Orally disintegrating tablets and methods of manufacture

Abstract

A tablet that rapidly disintegrates in the oral cavity comprising a compressed blend of rapidly dispersing microgranules prepared by granulating a sugar alcohol or a saccharide or a mixture thereof having an average particle size less than about 30 microns and a disintegrant, and a taste-masked microcapsule containing at least one drag, the microcapsule being prepared by granulating a pharmaceutically acceptable formulation comprising at least one drug in a therapeutically effective amount and at least one polymeric binder that improves resilience of the microgranules, wet milling the granulated mass, and microencapsulating the milled granules to provide microcapsules.

Claims

1. A tablet that rapidly disintegrates in the oral cavity comprising a compressed blend of: rapidly dispersing microgranules comprising a sugar alcohol or a saccharide or a mixture thereof having an average particle size not more than about 30 microns, and a disintegrant, and taste-masked microcapsules containing at least one drug, prepared by (a) granulating a pharmaceutically acceptable formulation comprising the at least one drug in a therapeutically effective amount and at least one polymeric binder imparting resilient characteristics to the resulting taste-masked microcapsules to provide a granulated mass, (b) wet milling the granulated mass to provide milled granules, and (c) coating the milled granules with one or more polymers to provide taste-masked microcapsules wherein the at least one polymeric binder is selected from the group consisting of hydroxypropylcellulose (HPC) of viscosity of 100 cps or higher, hydroxypropyl methylcellulose (HPMC) with a viscosity of 100 cps or more and, modified starches, and combinations thereof.

2. The tablet of claim 1, wherein the tablet is prepared by a process comprising: (a) granulating the pharmaceutically acceptable formulation comprising at least one drug in a therapeutically effective amount and at least one polymeric binder imparting resilient characteristics to the resulting taste-masked microcapsules to provide a granulated mass, (b) wet milling the granulated mass to produce microgranules which resist breakage during coating for taste-masking and whose average particle size is not more than about 300 μm, (c) microencapsulating the microgranules to provide taste-masked microcapsules with an average particle size of not more than about 400 μm, (d) separately granulating a sugar alcohol or a saccharide or a mixture thereof having an average particle size less than about 30 μm and a disintegrant to provide rapidly dispersing microgranules, (e) blending the taste-masked microcapsules from step (c) and the rapidly dispersing microgranules from step (d), and (f) compressing the blend from step (e) to form a tablet.

3. The tablet of claim 1, wherein the tablet is prepared by a process comprising: (a) granulating a powder mixture into rapidly dispersing microgranules with a fixed particle diameter, the powder mixture comprising a sugar alcohol, a saccharide or a combination thereof, each having an average particle diameter of not more than 30 μm; (b) granulating, wet milling and drying a pharmaceutically acceptable formulation comprising at least one drug with an average particle size of not more than about 50 μm, and at least one polymeric binder imparting resilient characteristics to the resulting taste-masked microcapsules to provide microgranules, the microgranules exhibiting not more than 15% fines (passing through 140 mesh screen) when tested in accordance with the procedure for friability test; (c) encapsulating the microgranules from step (b) by coacervation in a cyclohexane solution comprising ethylcellulose to provide taste masked microcapsules, (d) mixing the rapidly dispersing microgranules from step (a) and the taste masked microcapsules from step (c) and compressing the mixture.

4. The tablet of claim 1, wherein the tablet comprises: rapidly dispersing microgranules comprising about 30% to about 70% (by weight of the tablet) of a sugar alcohol, a saccharide or a combination thereof, each having an average particle size of not more than about 30 μm; about 0.01% to about 30% (by weight of the tablet) of taste-masked microcapsules having an average particle diameter of not more than about 400 μm; and about 1.0% to about 10% (by weight of the tablet) of a disintegrant.

5. The tablet of claim 4, wherein the sugar alcohol or saccharide is selected from the group consisting of D-mannitol, sorbitol, xylitol, maltitol, lactose and combinations thereof; and wherein the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, crosslinked carboxymethyl cellulose, low substituted hydroxypropyl cellulose, and combinations thereof, each having an average particle diameter of not more than about 30 μm.

6. The tablet of claim 4, wherein the at least one drug is selected from the group consisting of H.sub.2 antagonists, proton pump inhibitors, 5-HT.sub.1 receptor agonists, and selective histamine H.sub.1 receptor antagonists, each having an average particle size of not more than about 50 μm.

7. The tablet of claim 1, wherein the disintegrant is selected from the group consisting of cross-linked polyvinylpyrrolidone (crospovidone), cross-linked carmellose of sodium, low substituted hydroxypropylcellulose, and mixtures thereof.

8. The tablet of claim 5, wherein the sugar alcohol is D-mannitol.

9. The tablet of claim 5, wherein the saccharide is lactose.

10. The tablet of claim 6, wherein the at least one drug is selected from the group consisting of ranitidine, cimetidine, famotidine, omeprazole, lansoprazole, sumatriptan, rezatriptan, zolmitriptan and cetirizine.

11. The tablet of claim 10, wherein the at least one drug is sumatriptan.

12. The tablet of claim 11, wherein the disintegrant is crospovidone.

13. The tablet of claim 1, wherein the disintegration time in the buccal cavity of the tablet is not more than 120 seconds.

14. A method for manufacturing a tablet of claim 1 that rapidly disintegrates in the oral cavity comprising: (a) granulating a pharmaceutically acceptable formulation comprising at least one drug in a therapeutically effective amount and at least one polymeric binder imparting resilient characteristics to the resulting taste masked microcapsules to provide a granulated mass, and (b) wet milling the granulated mass using a size reduction mill to produce microgranules which resist breakage during coacervation for taste-masking and whose average particle size is not more than 300 μm, (c) microencapsulating the microgranules with one or more polymers to provide taste-masked microcapsules with an average particle size of not more than 400 μm, (d) separately granulating a sugar alcohol or a saccharide or a mixture thereof having an average particle size less than 30 μm and at least one disintegrant to provide rapidly dispersing microgranules, (e) blending the taste-masked microcapsules from step (c) and rapidly dispersing microgranules from step (d), and (f) compressing the blend from step (e) to form a tablet.

15. The method of claim 14, wherein the tablet comprises about 30% to about 70% (by weight of the tablet) of a sugar alcohol, a saccharide or a combination thereof, each having an average particle size of not more than about 30 μm, about 0.01% to about 30% (by weight of the tablet) of an active ingredient having an average particle diameter of not more than about 50 μm, and about 1.0% to about 10% (by weight of the tablet) of a disintegrant.

16. The method of claim 15, wherein the compression step (f) uses a tablet press and wherein the dies and punches of the tablet press are lubricated prior to tablet compression.

17. The method of claim 16, wherein the blend of step (e) is lubricated and the lubricated blend is compressed on a tablet press.

18. The method of claim 15, wherein the sugar alcohol, the saccharide or the combination thereof, is selected from the group consisting of D-mannitol, sorbitol, xylitol, maltitol, and lactose and the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, crosslinked carboxymethyl cellulose, and low substituted hydroxypropyl cellulose, each having an average particle diameter of not more than about 30 μm.

19. The method of claim 18, wherein the at least one drug is selected from the group consisting of H.sub.2 antagonists, proton pump inhibitors, 5-HT.sub.1 receptor agonists, each having an average particle size of not more than 50 μm, and the at least one drug is granulated with one or more diluents and at least one polymeric binder imparting resilient characteristics to the resulting taste masked microcapsules.

20. The method of claim 14, wherein the disintegrant is selected from the group consisting of cross-linked polyvinylpyrrolidone (crospovidone), cross-linked carmellose of sodium, low substituted hydroxypropyl cellulose, and mixtures thereof.

21. The method of claim 14, wherein the polymeric binder imparting resilient characteristics to the resulting taste masked microcapsules is selected from the group consisting of hydroxypropylcellulose (HPC) of viscosity of 100 cps or higher, hydroxypropyl methylcellulose (HPMC) of viscosity of 100 cps or higher, modified starch, and mixtures thereof.

22. The method of claim 14, wherein the tablet disintegrates within 60 seconds in the buccal cavity, the sugar is D-mannitol having an average particle size of not more than about 30 μm, the disintegrant is crospovidone, the active ingredient is ranitidine or sumatriptan having an average particle size of not more than about 50 μm, and the polymeric binder imparting resilient characteristics to the resulting taste masked microcapsules is HPMC with a viscosity of 100 cps or higher, modified starch, or mixtures thereof.

23. The tablet of claim 1, wherein not less than 55% of the at least one drug dissolves in about 60 minutes when dissolution is tested using USP Apparatus 2 (paddle at 50 RPM, 900 mL of 0.1N HCl at 37° C.).

24. The tablet of claim 1, wherein the at least one drug is selected from the group consisting of macrolide antibiotic agents, analgesics, antidepressants, antihistamines, antihypertensives, antimigrane agents, proton pump inhibitors, antipsychotic agents, antiemetic agents, antiparkinson agents, and H.sub.2 antagonists.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) From pharmaceutical and practical points of view, the inventors have examined various methods of taste-masking before coming up with a method which has wider applicability and also evaluated methods of producing intrabuccally rapidly disintegrating tablets, which don't require a special pharmaceutical production technique and can be simply and easily produced by a normal equipment. As a result, the inventors have developed, as a convenient method for effectively taste-masking bitter drug particles producing microcapsules of most desired particle size distributions, which are suitable for incorporation into tablets having the property of rapidly disintegrating in the buccal cavity and leaving no aftertaste (good creamy mouthfeel instead). The invention also provides a method of manufacturing pharmaceutical tablets, produced by mixing microgranules of a sugar alcohol such as D-mannitol or a saccharide such as lactose, each having an average particle diameter of not more than 30 μm, preferably not more than 20 μm and a disintegrant with one or more taste-masked microcapsules and other excipients (for example: flavor, color, sweetener etc.) and compressing the blend into rapidly disintegrating tablets, the tablet thus produced having the property that it is formed by compressing in a tablet press equipped with an externally lubricating system to pre-lubricate dies and punches and the tablet formulation otherwise being free of lubricant.

(2) A method of manufacturing tablets in accordance with one embodiment of the invention, which rapidly disintegrate in the buccal cavity without leaving undesirable mouth feel comprises the following steps: (a) granulating a sugar alcohol or a saccharide, or a combination thereof, each of which has an average particle diameter of not more than 30 μm with a disintegrant such as Crospovidone using water or an alcohol-water mixture at a ratio of 1:3 to 3:1, without the addition of a binder, in a typical high shear granulator, wet milling to produce a desired particle size distribution, and drying in a fluid bed equipment to produce dispersible microgranules with an average particle size of not more than 400 μm (typically the average particle size of not more than 300 μm); (b) granulating a bitter active pharmaceutical ingredient and optionally one or more pharmaceutically acceptable diluents such as mannitol, lactose and microcrystalline cellulose with at least one polymeric binder such as modified starch and hydroxypropylmethylcellulose with a viscosity of 100 cps or higher, which imparts resilient, characteristics to the dried granules and wet milling using a size reduction mill such as Comil™ equipped with an appropriate sieve size to produce granules with a desired particle size distribution in order to avoid excessive dry milling which typically results in fines undesirable from the taste-masking point of view; (c) microencapsulating these resilient granules (mean size: 200 μm or less) by coacervation in cyclohexane containing ethylcellulose to produce effectively taste-masked microcapsules with a desired particle size distribution (average particle size of not more than 400 μm, typically not more than 300 μm) wherein the average membrane thickness is in the range of 30% to 50% by weight of the coated granules; (d) blending dispersible microgranules of step (a), with taste-masked microcapsules of step (c), and other acceptable ingredients such as a flavoring agent, a coloring agent, a sweetener and additional disintegrant in sufficient quantities to provide a therapeutically effective unit dose; and (e) compressing into tablets using a conventional rotary tablet press equipped with m external lubrication system to pre-lubricate the dies and punches, wherein the ratio of effectively taste-masked microgranules to dispersible microgranules is in the range of 1:1 to 1:10, preferably 1:2 to 1:5 approximately.

(3) The term ‘drug’, ‘active’ or ‘active pharmaceutical ingredient’ as used herein, is meant to include any therapeutic active agent indicated for oral administration such as macrolide antibiotic agents, analgesics, antidepressants, antihistamines, antihypertensives, antimigrane agents, proton pump inhibitors, antipsychotic agents, antiemetic agents, antiparkinson agents, and H.sub.2 antagonists. In one embodiment, the drug candidates include ranitidine, cimetidine, clarithromycin, sumatriptan, lansoprazole, caffeine, cetirizine and their salts thereof. The active, in one embodiment has a particle size less than about 50 microns and is present in the tablet in an amount of about 0.01 to 30% by weight. In one embodiment the active has a particle size less than about 25 microns.

(4) Polymers which impart resilient characteristics to the dried microgranules, include hydroxypropylcellulose (Klucel LF from Aqualon) modified starch (e.g., Starch: 1551 and Starch 1500, commercially available from National Starch and Coloreon, respectively) and hydroxypropyl methylcellulose with a viscosity of 100 cps or more (e.g., Methocel K100LV or Metolose K400 commercially available from Dow Chemical and Shin Etsu Chemicals, respectively) alone or in combination with a widely used binder such as PVP (polyvinylpyrrolidone), hydroxypropylcellulose and hydroxypropyl methylcellulose with a viscosity of 15 cps or less (Methocel E5 or E15 and Pharmacoat 603 or 606 commercially available, from Dow Chemical and Shin Etsu Chemicals, respectively).

(5) Polymers suitable for microencapsulation of bitter drugs include ethylcellulose, cellulose acetate phthalate, hydroxypropyl rnethylcellulose phthalate depending on solubility in water or cyclohexane. No plasticizer is needed for forming membranes on active cores for effective taste-masking. One method for microencapsulating microgranules of the active to impart effective taste-masking characteristics is coacervation by phase separation of ethylcellulose in cyclohexane. Examples of such a coacervation process are disclosed in U.S. Pat. No. 6,139,865, which is incorporated in its entirety by reference.

(6) One or more sugar alcohols and/or saccharides with an average particle size of not more than 30 μm and a disintegrant are granulated with approximately 20-25% water in a high shear granulator, wet milled, dried in a fluid bed equipment to produce rapidly dispersible microgranules of desired particle size (average particle size of not more than about 300 μm in accordance with methods disclosed in USP Application No. 200100114340 published on Aug. 16, 2001). The sugar alcohol may be selected from the group consisting of mannitol, sorbitol, xylitol, maltitol and the like while the saccharide may be selected from the group consisting of lactose, sucrose, maltose or as a mixture of two or more, each of which is characterized by an average particle size of not more than about 30 μm. In one embodiment the sugar alcohol and/or saccharide is present in the tablet in an amount of about 30 to 70% by weight.

(7) A disintegrant is selected from the group consisting of crospovidone (crosslinked PVP), sodium starch glycolate, crosslinked sodium, carboxymethyl cellulose, calcium silicate and low substituted hydroxypropyl cellulose. The disintegrant is typically present in the tablet in an amount of about 1 to 10% by weight. The disintegrant has a particle size less than about 30 microns in one embodiment.

(8) In addition to coated microgranules of the active(s) in appropriate quantities, dispersible microgranules, and additional disintegrant as needed, the tablet produced in accordance with the embodiments of the present invention may contain suitable flavors, sweeteners, permissible colorants as needed. A lubricating agent such as magnesium stearate is not typically blended with this compression mix; but the punches and dies are pre-lubricated with a fine mist of of the lubricant using an external lubrication system. Thus the hydrophobic lubricant is only present in trace quantities and that too on the tablet surface. This act of external lubrication permits rapid penetration of the saliva in the month into the tablet core resulting in rapid disintegration/dispersion of the tablet into granules. These granules soaked in the saliva are carried down the throat into the stomach where the drug is released for maximum efficacy. The act of blending the lubricant with the compression mix and tableting using a conventional tablet press is also an embodiment of the present invention.

(9) It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples which follow below are intended to illustrate and not limit the scope of the invention. Any modification within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

EXAMPLE 1(COMPARISON)

(10) Dispersible Microgranules: The dispersible microgranules comprise a sugar alcohol such as mannitol and a disintegrant. 6.65 kg of mannitol with an average particle size of approximately 10 μm (Pearlitol 25 from Roquette, France) was blended with 350 g of crosslinked povidone (Crospovidone XL 10 from ISP) in a high shear granulator (GMX 25 from Vector) and granulated with sufficient amount of purified water (approximately 1.6 kg) and wet milled using Condi (from Quadro) and dried in a fluid bed drier, Glatt GPCG 5. The dispersible microgranules thus obtained has an average particle size of approximately 160 μm.

(11) Ranitidine Granulation: 400 g of ranitidine HCl was blended with 360 g of mannitol with an average particle size of not more than 25 μm, 40 g of low viscosity hydroxypropyl methylcellulose (Methocel E5) and granulated with purified water. The wet mass was milled using a Comil and dried in the oven at 40° C. for 3 hours.

(12) Microencapsulation: The granules thus obtained were suspended in a solution of cyclohexane containing ethylcellulose with a viscosity of approximately 100 cps and polyethylene at approximately 88° C. and membrane coated by properly cooling (coacervation). The microencapsulated granules were washed and dried. The granules (friable with 40% fines when tested by the friability test procedure) were found to undergo attrition due to agitation in the coacervation tank. The microcapsules thus obtained exhibited poor taste masking.

EXAMPLE 2

(13) Ranitidine Granulation: 400 g of ranitidine HCl was blended with 360 g of mannitol with an average particle size not more than 25 μm, 40 g of hydroxypropyl methylcellulose with an average viscosity of 400 cps and granulated with an aqueous solution of low viscosity hydroxypropyl methylcellulose (Methocel E5). The wet mass was milled using a Comil and dried in the oven at 40° C. for 3 hours. The granules thus obtained were rigid/less friable with a desired particle size distribution (range; most particles, in the range of 140-300 μm).

(14) Microencapsulation: These granules were taste-masked by coacervation following the procedure given in Example 1. The microcapsules thus obtained contained largely intact granules and exhibited improved taste masking. The Laser light scattering and palatability testing suggests that the microcapsules with most desired particle size distribution (average particle size: 368 μm) exhibits an improved taste-masking.

(15) Tableting: Dispersible microgranules (59.5%) were blended with taste-masked microcapsules (30.5%) and other pharmaceutical acceptable ingredients, such as flavor, sweetener, colorant, and additional disintegrant in sufficient quantity to provide a therapeutically effective unit dose (75 mg ranitidine), in a twin shell V-blender for a sufficient time to get homogeneously distributed blending for compression. Unit dose was measured on an analytical balance and compressed into tablet (weighing approximately one gram with a disintegration, time of 45-60 seconds) at an optimized compression force on a carver press.

(16) Dissolution Testing: Both microcapsules and tablets were tested for dissolution using USP Apparatus 2 (paddles @50 rpm) in 900 mL medium at 3° C. and percentage of drug released was determined by HPLC. The results are presented in the table below:

(17) TABLE-US-00001 Drug released % Microcaps Tablet Time (966-DLG-183) (984-VS-133-D) 5 min 8 67 10 min 24 85 20 min 48 92 30 min 60 97 45 min 70 100 60 min 77 100 120 min 87 100

EXAMPLE 3

(18) Granulation: 651 g of ranitidine HCl was blended with 49 g of hydroxypropyl methylcellulose with an average viscosity of 400 cps and granulated with purified water. The wet mass was milled using a Comil and dried in the oven at 40° C. for 3 hours. The granules thus obtained were rigid/less friable with a desired particle size distribution (range: most particles in the range of 200-400 μm).

(19) Microencapsulation: These granules were taste-masked by coacervation following the procedure given in Example 1. The microcapsules thus obtained contained largely intact granules and exhibited improved taste masking. The Laser light scattering and palatability testing suggests that the microcapsules with most desired particle size distribution (average particle size: 400 μm) exhibits an improved taste-masking.

(20) Tableting Dispersible microgranules (73.9%) were blended with taste-masked microcapsules (16.1%) and other pharmaceutical acceptable ingredients, such as flavor, sweetener, colorant, and additional disintegrant in sufficient quantity to provide a therapeutically effective unit does, in a twin shell V-blender for a sufficient time to get homogeneously distributed blending for compression. Unit dose (approximately 1 g) was measured on an analytical balance and compressed into tablet at an optimized compression force on a carver press.

(21) Dissolution testing: Microcapsules and tablets were tested for dissolution using USP Apparatus 2 (paddles @50 rpm) in 900 ml medium at 3° C. and percentage of drug released was determined by HPLC. The results are presented in the table below:

(22) TABLE-US-00002 Drug released % Microcaps Tablet (1088-KKQ-094- (984-VS- Time B-1) 133-C) 5 min 11 43 10 min 27 63 20 min 47 77 30 min 57 84 45 min 68 88 60 min 74 90 120 min 89 94

EXAMPLE 4

(23) Granulation: 600 g of ranitidine HCl was blended with 66.7 g of modified starch, Starch 1500 from Colorcon and granulated with purified water. The wet mass was milted using a Comil and dried in the oven at 40° C. for 3 hours. The granules thus obtained were rigid/less friable with a desired particle size distribution (range: most particles in the range of 140-300 μm).

(24) Microencapsulation: These granules were suspended in cyclohexane containing ethylcellulose with a viscosity of approximately 100 cps and polyethylene at approximately 80° C. and membrane coated by properly cooling (coacervation). The microencapsulated granules were washed and dried. The microcapsules thus obtained contained largely intact granules and exhibited excellent taste-masking.

(25) Tableting: Dispersible microgranules (68.9%) were blended with taste-masked microcapsules (20.1%) and other pharmaceutical acceptable ingredients, such as flavor, sweetener, colorant, and additional disintegrant in sufficient quantity to provide a therapeutically effective unit does, in a twin shell V-blender for a sufficient time to get homogeneously distributed blending for compression. Unit dose weighing approximately one gram was measured on an analytical balance and compressed into tablet at an optimized compression force on a carver press.

(26) Dissolution testing: Both microcapsules and tablets were tested for dissolution using USP Apparatus 2 (paddles @50 rpm) in 900 mL medium, at 37° C. and percentage of drug released was determined by HPLC. The results are presented in the table below:

(27) TABLE-US-00003 Drug Released % Tablet Microcaps (1008-KKQ- Time (1029-DLG-006) 134-C-AdvaTab) 5 min 12 42 10 min 27 63 20 min 45 80 30 min 54 86 45 min 63 91 60 min 68 93 120 min 80 96

EXAMPLE 5

(28) Dispersible Microgranules: The dispersible microgranules comprise a sugar alcohol such as mannitol and a disintegrant. 152 kg of mannitol with an average particle size of approximately 10 μm (Pearlitol 25 from Roquette, France) was blended with 8 kg of crosslinked povidone (Crospovidone XL 10 from ISP) in a high shear granulator (GMX 600 from Vector) and granulated with sufficient amount of purified water (approximately 32 kg) and wet milled using Comil (from Quadro) and dried in a fluid bed drier, Glatt GPCG 200. The dispersible microgranules thus obtained has an average particle size of approximately 160 μm.

(29) Granulation: 5.0 kg of ranitidine HCl was blended with 600 g of modified starch, Starch 1500 from Colorcon and granulated with purified water in high shear mixer GMX 25 (from Vector). The wet mass was milled using a Comil and dried in the oven at 40° C. for 3 hours. The granules thus obtained were hard/non-brittle with a desired particle size distribution (average particle size: 150 μm).

(30) Microencapsulation: These granules were suspended in cyclohexane containing ethylcellulose with a viscosity of approximately 100 cps and polyethylene at approximately 80° C. and membrane coated by properly cooling (coacervation). The microencapsulated granules were washed and dried. The microcapsules thus obtained contained largely intact granules with an average particle size of 150 μm and exhibited excellent taste-masking.

(31) Tableting: Dispersible microgranules (5.4 kg) were blended with taste-masked microcapsules (1.06 kg from lots (1029-DLG-16 and 1029-DLG-17)) and other pharmaceutical acceptable ingredients, such as flavor, sweetener, colorant, and additional disintegrant in sufficient quantity to provide a therapeutically effective unit does, in a twin shell V-blender for a sufficient time to get homogeneously distributed blending for compression. Tablets weighing approximately 1 g were compressed using a production scale Hata Tablet press equipped with Matsui external lubrication system at an average hardness of 5.5 and 6.9 kP, respectively.

(32) Dissolution testing: Microcapsules and tablets were tested for dissolution using USP Apparatus 2 (paddles @50 rpm) in 900 mL medium at 37° C. and percentage of drug released was determined by HPLC. The results are presented in the table below:

(33) TABLE-US-00004 Drug Released % Microcaps 1029- 1029- Tablets DLG- DLG- 984-VS-152-2 Time 016 017 (Hardness: 7.8 kP) 5 min 8 4 27 10 min 23 15 47 20 min 42 33 65 30 min 52 44 75 45 min 63 53 80 60 min 70 62 82 120 min 81 75 90

EXAMPLE 6

(34) Compressible Microcaps: The microcapsules obtained in Example 4 were provided with a compressible coating of an aqueous dispersion of ethylcellulose (a fracture resistant, compressibility enhancing coating at 4% weight gain) in the fluid bed equipment. The coated microcaps were dried and cured. The microcapsules thus obtained exhibited excellent taste-masking. The dissolution was not affected.

(35) Tableting: Dispersible microgranules were blended with taste-masked microcapsules and other pharmaceutical acceptable ingredients, such as flavor, sweetener, colorant, and additional disintegrant in sufficient quantity to provide a therapeutically effective unit does, in a twin shell V-blender for a sufficient time to get homogeneously distributed blending for compression. Unit dose was measured on an analytical balance and compressed into tablet at an optimized compression force on a carver press.

(36) Dissolution testing: Microcapsules and tablets were tested for dissolution using USP Apparatus 2 (paddles @50 rpm) in 900 ml medium at 37° C. and percentage of drug released was determined by HPLC. The results are presented in the table below:

(37) TABLE-US-00005 Drug Released % Microcaps (1029-DLG-015/ Time 904-MDS-151) Tablets 5 min 7 24 10 min 21 45 20 min 39 63 30 min 50 74 45 min 58 85 60 min 66 88 120 min 80 98

EXAMPLE 7

(38) Granulation: 500 g of sumatriptan succinate was blended with 56 g of hydroxypropyl methylcellulose, HPMC K100LV, Hypromellose K100LV from Dow Chemical and granulated with purified water. The wet mass was milled using a Comil and dried in the oven at 40° C. for 3 hours. The granules thus obtained were rigid/less friable with a desired particle size distribution (range: most particles in the range of 280-360 μm).

(39) Microencapsulation: These granules were suspended in cyclohexane containing ethylcellulose with a viscosity of approximately 100 cps and polyethylene at approximately 80° C. and membrane coated by coacervation at two coating levels (lot #1029-DLG-018 at 45% coating and lot #1029-DLG-024 at 35% coating). The microencapsulated granules were washed and dried. The microcapsules thus obtained contained largely intact granules and exhibited excellent taste-masking.

(40) Tableting: Dispersible microgranules of both microcapsule batches were blended with taste-masked microcapsules and other pharmaceutical acceptable ingredients, such as flavor, sweetener, colorant, and additional disintegrant in sufficient quantity to provide a therapeutically effective unit does, in a twin shell V-blender for a sufficient time to get homogeneously distributed blending for compression. Unit dose was measured on an analytical balance and compressed into tablet at similar compression force on a carver press (100 mg (as sumatriptan base) tablets weighing 1200 mg, hardness: 8-9 kP and disintegration time: approximately 30 seconds).

(41) Dissolution testing: Microcapsules were tested for dissolution using USP Apparatus 2 (paddles @50 rpm) in 900 ml medium (0.1N HCl with 0.1% sodium lauryl sulfate) at 3° C. and percentage of drug released was determined by HPLC. The results are presented in the table below:

(42) TABLE-US-00006 Drug Released % Microcaps Tablet Microcaps Tablet (1029-DLG- (1034-KKQ- (1029-DLG- (1029-DLG- 018) 45% 009-C-T) 024) 35% 024-T) 35% Time Coating 45% Coating Coating Coating 5 min — 3 1 8 15 min 3 9 7 21 30 min 14 25 30 47 45 min 37 50 62 72 60 min 64 75 84 89 90 min 94 102 99 102 120 min 102 109 102 104

(43) Friability Testing:

(44) The table presents the friability data for Ranitidine HCl and Sumatriptan succinate microgranules of examples 1 to 5 and 7.

(45) TABLE-US-00007 Friability Granulation Friability (% Example batch fines generated) No 1 1008-KKQ-025-A 40 No 2 1008-KKQ-027-K 12 No 3 1008-KKQ-094-B 9 No 4 1008-KKQ-134-C 10 No 5 1008-KKQ-140-B-1 8 No 6 1034-KKQ-009-C 9

(46) Fine powders of pharmaceuticals, ores, foods, ceramics, and other materials are often agglomerated in various industrial processes and used as granules to overcome difficulties in handling or processing. These agglomerates or granules are required to have various properties, depending on the end use. Above all, granules must have the property of maintaining their integrity during handling and processing. Granules must flow for easy handling and transportation, and that means granules must have proper shape and particle size distribution. Furthermore, granules must be strong enough to maintain their integrity, e.g. shape/size, i.e., should not break or attrition or should exhibit sufficient strength and sufficiently low friability to withstand attrition during handling or processing, such as microencapsulation. At the same time, the microcapsules produced from these granules must be capable of being compacted into tablets with minimal membrane fracture; otherwise, tablets may exhibit undesirable aftertaste.

(47) Granule size can be evaluated using a set of sieves or using a laser light scattering instrument. However, there are no well-established methods or instrumental techniques for rapid/easy testing of granule strength. An in-house method for evaluation of friability of granules to be used for microencapsulation has been developed and described below. This is a measure of the friability or integrity of the granules under dynamic or usage conditions.

(48) The new test method uses a sieve shaker, an apparatus for the measurement of particle size distribution, with a test sieve (typically 140 mesh screen with an opening of approximately 105 μm or as appropriate depending on the particle size distribution of granules), a pan and grinding balls. During the testing, fines produced if the test sample is friable, pass through the sieve and are collected in the pan. Typically 20 grams granules and 100 g of 7-mm diameter ceramic grind balls are placed on the sieve and are subjected to shaking at medium setting for 10 min. At the end of the test, the ceramic balls are separated, the sieve containing the test sample is weighed and % friability is calculated. Based on several measurements and visual and microscopic observations on the microcapsules producing using granules subjected to friability testing, a friability value of 15% is considered an upper limit for granules to be suitable for microencapsulation.

(49) Changes may be made by persons skilled in the art in the construction and the various components and assembly described herein or in the steps or the sequence of steps of the method of manufacture described therein without departing from the spirit and scope of the invention as defined in the following claims: