Direct Compression Formulation And Process

Abstract

Dipeptidylpeptidase IV inhibitor (herein referred to as DPP-IV) that may be 98.5-100% pure is a high-dose drug capable of being directly compressed with specific excipients into sold form dosage forms, such as tablets and capsules having desired, hardness, disintegrating ability and acceptable dissolution characteristics. DPP-IV is not inherently compressible and thus presents formulation problems. Excipients used in the formulation enhance the flow and compaction properties of the drug and tableting mix. Optimal flow contributes to uniform die fill and weight control. The binder used ensures sufficient cohesive properties that allow DPP-IV to be compressed using the direct compression method. The tablets produced provide an acceptable in vitro dissolution profile.

Description

EXAMPLE 1

To prepare the 25 mg tablet size (directly compressed tablet), a batch size of 7 kg is prepared using amounts corresponding to the following per unit: 25 mg per unit of the compound 1-[3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile is mixed with 35.1 mg of microcrystalline cellulose, 17.5 mg anhydrous lactose and 1.6 mg sodium starch glycolate. The ingredients are pre-blended together in a commercial bin blender, then sieved through a 500 μm or 850 μm screen. The mix is blended again in the bin blender, then the necessary amount of the magnesium stearate to yield the 0.8 mg magnesium stearate per 25 mg tablet size, is added. Blending in each step is conducted at about 150-450 rotations, to ensure homogeneity of the mixture. Following blending again in the bin blender, the mix can be tabletted in a conventional tableting machine. The individual tablet weight for the 25 mg tablet is 80 mg. Tablets having 50 mg active ingredient weigh 160 mg, and 100 mg active ingredient tablets weigh 320 mg, respectively. The blend is a powder which has excellent compressibility into the desired tablet size.

EXAMPLE 2

The same process as described above in example 1, can be applied to produce the below described preferred 50 mg tablet (directly compressed).

	Composition per	Quantity per
Components	unit (mg)	batch (kg)
LAF 237 drug substance	50.00	65.0
Microcrystalline cellulose, PH102	95.68	124.38
(Ph.Eur., NF)
Lactose anhydrous DT (USP, Ph.Eur.)	47.82	62.17
Sodium starch glycolate (USP, Ph.Eur.)	4.00	5.2
Magnesium stearate (Ph.Eur, NF)	2.50	3.25
Total weight, per tablet or per batch	200.0	260.0

EXAMPLE 3

The Tablets Prepared in Accordance with the Above Description and Examples Can Be tested as Follows.

Tablet Evaluation Methods

1. Average tablet weight. Twenty tablets are weighed on an analytical balance and the average tablet weight calculated.

2. Tablet breaking strength (kilo bond-kp). 5 tablets are individually tested using a Schleuniger crushing strength tester, and the average breaking strength calculated.

3. Friability (% loss). 10 tablets, accurately weighed, are subjected to 10 minutes friability testing using a Roche Friabilator. The tablets are dedusted, reweighed, and the weight loss due to the friability is calculated as a percentage of the initial weight.

4. Dispersion Disintegration time DT (The test for dispersible tablets defined in the British Pharmacopoeia, 1988, Volume II, page 895—BP 1988). 6 tablets are tested in accordance to the above-defined BP test (without discs) for dispersible tablets. This utilizes water at a temperature of 19°-21° C.

5. Dispersion Quality. In accordance with the BP uniformity of dispersion test for dispersible tablets (BP 1988 Volume II page 895), two tablets are placed in 100 ml of water at 19°-21° C. and allowed to disperse.

Granule Evaluation Methods

1. Loss on Drying (LOD). The residual moisture content of the granule (LOD) can be determined on a 3-4 g sample using a Computrac moisture analyser set at 90° C. operated in accordance with the manufacturer's procedure.

2. Weight Median Diameter (WMD). A 10 g sample of granule is sifted for 2 minutes at suitable pulse and sift amplitudes in an Allen Bradley sonic sifter in accordance with manufacturer's instructions. Sieves of 300 μm, 250 μm, 200 μm, 150 μm, 100 μm, 53 μm and 40 μm are used. The WMD is calculated from the cumulative percentage undersize size distribution using a computer program.

EXAMPLE 4

Improved Manufacturing Robustness

A preliminary compactibility assessment is carried out on a Carver press using different formulations as well as binary mixtures of LAF 237 with different excipients e.g. microcrystalline cellulose (Avicel PH102).

Data demonstrate that our claimed compositions on being compressed with increasing levels of pressure (compression force) show a substantially useful increase in tablet strength. In particular e.g. mixture of LAF237 and Avicel show a substantially useful increase in tablet strength. These results indicated that from compactibility point of view microcrystalline cellulose e.g. Avicel would a preferred excipient to be combined with LAF237. With increasing pressure (compression force) our claimed formulations and selected ranges show a substantially useful increase in tablet strength.

A compactibility study (D. Becker, personal communication) is carried out on an instrumented Korsch single station press with force and displacement sensors on both upper and lower punches.

A clear indication is afforded from these data that LAF237 tablets are very likely to have poor tablet hardness/crushing strength unless diluted out using sufficient filler with excellent compactibility. Our claimed formulations and selected ranges are particularly adapted to provide the required compactibility. Microcrystalline cellulose e.g. Avicel is a good choice for a filler in this respect.

EXAMPLE 5

Friability

Evaluation is carried out using a Manesty Betapress at 6 different settings: strain rate settings of 66-90 rpm (63,000-86,000 TPH) and force of 7.5-15 kN. The trials uses Flat-faced Beveled-edge (FFBE) tooling of 9 mm diameter for 250 mg tablets and 10 mm diameter for 310 mg tablets (other diameters are used depending on the weight of the tested tablet). Total tablet weights were selected so that both the 9 and 10 mm FFBE tablets would have 100 mg of LAF237 and identical tablet thickness. Friability, Compression profile, Strain rate profile and Weight variation are the measured outcomes. Study design and the friability results obtained from the study are used to determine the variables (particle size distribution in the formulation, tablet weight, tablet thickness and weight, water content in the tablet etc) impacting the outcome of hardness.

EXAMPLE 6

Mechanical Stress (Particle Size Distribution)

The material in the desired particle size range can be produced from any form of vildagliptin e.g. amorphous vildagliptin, by mechanical stress. This stress can be mediated by impact, shear or compression. In most commercially available grinding equipment a combination of these principles occurs. For vildagliptin preferably a mechanical impact or jet mill is used. The most preferable mechanical impact mill can be equipped with different kind of beaters, screens, liners or with pin plates. For our process preferably an impact mill with plate beater and a slit screen 5*2.5 cm is used. The impact speed should be variable between 20 and 100 m/s (as peripheral speed) to adapt to any batch to batch variation. In our case a peripheral speed of the beater of about 40-50 m/s is used.

Claims

1. A pharmaceutical composition comprising: (a) 5-60% by weight on a dry weight basis of a DPP-IV inhibitor in free form or in acid addition salt form;(b) 40-95% by weight on a dry weight basis of a pharmaceutically acceptable diluent;(c) 0-20% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant; and optionally(d) 0.1-10% by weight on a dry weight basis of a pharmaceutically acceptable lubricant.

2. A composition according to claim 1 comprising: (a) 20-40% by weight on a dry weight basis of a DPP-IV inhibitor in free form or in acid addition salt form;(b) 40-95% by weight on a dry weight basis of a pharmaceutically acceptable diluent;(c) 0-10% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant; and optionally(d) 0.25-6% by weight on a dry weight basis of a pharmaceutically acceptable lubricant.

3. A composition according to claim 1, comprising: (a) 20-35% by weight on a dry weight basis of a DPP-IV inhibitor in free form or in acid addition salt form;(b) 62-78% by weight on a dry weight basis of a pharmaceutically acceptable diluent;(c) 0-10% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant; and optionally(d) 0.1-10% by weight on a dry weight basis of a pharmaceutically acceptable lubricant.

4. A composition according to claim 1 comprising: (a) 22-28% by weight on a dry weight basis of a DPP-IV inhibitor in free form or in acid addition salt form.

5. A composition according to claim 1 comprising: (a) 30-35% by weight on a dry weight basis of a DPP-IV inhibitor in free form or in acid addition salt form, and(b) 58-72% by weight on a dry weight basis of a pharmaceutically acceptable diluent;

6. A composition according to claim 1 comprising: i) one or two diluents selected from microcrystalline cellulose and lactoseii) the two diluents microcrystalline cellulose and lactose,iii) 25-70% by weight on a dry weight basis of a pharmaceutically acceptable microcrystalline cellulose, oriv) 25-70% by weight on a dry weight basis of a pharmaceutically acceptable microcrystalline cellulose and 5-40% by weight on a dry weight basis of lactose.

7. A composition according to claim 1 comprising: (c) 1-6% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant, and/or(d) 0.1-10% by weight on a dry weight basis of a pharmaceutically acceptable lubricant.

8. A composition according to claim 1 comprising: (a) 20-35% by weight on a dry weight basis of DPP-IV inhibitor;(b) 25-70% by weight on a dry weight basis of a pharmaceutically acceptable microcrystalline cellulose;(c) 5-40% by weight on a dry weight basis of a pharmaceutically acceptable lactose;(d) 0-10% by weight on a dry weight basis of a pharmaceutically acceptable sodium starch glycolate;(e) 0.25-6% by weight on a dry weight basis of magnesium stearate.

9. A composition according to claim 1 comprising: (a) 25-35% by weight on a dry weight basis of a DPP-IV inhibitor in free form or in acid addition salt form;(b) 25-70% by weight on a dry weight basis of a pharmaceutically acceptable microcrystalline cellulose;(c) 5-40% by weight on a dry weight basis of a pharmaceutically acceptable lactose;(d) 0-10% by weight on a dry weight basis of a pharmaceutically acceptable sodium starch glycolate;(e) 0.25-6% by weight on a dry weight basis of magnesium stearate.

10. A composition according to claim 1 comprising: (a) 30-35% by weight on a dry weight basis of DPP-IV inhibitor e.g. LAF237;(b) 35-50% by weight on a dry weight basis of a pharmaceutically acceptable microcrystalline cellulose;(c) 18-35% by weight on a dry weight basis of a pharmaceutically acceptable lactose;(d) 1-4% by weight on a dry weight basis of a pharmaceutically acceptable sodium starch glycolate; and(e) 0.5-4% by weight on a dry weight basis of magnesium stearate.

11. A composition according to claim 1 comprising: (a) 20-35% by weight on a dry weight basis of DPP-IV inhibitor;(b) 35-55% by weight on a dry weight basis of a pharmaceutically acceptable microcrystalline cellulose;(c) 18-35% by weight on a dry weight basis of a pharmaceutically acceptable lactose;(d) 1-4% by weight on a dry weight basis of a pharmaceutically acceptable sodium starch glycolate; and(e) 0.5-4% by weight on a dry weight basis of magnesium stearate.

12. A composition according to claim 1 comprising: (a) from about 22% to about 28% by weight on a dry weight basis of a DPP-IV inhibitor or a DPP-IV inhibitor of formula (I);(b) from about 45% to about 50% by weight on a dry weight basis of a pharmaceutically acceptable microcrystalline cellulose;(c) from about 20% to about 25% by weight on a dry weight basis of a pharmaceutically acceptable lactose;(d) from about 1.5% to about 2.5% by weight on a dry weight basis of a pharmaceutically acceptable sodium starch glycolate; and(e) from about 0.1% to about 2% by weight on a dry weight basis of magnesium stearate.

13. A composition according to claim 1, wherein the DPP-IV inhibitor is selected from 1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidine dihydrochloride, (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine, L-threo-isoleucyl thiazolidine, MK-0431, GSK23A, BMS-477118, 3-(aminomethyl)-2-isobuthyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2-{[3-(aminomethyl)-2-isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy}acetamide and optionally in any case pharmaceutical salts thereof.

14. A composition according to claim 1, wherein the DPP-IV inhibitor is 1-[3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile or a pharmaceutical salt thereof.

15. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet, wherein the dispersion contains particles comprising a DPP-IV inhibitor, in free form or in acid addition salt form, and wherein at least 60% of the particle size distribution in the tablet is less than 250 μm.

16. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet wherein the dispersion contains particles comprising DPP-IV inhibitor, in free form or in acid addition salt form, and wherein tablet thickness to tablet weight ratios is of 0.002 to 0.06 mm/mg.

17. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet wherein the dispersion contains particles comprising DPP-IV inhibitor in free form or in acid addition salt form, and wherein; i) at least 60% of the particle size distribution in the tablet is less than 250 μm, andii) tablet thickness to tablet weight ratios is of 0.002 to 0.06 mm/mg or of 0.01 to 0.03 mm/mg.

18. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet wherein the dispersion contains particles comprising DPP-IV inhibitor, in free form or in acid addition salt form, and wherein; i) at least 60% of the particle size distribution in the tablet is less than 250 μm,ii) the water content of the tablet is less than 10% after 1 week at 25° C. and 60% RH, andiii) tablet thickness to tablet weight ratios is of 0.002 to 0.06 mm/mg.

19. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet according to claim 15, wherein the particle size distribution in the tablet is between 50 to 150 μm.

20. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet according to claim 15, wherein the water content of the tablet is less than 5% after 1 week at 25° C. and 60% RH

21. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet according to claim 15, wherein tablet thickness to tablet weight ratios is of 0.01 to 0.03 mm/mg.

22. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet according to claim 15, wherein at least 60% or at least 80% of the particle size distribution in the tablet is between 10 to 250 μm.

23. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet according to claim 15, wherein at least 25% or at least 35% of the particle size distribution in the tablet is between 50 to 150 μm.

24. (canceled)

25. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet according to claim 15, wherein i) between 0 and 10 minutes 85 to 99.5% of the active ingredient is released, andii) between 10 and 15 minutes 90 to 99.5% of the active ingredient is released.

26. A compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet according to claim 15, wherein the particle size distribution of the pharmaceutical excipients in the tablet is between 5 and 400 μm.

27. The compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet according to claim 15, in which the DPP-IV inhibitor is selected from 1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidine dihydrochloride, (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine, L-threo-isoleucyl thiazolidine, MK-0431, GSK23A, BMS-477118, 3-(aminomethyl)-2-isobuthyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2-{[3-(aminomethyl)-2-isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy}acetamide and optionally in any case pharmaceutical salts thereof.

28. The compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet according to claim 15, in which the DPP-IV inhibitor is N-(substituted glycyl)-2-cyanopyrrolidine is 1-[3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile or a pharmaceutical salts thereof.

29. A compressed pharmaceutical tablet according to claim 15, which is a direct compressed tablet.

30. A solid dosage form of the composition according to claim 1.

31. The solid dosage form of claim 30 which is a tablet.

32. The solid dosage form of claim 30 which is a capsule.

33. A solid dosage form of the composition according to claim 1 which is a direct compressed tablet.

34. Process for preparing a direct compressed tablet according to claim 15, in unit dosage form, which comprises: (a) blending as a % by weight on a dry weight basis: (i) 6-60% by weight on a dry weight basis of DPP-IV inhibitor; and(ii) and at least one excipient selected from a diluent, a disintegrant and a lubricant,to form a DPP-IV inhibitor formulation in the form of a tableting powder, capable of being directly compressed into a tablet; and(b) compressing the formulation prepared during step (a) to form the compressed DPP-IV inhibitor tablet in unit dosage form.

35. Process for preparing a direct compressed tablet according to claim 15, in unit dosage form, which comprises: (a) blending as a % by weight on a dry weight basis: (i) 25-35% by weight on a dry weight basis of DPP-IV inhibitor;(ii) 40-95% by weight on a dry weight basis of a pharmaceutically acceptable diluent;(iii) 0-10% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant; and(iv) 0.25-6% by weight on a dry weight basis of a pharmaceutically acceptable lubricant,to form a DPP-IV inhibitor formulation in the form of a tableting powder, capable of being directly compressed into a tablet; and(b) compressing the formulation prepared during step (a) to form the compressed DPP-IV inhibitor tablet in unit dosage form.

36. Process according to claim 35 wherein the blended formulation comprises: (i) 20-35% or preferably 25-30% by weight by weight on a dry weight basis of DPP-IV inhibitor, in free form or in acid addition salt form;(ii) 25-70% by weight on a dry weight basis of a pharmaceutically acceptable microcrystalline cellulose;(iii) 5-40% by weight on a dry weight basis of a pharmaceutically acceptable lactose;(iv) 0-10% by weight on a dry weight basis of a pharmaceutically acceptable sodium starch glycolate; and(v) 0.25-6% by weight on a dry weight basis of a pharmaceutically acceptable magnesium stearate.

37. (canceled)

38. The process according to claim 34, in which the DPP-IV inhibitor is selected from 1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidine dihydrochloride, (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine, L-threo-isoleucyl thiazolidine, MK-0431, GSK23A, BMS-477118, 3-(aminomethyl)-2-isobuthyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2-{[3-(aminomethyl)-2-isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy}acetamide and optionally in any case pharmaceutical salts thereof.

39. The process according to claim 34, in which the which the DPP-IV inhibitor is 1-[3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile or pharmaceutical salts thereof.

40. A pharmaceutical composition comprising: (a) a DPP-IV inhibitor in free form or in acid addition salt form,(b) a pharmaceutically acceptable diluent,

41. A composition according to claim 40 wherein the diluent is selected from a microcrystalline cellulose and lactose.

42. A composition according to claim 40, wherein at least one diluent is a microcrystalline cellulose and wherein in the unit dosage form, the weight of DPP-IV inhibitor on a dry weight basis to tablet weight of microcrystalline cellulose ratio is of 2 to 0.333.

43. A composition according to claim 40 comprising lactose as diluent in addition to a microcrystalline cellulose.

44. Composition according to claim 40 wherein the DPP-IV inhibitor is selected from 1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidine dihydrochloride, (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine, L-threo-isoleucyl thiazolidine, MK-0431, GSK23A, BMS-477118, 3-(aminomethyl)-2-isobuthyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2-{[3-(aminomethyl)-2-isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy}acetamide and optionally in any case pharmaceutical salts thereof.

45. Composition according to claim 40 wherein the DPP-IV inhibitor is 1-[3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile or pharmaceutical salts thereof.

46. Composition according to claim 1, comprising between 20 and 120 mg of 1-[3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile or a pharmaceutically acceptable acid addition salt thereof.

47. Composition according to claim 40, which further comprises: (c) 0-20% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant;(d) 0.1-10% by weight on a dry weight basis of a pharmaceutically acceptable lubricant.

48. Composition according to claim 40, which further comprises: (c) 1-6% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant;(d) 0.25-6% by weight on a dry weight basis of a pharmaceutically acceptable lubricant.

49. Composition according to claim 40, which further comprises: (c) 1-4% by weight on a dry weight basis of a pharmaceutically acceptable sodium starch glycolate; and(d) 0.5-4% by weight on a dry weight basis of magnesium stearate.

50. (canceled)

51. (canceled)

52. The composition according to claim 40 which is a tablet.

53. The composition according to claim 40 which is a capsule.

54. A compressed pharmaceutical tablet, comprising a DPP-IV inhibitor, in free form or in acid addition salt form.

55. A compressed pharmaceutical tablet according to claim 54, wherein the DPP-IV inhibitor is selected from 1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidine dihydrochloride, (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine, L-threo-isoleucyl thiazolidine, MK-0431, GSK23A, BMS-477118, 3-(aminomethyl)-2-isobuthyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2-{[3-(aminomethyl)-2-isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy}acetamide and optionally in any case pharmaceutical salts thereof.