy 656-657(A.R. Gennaro Ed., Lippincott Williams & Wilkins: Philadephia 2000). Drugs that are superficially ground to fine particles sometimes exhibit dissolution characteristics of larger particles due to agglomeration or the like.

There is a need in the art to improve the solubility and bioavailability of pabocillin compositions.

Disclosure of Invention

The present invention includes a palbocillin composition with improved solubility and bioavailability, methods of preparing the same and methods of treating cancer using the same.

in one aspect, the invention includes a palbocillin composition comprising co-milled palbocillin with at least one hydrophilic excipient, in another aspect, the invention includes a method of preparing the palbocillin composition comprising co-milling palbocillin with at least one hydrophilic excipient to form a palbocillin composition.

The invention also includes the use of the palbocillin compositions prepared by the methods of the invention in methods of treating breast cancer.

Detailed Description

The present invention includes a pabocillin composition with improved solubility and bioavailability, methods of preparation and methods of using the same for treating cancer.

The process for preparing a solution of palbocillin free base comprises dissolving palbocillin dihydrochloride in water to form a solution, adding the solution dropwise to a mixture of ammonium hydroxide (15%), methanol and dichloromethane, followed by layering to form an upper layer and a lower layer, collecting the lower layer solution, and adding at least one hydrophilic excipient to the collected lower layer solution.

a method of preparing a co-milled palbocillin composition with at least one hydrophilic excipient comprises adding the hydrophilic excipient together with an organic solvent to a solution of palbocillin in the solvent (i.e., the palbocillin without separation) to form a dispersion, partially removing the solvent, drying, and then vacuum drying to obtain a dried mixture of palbocillin and the at least one hydrophilic excipient, and co-milling by using a jet mill, a rolling mill, a hammer mill, a centrifugal impact mill, and at least one of a screen, a pebble mill, a chopper, a flow channel mill, or a masher and a mill.

It has been found that the solubility of palbocillin can be improved by adding hydrophilic saccharides, polysaccharides or disaccharide excipients to palbocillin, for example co-ground palbocillin compositions containing starch, lactose.

In one aspect, the invention includes a palbocillin composition comprising co-ground palbocillin with at least one hydrophilic excipient which may be one or more of a saccharide, polysaccharide and/or disaccharide (e.g., starch, pregelatinized starch, mannitol or sorbitol, lactose, etc.), calcium carbonate, cellulose, sorbitol, povidone, silicic acid, beta cyclodextrin and polyethylene glycol.

Preferably, the palbocillin composition prepared by the invention has a dissolution rate of more than 85% in 30 minutes under the condition of pH value of 1.2.

The co-grinding may use conventional grinding processes including jet grinding, roll grinding, hammer grinding, centrifugal impact grinding, sieving, pebble grinding, cutting grinding, use of a pestle and masher. The particle size distribution of the co-milled palbocillin composition is as follows: d (10) ≦ 50 μm, d (50) ≦ 200 μm, d (90) ≦ 400 μm, or d (10) ≦ 25 μm, d (50) ≦ 100 μm, d (90) ≦ 200 μm, or d (10) ≦ 15 μm, d (50) ≦ 50 μm, d (90) ≦ 100 μm, most preferably having a particle size of 1 < d (10) < 5 μm, 5 < d (50) < 10 μm and d (90) < 20 μm.

Preferably, the ratio of the palbocillin: the weight ratio of the hydrophilic auxiliary materials is 1:10-10:1, preferably 1:5-5:1, more preferably 1:3-1:1, even more preferably 1: 2.

preferably, the palbocillin composition is in the form of granules or powder.

Preferably, the palbocillin composition of the invention further comprises one or more pharmaceutically acceptable excipients besides the hydrophilic excipients. Preferably, more than 85% of the palbocillin composition added with pharmaceutically acceptable auxiliary materials can be dissolved within 30 minutes. Preferably, the pharmaceutically acceptable excipients include at least one of a binder, a filler, a disintegrant or glidant, a lubricant, and a hard gelatin shell, and more particularly, the pharmaceutically acceptable excipients may be povidone, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and a hard gelatin capsule shell.

Preferably, the palbocillin composition further comprises one or more dispersants, such as povidone.

in another aspect, the invention includes a method of preparing a palbocillin composition, the method comprising co-milling palbocillin with at least one hydrophilic excipient to form a palbocillin composition.

Preferably, the present invention includes a method of preparing a palbocillin composition comprising co-milling palbocillin with at least one hydrophilic excipient, wherein the palbocillin is present in an amount of greater than or equal to 40%, preferably from 40% to 70%, more preferably greater than or equal to 50%, and even more preferably greater than or equal to 60%.

Preferably, the palbocillin composition formed by co-grinding further comprises an organic solvent, and the palbocillin composition is dissolved in the organic solvent to obtain a palbocillin dispersion, wherein the organic solvent can be one or more selected from methanol, ethanol, isopropanol, ethyl acetone, dichloromethane and tetrahydrofuran.

the palbocillin compositions may be prepared by methods known in the art, such as dry granulation, wet granulation, direct compression. Preferably, the palbocillin composition is prepared by wet granulation or dry granulation. The wet granulation mixture contains a dispersing agent, which may or may not optionally be added with a binder, such as povidone. The co-milled palbocillin and hydrophilic excipients may be combined with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients include binders, fillers, disintegrants, glidants, and lubricants.

The method of preparing a palbocillin composition may further comprise compressing co-ground palbocillin and a hydrophilic excipient to form a mass, and grinding the mass to a powder; or passing the co-ground palbocillin and hydrophilic adjuvant through a screen to obtain palbocillin composition granules.

In another embodiment, the invention includes a method of making a palbocillin composition, the method comprising co-grinding palbocillin and starch/lactose to an average particle size of less than 20 μm; and then mixed with a disintegrant, wherein the disintegrant is sodium starch glycolate or croscarmellose sodium. Mixing the co-ground palbocillin composition with a disintegrant to prepare a compressed tablet; grinding and crushing by using a multi-grinding crusher with a 2.5mm screen, and then sieving by using a 1.5mm screen; all granules were sieved through 20 mesh, then mixed with additional excipients and then encapsulated into hard gelatin capsules or compressed into tablets.

The palbocillin compositions of the invention may contain inactive ingredients which may be diluents, carriers, fillers, binders, disintegrants, glidants or lubricants.

Diluents which increase the bulk of the solid pharmaceutical composition and may make the pharmaceutical dosage form containing the composition easier for the patient and care giver to handle include microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, calcium hydrogen phosphate, or the like.

Carriers for the composition may include, but are not limited to, pregelatinized starch, mannitol, sorbitol, lactose, calcium carbonate, cellulose, povidone, silicic acid, or beta cyclodextrin polyethylene glycol, and the like.

binders are useful for combining the active ingredient with other excipients after compression, and binders for solid pharmaceutical compositions include carbomers (e.g., carbomer, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylcellulose (e.g., Klucel), hydroxypropylmethylcellulose (e.g., meduoxix), and povidone (e.g., Kollidon, Plasdone).

Disintegrants may increase dissolution and include sodium carboxymethylcellulose (e.g., Ac-Di-Sol, Primellose), sodium starch glycolate, colloidal silicon dioxide, crospovidone (e.g., Kollidon, Polyplasone), microcrystalline cellulose, starch, and the like.

Lubricants, including magnesium stearate, hydrogenated petroleum ether, mineral oil, polyethylene glycol, sodium fumarate, and sodium lauryl sulfate, may be added to the composition to reduce binding and ease release of the product from the punch or colorant during encapsulation.

Glidants are added to improve the flowability of the uncompacted composition and the accuracy of the dosage, and excipients which act as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and the like.

The powdered or granulated panocillin composition prepared by the present invention may be filled into capsules.

As mentioned above, the palbocillin formulations of the invention may be prepared by wet granulation using co-ground palbocillin, the excipients being uniformly blended in the form of a powder and then further mixed in the presence of a liquid (usually water and/or alcohol or hydroalcoholic) to agglomerate the powder into granules. The granulation liquid may or may not contain a dispersing agent, such as povidone. The granules so formed are optionally sieved and/or milled, dried, then sieved and/or milled through a 30 mesh screen. These granules may then be encapsulated directly or may be encapsulated after addition of other excipients, such as glidants, lubricants and/or disintegrants.

Preferably, the palbocillin composition further comprises an organic solvent used in the wet granulation process, wherein the organic solvent is selected from one or more of methanol, ethanol and isopropanol.

The preferred dosage form is a capsule. The palbocillin composition may be prepared by conventional dry granulation. For example, the co-milled palbocillin composition and other excipients may be compressed into a mass and then comminuted into compacted granules, which are then filled into capsules.

direct compression of the blended composition into a compacted dosage form may be used as an alternative to dry granulation using direct compression techniques.

Alternatively, the co-milled palbocillin composition is mixed directly with the additional excipients and filled into hard gel capsules.

The capsule fill of the present invention may comprise any of the blends and granules described above in relation to tableting, except that they are not subjected to final tableting.

The invention also includes methods of preparing the pabocillin compositions and methods of treating breast cancer.