Pharmaceutical excipient having improved compressibility

• US 5,725,884 A
• Filed: 09/30/1996
• Issued: 03/10/1998
• Est. Priority Date: 01/09/1995
• Status: Expired due to Fees

• Current Assignee: J Rettenmaier & Sohne GmbH Company KG
• Original Assignee: Edward Mendell Co., Inc.
• Inventors: Staniforth, John H., Hunter, Edward A., Sherwood, Bob E.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): BENSTON JR, WILLIAM E
• Application Number:
  US08/724,613
• Time in Patent Office: 526 Days
• Field of Search: 424/489, 424/472, 424/156, 424/480, 424/488
• 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: Y10S 977/727 formed from biological material
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/775 Nanosized powder or flake, e.g. nanosized catalyst
• CPC Class Codes: Y10S 977/801 Drug
• CPC Class Codes: Y10S 977/89 Deposition of materials, e.g. coating, cvd, or ald
• CPC Class Codes: Y10S 977/896 Chemical synthesis, e.g. chemical bonding or breaking
• 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
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

A microcrystalline cellulose-based excipient having improved compressibility, whether utilized in direct compression, dry granulation or wet granulation formulations, is disclosed. The excipient is an agglomerate of microcrystalline cellulose particles and from about 0.1% to about 20% silicon dioxide particles, by weight of the microcrystalline cellulose, wherein the microcrystalline cellulose and silicon dioxide are in intimate association with each other. The silicon dioxide utilized in the novel excipient has a particle size from about 1 nanometer to about 100 microns. Most preferably, the silicon dioxide is a grade of colloidal silicon dioxide.

Claims

1. 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 silicon dioxide based on the weight of said microcrystalline cellulose, said silicon dioxide having an average primary particle size from about 1 nm to about 100 μ

m, the solids content of said aqueous slurry being from about 0.5% to about 25% by weight.

2. A solid dosage form of a compressed mixture of from about 1% to about 99% of an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 20% by weight silicon dioxide, the microcrystalline cellulose and silicon dioxide being in intimate association with each other, said silicon dioxide portion of said agglomerate being derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 μ

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

3. The solid dosage form of claim 2, wherein the silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size from about 5 μ

m to about 50 μ

m.

4. The solid dosage form of claim 2, wherein the silicon dioxide portion of said agglomerate is derived from colloidal silicon dioxide.

5. The solid dosage form of claim 4, which has been wet granulated prior to compression.

6. The solid dosage form of claim 2, which is incorporated into an oral dosage form.

8. The solid dosage form of claim 2, wherein said silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size from about 5 nm to about 40 μ

m.

9. The solid dosage form of claim 2, wherein said silicon dioxide is included in amount from about 0.1% to about 20% by weight, based on the weight of microcrystalline cellulose.

10. The solid dosage form of claim 2, wherein said silicon dioxide is present in an amount ranging from about 0.5% to about 10% by weight, based on the weight of said microcrystalline cellulose.

11. The composition of claim 2, 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.

12. The solid dosage form of claim 2, wherein said excipient particles have an average particle size of from about 10 μ

m to about 1,000 μ

m.

13. The solid dosage form of claim 2, wherein said excipient particles have an average particle size of from about 10 μ

m to about 500 μ

m.

14. The solid dosage form of claim 2, wherein said excipient particles have an average particle size of from about 30 μ

m to about 250 μ

m.

15. The solid dosage form of claim 2, wherein said excipient particles have a moisture content from about 0.5% to about 15%.

16. The solid dosage form of claim 2, wherein said excipient particles further comprise a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, celluloses, cellulose ethers, cellulose esters and mixtures thereof.

17. The solid dosage form of claim 2, wherein said silicon dioxide portion of said agglomerate is derived from a silicon dioxide having a surface area from about 10 m² /g to about 500 m² /g.

18. The solid dosage form of claim 2, wherein said silicon dioxide portion of said agglomerate is derived from a silicon dioxide having a surface area from about 175 m² /g to about 350 m² /g.

19. The solid dosage form of claim 2, wherein said excipient has a bulk density from about 0.2 g/ml to about 0.6 g/ml.

20. The solid dosage form of claim 2, wherein said excipient has a bulk density from about 0.35 g/ml to about 0.55 g/ml.

21. The solid dosage form of claim 2, prepared by a process comprising the steps of

(a) forming an aqueous slurry containing a mixture of microcrystalline cellulose and silicon dioxide having a particle size from about 1 nm to about 100 μ

m, the amount of silicon dioxide being from about 0.1% to about 20% relative to the amount of microcrystalline cellulose, by weight;

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

(c) mixing an active ingredient with said excipient in a ratio from about 1;

99 to about 99;

1;

(d) incorporating said mixture obtained in step (c) into a plurality of solid dosage forms.

7. 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 and silicon dioxide having an average primary particle size from about 1 nm to about 100 μ

m, the amount of silicon dioxide being from about 0.1% to about 20% relative to the amount of microcrystalline cellulose, by weight; and

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