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Claims for Patent: 6,106,865

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Claims for Patent: 6,106,865

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, GB), Hunter; Edward A. (Glenham, NY), Sherwood; Bob E. (Amenia, NY)
Assignee: Edward Mendell Co., Inc. (Patterson, NY)
Application Number:09/037,841
Patent Claims: 1. A composition, comprising

microcrystalline cellulose; and

an effective amount of a compressibility augmenting agent selected from the group consisting of silicon dioxide, a surfactant, a highly polar compound, and mixtures thereof, provided that when the compressibility augmenting agent consists of said surfactant, said surfactant is present in an amount from about 0.1% to about 0.5% by weight of said microcrystalline cellulose;

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 silicon dioxide has an average primary particle size from about 1 nm to about 100 .mu.m.

4. The composition of claim 1, wherein said silicon dioxide is colloidal silicon dioxide.

5. The composition of claim 1, wherein said surfactant has an HLB value of at least 10.

6. The composition of claim 1, wherein said surfactant has an HLB value of from about 15 to about 50.

7. The composition of claim 1, wherein said surfactant is sodium lauryl sulfate.

8. The composition of claim 1, wherein said surfactant is polysorbate 40.

9. The composition of claim 1, wherein said highly polar compound 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-2-hydroxy-1-(4-sulfonato-1-naphthylazo)naphthalene-6,8-disulfona te); 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.

10. The composition of claim 1, 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.

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

12. The composition of claim 10, wherein the drying step is accomplished via spray drying.

13. The composition of claim 1, wherein said silicon dioxide is included in amount from about 0.1% to about 20% by weight, based on the weight of microcrystalline cellulose.

14. The composition of claim 13, 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.

15. 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.

16. 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.

17. The composition of claim 1, 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.

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

19. The composition of claim 18, wherein said agglomerated particles and said active agent are wet granulated.

20. 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 selected from the group consisting of silicon dioxide, a surfactant, a highly polar compound, and mixtures thereof; provided that when the compressibility augmenting agent consists of said surfactant, said surfactant is present in an amount which from about 0.1% to about 0.5% by weight of said microcrystalline cellulose; and from about 99% to about 1% of a therapeutically active ingredient.

21. The composition of claim 20, which has been wet granulated prior to compression into a tablet.

22. A method of enhancing the compressibility of microcrystalline cellulose in wet granulation products, comprising:

(a) forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake, and an effective amount of a compressibility augmenting agent to improve the compressibility of said microcrystalline cellulose, said compressibility augmenting agent selected from the group consisting of silicon dioxide, a surfactant, a highly polar compound, and mixtures thereof; 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,

provided that when the compressibility augmenting agent consists of said surfactant, said surfactant is present in an amount from about 0.1% to about 0.5% by weight of said microcrystalline cellulose.

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 in the form of a wet cake and an effective amount of a compressibility augmenting agent, said compressibility augmenting agent selected from the group consisting of silicon dioxide, a surfactant, a highly polar compound and mixtures thereof; 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 augmenting agent;

(c) mixing 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; said effective amount of the compressibility augmenting agent being sufficient to improve the compressibility of said microcrystalline cellulose, provided that when the compressibility augmenting agent consists of said surfactant, said surfactant is present in an amount from about 0.1% to about 0.5% by weight of said microcrystalline cellulose.

27. The method of claim 26, wherein said mixing in step (c) is performed via wet granulation.

28. The method of claim 22, wherein the surfactant is selected from the group consisting of polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glycerol esters, polyglycerol fatty acid esters, SPAN's, sucrose esters, glucose (dextrose) esters, acacia, benzalkonium chloride, cholesterol, emulsifying wax, glycerol monostearate, lanolin alcohols, lecithin, poloxamer, polyoxyethylene, and castor oil derivatives.

29. The method of claim 22, wherein the surfactant is sodium lauryl sulfate.

30. The method of claim 22, wherein the wherein the highly polar compound is 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-2-hydroxy-1-(4-sulfonato-1-naphthylazo)naphthalene-6,8-disulfona te); 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.

31. The method of claim 26, wherein the surfacant is selected from the group consisting of polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glycerol esters, polyglycerol fatty acid esters, SPAN's, sucrose esters, glucose (dextrose) esters, acacia, benzalkonium chloride, cholesterol, emulsifying wax, glycerol. monostearate, lanolin alcohols, lecithin, poloxamer, polyoxyethylene, and castor oil derivatives.

32. The method of claim 26, wherein the surfactant is sodium lauryl sulfate.

33. The method of claim 26, wherein the highly polar compound is 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-2-hydroxy-1-(4-sulfonato-1-naphthylazo)naphthalene-6,8-disulfona te); 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.
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