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Claims for Patent: 5,866,166

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Claims for Patent: 5,866,166

Title: Pharmaceutical excipient having improved compressibility
Abstract:A composition, comprising (a) microcrystalline cellulose; and (b) a compressibility augmenting agent which (i) physically restricts the proximity of the interface between adjacent cellulose surfaces; or (ii) inhibits interactions between adjacent cellulose surfaces; or (iii) accomplishes both (i) and (ii) above, is disclosed. The composition is in the form of agglomerated particles of microcrystalline cellulose and the compressibility augmenting agent in intimate association with each other.
Inventor(s): Staniforth; John N. (Bath, GB2), Sherwood; Bob E. (Amenia, NY), Hunter; Edward A. (Glenham, NY)
Assignee: Edward Mendell Co., Inc. (Patterson, NY)
Application Number:08/660,553
Patent Claims: 1. A composition, comprising

(a) microcrystalline cellulose; and

(b) a compressibility augmenting agent which

(i) physically restricts the proximity of the interface between adjacent cellulose surfaces; or

(ii) physically restricts the Proximity of the interface between adjacent cellulose surfaces and inhibits interactions between adjacent cellulose surfaces;

said composition comprising agglomerated particles of said microcrystalline cellulose and said compressibility augmenting agent in intimate association with each other.

2. The composition of claim 1, wherein said compressibility augmenting agent provides a hydrophobic boundary at cellulose surfaces.

3. The composition of claim 1, wherein said compressibility augmenting agent (i) is a silicon dioxide having an average primary particle size from about 1 nm to about 100 .mu.m.

4. The composition of claim 1, wherein said compressibility augmenting agent (i) is colloidal silicon dioxide.

5. The composition of claim 1, which is prepared by preparing an aqueous slurry of microcrystalline cellulose, compressibility augmenting agent(s), and other optional ingredients, and drying the mixture in a manner which inhibits quasi-hornification.

6. The composition of claim 3, wherein said silicon dioxide is included in amount from about 0.1% to about 20% by weight, based on the weight of microcrystalline cellulose.

7. The composition of claim 4, wherein said silicon dioxide is included in an amount of from about 1.25% to about 5%, based on the weight of said microcrystalline cellulose.

8. The composition of claim 1, wherein said agglomerated particles have an average particle size of from about 10 .mu.m to about 1,000 .mu.m.

9. The composition of claim 1, wherein said agglomerated particles further comprise a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, polyalkylene oxides, stearic acid, kaolin, polydimethylsiloxane, silica gel, diatomaceous earth, and mixtures thereof.

10. The composition of claim 3, wherein said silicon dioxide portion of said agglomerate is derived from a silicon dioxide having a surface area from about 10 m.sup.2 /g to about 500 m.sup.2 /g.

11. The composition of claim 1, further comprising an active agent.

12. The composition of claim 11, wherein said agglomerated particles and said active agent are wet granulated.

13. An aqueous slurry useful in the preparation of a compressible pharmaceutical excipient, comprising a mixture of microcrystalline cellulose and from about 0.1% to about 20% by weight of a compressibility augmenting agent which (i) physically restricts the proximity of the interface between adjacent cellulose surfaces; or (ii) physically restricts the proximity of the interface between adjacent cellulose surfaces and inhibits interactions between adjacent cellulose surfaces; the solids content of said aqueous slurry being from about 0.5% to about 25% by weight.

14. The slurry of claim 13, which has a solids content from about 15% to about 20%.

15. The slurry of claim 13, which has a solids content from about 17% to about 19%.

16. The slurry of claim 13, wherein said compressibility augmenting agent (i) is a silicon dioxide having an average primary particle size from about 1 nm to about 100 .mu.m.

17. The slurry of claim 13, wherein said compressibility augmenting agent comprises effective amounts of a silicon dioxide having an average primary particle size from about 1 nm to about 100 .mu.m and a surfactant having an HLB value from about 15 to about 50.

18. The slurry of claim 16, wherein the silicon dioxide is colloidal silicon dioxide.

19. A solid dosage form of a compressed mixture of from about 1% to about 99% of an excipient comprising a particulate agglomerate of microcrystalline cellulose and an effective amount of a compressibility augmenting agent to improve the compressibility of said microcrystalline cellulose, said compressibility augmenting agent acting to (i) physically restrict the proximity of the interface between adjacent cellulose surfaces; or (ii) physically restrict the proximity of the interface between adjacent cellulose surfaces and inhibit interactions between adjacent cellulose surfaces; from about 99% to about 1% of a therapeutically active ingredient.

20. The composition of claim 19, wherein said compressibility augmenting agent (i) is a silicon dioxide having an average primary particle size from about 1 nm to about 100 .mu.m.

21. The composition of claim 19, which has been wet granulated prior to compression into a tablet.

22. A method of forming a compressible granulate, comprising:

(a) forming an aqueous slurry containing a mixture of microcrystalline cellulose and an effective amount of a compressibility augmenting agent to improve the compressibility of said microcrystalline cellulose, said compressibility augmenting agent acting to (i) physically restrict the proximity of the interface between adjacent cellulose surfaces; or (ii) inhibit interactions between adjacent cellulose surfaces; or (iii) both (i) and (ii) above; and

(b) drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of said microcrystalline cellulose in intimate association with said compressibility enhancing agent; and

(c) wet granulating said excipient with an active ingredient to form a compressible granulate.

23. The method of claim 22, further comprising drying said slurry such that the resultant excipient particles have an average particle size from about 10 .mu.m to about 1,000 .mu.m.

24. The method of claim 22, further comprising drying said slurry such that the resultant excipient particles have a moisture content of from about 0.5 to about 15%.

25. The method of claim 22, further comprising incorporating into said slurry a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, polyalkylene oxides, stearic acid, kaolin, polydimethylsiloxane, silica gel, diatomaceous earth, and mixtures thereof.

26. A method of preparing a solid dosage form, comprising:

(a) forming an aqueous slurry containing a mixture of microcrystalline cellulose and an effective amount of a compressibility augmenting agent to improve the compressibility of said microcrystalline cellulose, said compressibility augmenting agent acting to (i) physically restrict the proximity of the interface between adjacent cellulose surfaces, or (ii) inhibit interactions between adjacent cellulose surfaces, or (iii) both (i) and (ii) above; and

(b) drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of said microcrystalline cellulose in intimate association with said compressibility enhancing

(c) wet granulating an active ingredient with said excipient in a ratio from about 1:99 to about 99:1; and

(d) compressing said mixture obtained in step (c) into tablets.

27. A composition, comprising:

(a) microcrystalline cellulose; and

(b) a compressibility augmenting agent which inhibits interactions between adjacent cellulose surfaces, the compressibility augmenting agent selected from a group consisting of (i) a highly polar molecule in an amount effective to augment the compressibility of the microcrystalline cellulose and a (ii) surfactant in an amount from about 0.1% to 0.5% by weight of the microcrystalline cellulose,

said composition comprising agglomerated particles of said microcrystalline cellulose and said compressibility augmenting agent in intimate association with each other.

28. The composition of claim 27, wherein said agglomerated particles and said active agent are wet granulated.

29. The composition of claim 27, which is prepared by preparing an aqueous slurry of microcrystalline cellulose, compressibility augmenting agent(s), and other optional ingredients, and drying the mixture in a manner which inhibits quasi-hornification.

30. The composition of claim 27, wherein said agglomerated particles have an average particle size of from about 10 .mu.m to about 1,000 .mu.m.

31. The composition of claim 27, wherein said agglomerated particles further comprise a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, polyalkylene oxides, stearic acid, kaolin, polydimethylsiloxane, silica gel, diatomaceous earth, and mixtures thereof.

32. An aqueous slurry useful in the preparation of a compressible pharmaceutical excipient, comprising a mixture of microcrystalline cellulose and from about 0.1% to about 20% by weight of a compressibility augmenting agent which inhibits interactions between adjacent cellulose surfaces, the compressibility augmenting agent selected from the group consisting of (i) a highly polar molecule in an amount effective to augment the compressibility of the microcrystalline cellulose and (ii) a surfactant in an amount from about 0.1% to 0.5% by weight of the microcrystalline cellulose; the solids content of said aqueous slurry being from about 0.5% to about 25% by weight.

33. The slurry of claim 31, which has a solids content from about 15% to about 20%.

34. The slurry of claim 31, which has a solids content from about 17% to about 19%.

35. A solid dosage form of a compressed mixture of from about 1% to about 99% of an excipient comprising

a particulate agglomerate of microcrystalline cellulose;

an effective amount of a compressibility augmenting agent to improve the compressibility of said microcrystalline cellulose, the compressibility augmenting agent selected from a group consisting of (i) a highly polar molecule in an amount effective to augment the compressibility of the microcrystalline cellulose and (ii) a surfactant in an amount from about 0.1% to 0.5% by weight of the microcrystalline cellulose; and

from about 99% to about 1% of a therapeutically active ingredient.

36. A compressible granulate comprising

(a) a composition including monocrystalline cellulose and a compressibility augmenting agent, said compressibility augmenting agent acting to (i) physically restrict the proximity of the interface between adjacent cellulose surfaces, or (ii) inhibit interactions between adjacent cellulose surfaces, or (iii) both (i) and (ii) above, the composition comprising agglomerated particles of said microcrystalline cellulose and said compressibility augmenting agent in intimate association with each other; and

(b) an active agent, the composition and the active agent being wet granulated to form a compressible granulate.

37. The composition of claim 27, wherein said compressibility augmenting agent is a surfactant having an HLB value of at least 10.

38. The composition of claim 27, wherein said compressibility augmenting agent is a surfactant having an HLB value from about 15 to about 50.

39. The composition of claim 27, wherein said compressibility augmenting agent is sodium lauryl sulfate.

40. The composition of claim 27, wherein said compressibility augmenting agent is polysorbate 40.

41. The composition of claim 27, wherein said compressibility augmenting agent is a highly polar compound.

42. The composition of claim 27, wherein said compressibility augmenting agent is a highly polar dye selected from the group consisting of 3,3'-[[1,1'Biphenyl-4,4'-diylbis-(azo)]bis[4-amino-1-naphthalenesulfonic acid] disodium salt; disodium salt of 6-hydroxy-5[(2-methyl-4-sulfophenyl) azo]-2-naphthalenesulfonic acid); 5-oxo-1-(p-sulfophenyl)-4-[(p-sulfophenyl) azo]-2-pyrazoline-3-carboxylic acid, trisodium salt); disodium salt of 1-p-sulphophenylazo-2-naphthol-6-sulfonic acid); trisodium-7-hydroxy-3-(4-sulfonato-1-naphthylazo) naphthalene-6, 8-disulfonate); disodium 4,4'-(2,4-dihydroxy-5-hydroxymethyl-3, 3-phenylene bisazo)di(napthalene-1-sulfonate)); tetrasodium 4-acetamido-5-hyroxy-6-[7-sulfonato-4-(4-sulfonatophenylazo) -1-naphthylazo]naphthalene-1,7-disulfonate); disodium 4-hydroxy-3-(4-sulfanato-1-naphythylazo) Naphthalene-1-sulfonate); trisodium 2-hydroxy-1-(4-sulfonato-1-naphthylazo) naphthalene-3, 6-disulfonate); and mixtures thereof.

43. The composition of claim 27, which is prepared in a manner which significantly reduces the hydrogen bonding between inter- and/or intra-molecular cellulose-to-cellulose bonding which occurs when microcrystalline cellulose is exposed to water.

44. The composition of claim 43, wherein the drying step is accomplished via spray drying.

45. The slurry of claim 32, wherein said compressibility augmenting agent is a surfactant having all HLB value from about 15 to about 50.
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