Sustained release formulations utilizing pharmaceutical excipient having improved compressibility with modified microcrystalline

• US 5,858,412 A
• Filed: 12/17/1997
• Issued: 01/12/1999
• Est. Priority Date: 01/09/1995
• Status: Expired due to Term

• Current Assignee: J Rettenmaier & Sohne GmbH Company KG
• Original Assignee: Edward Mendell Co., Inc.
• Inventors: Hunter, Edward A., Staniforth, John N., Sherwood, Bob E.
• Primary Examiner(s): Dees, Jose G.
• Assistant Examiner(s): Williamson, Michael A.
• Application Number:
  US08/982,224
• Time in Patent Office: 391 Days
• Field of Search: 424/489, 424/494, 424/480, 424/486, 424/487, 424/468, 424/490, 424/461
• US Class Current: 424/489
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2036 Silicones; Polysiloxanes
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

Sustained release formulations include an augmented microcrystalline cellulose, an active agent, and a sustained release carrier and methods for making same are disclosed.

Claims

1. A method of preparing a sustained-released pharmaceutical formulation, comprising:

forming an aqueous slurry containing a mixture of microcrystalline cellulose and a compressibility augmenting agent which (i) physically restricts the proximity of the interface between adjacent cellulose surfaces, (ii) inhibits interactions between adjacent cellulose surfaces, or (iii) accomplishes both (i) and (ii) above;

drying said slurry to obtain an augmented microcrystalline cellulose comprising a plurality of agglomerated particles of said microcrystalline cellulose in intimate association with said augmenting agent;

adding an effective amount of an active agent to said slurry or said dried augmented microcrystalline cellulose; and

incorporating an effective amount of a sustained-release carrier to obtain a final product which provides sustained-release of said active agent in an environment of use.

2. The method of claim 1, further comprising wet granulating said augmented microcrystalline cellulose and at least a portion of said sustained-release carrier to form a matrix.

3. The method of claim 1, further comprising incorporating said active agent into said matrix.

4. The method of claim 3, further comprising compressing said matrix to form a tablet.

5. The method of claim 3, further comprising coating said tablet with a portion of said sustained-release carrier.

6. The method of claim 1, further comprising compressing said excipient together with said therapeutic agent to form an immediate release core.

7. The method of claim 3, wherein said immediate release core is coated with at least a portion of said sustained-release carrier.

8. The method according to claim 1, wherein said compressibility augmenting agent is a surfactant included in an amount from about 0.1% to about 0.5% by weight, based on the weight of microcrystalline cellulose.

9. The method according to claim 1, further comprising the step of wet granulating said augmented microcrystalline cellulose with said sustained-release carrier.

10. The method according to claim 1, further comprising the step of wet granulating said augmented microcrystalline cellulose with said active agent.

11. The method according to claim 9, further comprising the step of compressing said active agent, augmented microcrystalline cellulose and said sustained-release carrier into a tablet.

12. The method according to claim 10, further comprising the step of compressing said active agent, augmented microcrystalline cellulose and said sustained-release carrier into a tablet.

13. The method according to claim 11, wherein said sustained-release carrier comprises a retardant selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, polylactides, polyglycolides, cellulose ethers, cellulose esters, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, polypeptides, polyesters, polyorthoesters, hydrophilic polymers, hydrophilic gums, waxes and wax-like materials, and mixtures thereof.

14. The method according to claim 12, wherein said sustained-release carrier comprises a retardant selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, polylactides, polyglycolides, cellulose ethers, cellulose esters, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, polypeptides, polyesters, polyorthoesters, hydrophilic polymers, hydrophilic gums, waxes and wax-like materials, and mixtures thereof.

15. The method according to claim 1, wherein said augmented microcrystalline cellulose includes a compressibility augmenting agent which inhibits interaction between adjacent cellulose surfaces via the creation the hydrophobic boundary at cellulose surfaces.

16. The method according to claim 10, further comprising the steps of compressing said augmented microcrystalline cellulose and said active agent into a tablet and applying said sustained-release carrier as a coating on said tablet.

17. The method of claim 1, wherein said compressibility augmenting agent is a surfactant having an HLB of at least about 10.

18. The method of claim 1, wherein said compressibility augmenting agent is a surfactant having an HLB of from about 15 to about 40.

19. The method of claim 1, wherein said compressibility augmenting agent is a silicon dioxide derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 nm.

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

21. The method of claim 19, wherein said silicon dioxide is colloidal silicon dioxide.

22. The method of claim 1, wherein said compressibility augmenting agent is a surfactant.

23. The method of claim 22, wherein said compressibility augmenting agent is sodium lauryl sulfate.

24. The method of claim 1, wherein said compressibility augmenting agent is a polysorbate.

25. The method of claim 11, wherein said surfactant is included in an amount from about 0.1% to about 20% by weight, based on the weight of microcrystalline cellulose.

26. The method of claim 1, wherein said compressibility augmenting agent is a pharmaceutically acceptable highly polar compound.

27. The method of claim 26, wherein said highly polar compound is a suitable 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(2-methyl-4-sulfophenyl)azo!-2-naphtalenesulfonic 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-disulfonate);

disodium 4,4'"'"'-(2,4-dihydroxy-5-hydroxymethyl-3,3-phenylene bisazo)di(napthalene-1-sulfonate));

tetrasodium 4-acetamido-5-hydroxy-6- 7-sulfonato-4-(4-sulfonatophenylazo)-1-Naphthylazo!naphthalene-1,7-disulfonate);

disodium 4-hydroxy-3-(4-sulfonato-1-naphythylazo)naphthalene-1-sulfonate);

trisodium 2-hydroxy-1-(4-sulfonato-1-naphthylazo)naphthalene-3,6-disulfonate); and

mixtures thereof.

28. The method of claim 1, wherein said sustained-release carrier comprises a retardant selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, polylactides, polyglycolides, cellulose ethers, cellulose esters, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, polypeptides, polyesters, polyorthoesters, hydrophilic polymers, hydrophilic gums, waxes and wax-like materials, and mixtures thereof.

29. The method of claim 28, wherein said retardant is a hydrophilic gum.

30. The method of claim 28, wherein said retardant is a hydrophilic polymer.

31. The method of claim 1, which further comprises the steps of:

forming an immediate release core comprising the augmented microcrystalline cellulose including the compressibility augmenting agent, and the effective amount of a therapeutic agent; and

coating the core with at least a portion of the sustained released carrier.

32. The method of claim 31, wherein said step of forming said immediate release core includes forming said immediate release core as a tablet.

33. The method of claim 1, further comprising the step of forming a matrix including said augmented microcrystalline cellulose, at least a portion of said sustained release carrier, and said active agent.

34. The method of claim 33, further comprising the step of compressing said matrix into a tablet.

35. The method of claim 34, further comprising the step of coating the surface of the tablet with a portion of said sustained-release carrier.

36. The method of claim 33, wherein said compressibility augmenting agent is a highly polar compound, said highly polar compound being a suitable 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-disulfonate);

disodium 4,4'"'"'-(2,4-dihydroxy-5-hydroxymethyl-3,3-phenylene bisazo)di(napthalene-1-sulfonate));

tetrasodium 4-acetamido-5-hydroxy-6- 7-sulfonato-4-(4-sulfonatophenylazo)-1-naphthylazo!naphthalene-1,7-disulfonate);

disodium 4-hydroxy-3-(4-sulfonato-1-naphythylazo)Naphthalene-1-sulfonate);

trisodium 2-hydroxy-1-(4-sulfonato-1-naphthylazo)naphthalene-3,6-disulfonate); and

mixtures thereof.