Sustained-release formulations utilizing pharmaceutical excipient having improved compressibility

• US 5,741,524 A
• Filed: 07/08/1996
• Issued: 04/21/1998
• 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): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/676,654
• Time in Patent Office: 652 Days
• Field of Search: 424/490, 424/489, 424/78.1, 424/461, 424/468, 424/486, 424/487, 424/480, 424/494
• 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 sustained-release formulation comprising:

an active agent;

an augmented microcrystalline cellulose comprising agglomerated particles 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; and

a matrix comprising a sustained-release carrier to promote sustained-release of said active agent.

2. The sustained-release formulation of claim 1, wherein said compressibility augmenting agent is a surfactant having an HLB of at least about 10.

3. The sustained-release formulation of claim 1, wherein said compressibility augmenting agent is a surfactant having an HLB of from about 15 to about 40.

4. The sustained release formulation 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.

5. The sustained-release formulation 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.

6. The sustained release formulation of claim 4, wherein said silicon dioxide is colloidal silicon dioxide.

7. The sustained-release formulation of claim 1, wherein said compressibility augmenting agent is a surfactant.

8. The sustained-release formulation of claim 7, wherein said compressibility augmenting agent is sodium lauryl sulfate.

9. The sustained release formulation of claim 1, wherein said compressibility augmenting agent is a polysorbate.

10. The sustained-release formulation of claim 2, wherein said surfactant is included in an amount from about 0.1% to about 20% by weight, based on the weight of microcrystalline cellulose.

11. The sustained-release formulation of claim 1, wherein said compressibility augmenting agent is a pharmaceutically acceptable highly polar compound.

12. The sustained-release formulation of claim 11, 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-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-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.

13. The sustained-release formulation 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.

14. The sustained-release formulation of claim 13, wherein said retardant is a hydrophilic gum.

15. The sustained-release formulation of claim 13, wherein said retardant is a hydrophilic polymer.

16. The sustained-release formulation of claim 13, which comprises

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

said core coated with at least a portion of solid sustained released carrier.

17. The sustained-release formulation of claim 16, wherein said immediate release core is in the form of a tablet.

18. The sustained-release formulation of claim 13, which comprises a matrix including said augmented microcrystalline cellulose, at least a portion of said sustained release carrier, and said active agent.

19. The sustained-release formulation of claim 18, wherein said matrix is compressed into a tablet.

20. The sustained-release formulation of claim 19, wherein a portion of said sustained-release carrier is coated onto the surface of said tablet.

21. The sustained-release formulation of claim 18, 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-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-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.

22. The sustained-release formulation of 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.

23. The sustained-release formulation of claim 1, wherein said augmented microcrystalline cellulose is wet granulated with said sustained-release carrier.

24. The sustained-release formulation of claim 1, wherein said augmented microcrystalline cellulose is wet granulated with said active agent.

25. The sustained-release formulation of claim 23, wherein said active agent, augmented microcrystalline cellulose and said sustained-release carrier are compressed into a tablet.

26. The sustained-release formulation of claim 24, wherein said active agent, augmented microcrystalline cellulose and said sustained-release carrier are compressed into a tablet.

27. The sustained-release formulation of claim 25, 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.

28. The sustained-release formulation of claim 26, 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 sustained-release formulation of 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.

30. The sustained-release of claim 24, wherein said augmented microcrystalline cellulose and said active agent are compressed into tablets and said sustained-release carrier is applied as a coating on said tablets.