Therapeutic compositions with enhanced bioavailability

• US 4,344,934 A
• Filed: 02/21/1980
• Issued: 08/17/1982
• Est. Priority Date: 11/20/1978
• Status: Expired due to Term

• Current Assignee: American Home Products Corporation (Pfizer Inc.)
• Original Assignee: American Home Products Corporation (Pfizer Inc.)
• Inventors: Tsuk, Andrew G., Martin, Frederick H.
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/123,143
• Time in Patent Office: 908 Days
• Field of Search: 424/80, 424/285, 424/177
• US Class Current: 514/462
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921

Abstract

Novel compositions comprising wetted mixtures of poorly soluble drugs with water soluble polymers useful in increasing bioavailability are disclosed.

Claims

1. A pharmaceutical composition in dry solid form comprising a mixture of a therapeutically effective amount of a poorly water soluble drug and a non-toxic, pharmacologically acceptable, water-soluble polymer;

said mixture being the product of a melt mix or of a dried solution and said mixture in dry solid form having been treated with solution comprising water and a minor amount of a wetting agent selected from anionic and cationic surfactants and then dried.

2. The composition of claim 1 wherein said polymer is selected from at least one of polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, block co-polymers of ethylene oxide and propylene oxide, and polyethylene glycol.

3. The composition of claim 1 wherein said wetting agent is an anionic surfactant selected from sodium lauryl sulfate, sodium laurate, dioctylsodium sulfosuccinate, sodium stearate, potassium stearate and sodium oleate.

4. The composition of claim 1 wherein said wetting agent is a cationic surfactant selected from benzalkonium chloride and bis-2-hydroxyethyl oleyl amine.

5. The composition of claim 1 or 2 wherein the concentration of said drug is from about 0.1% to about 95% by weight and the concentration of said polymer is from about 5% to about 99% by weight.

6. The composition of claim 1 or 2 wherein the concentration of said drug is from about 50% to about 90% by weight and the concentration of said polymer is from about 10% to about 50% by weight.

7. The composition of claim 1 or 2 wherein the concentration of said drug is about 50% to about 80% by weight and the concentration of said polymer is from about 20% to about 50% by weight.

8. The composition of claim 1, 2, 3 or 4 wherein the concentration of the wetting agent in the drug-polymer mixture is from about 0.025% to about 2.0% by weight.

9. The composition of claim 1, 2, 3 or 4 wherein the concentration of the wetting agent in the drug-polymer mixture is from about 0.2% to about 1.0% by weight.

10. The composition of claim 1, 2 3 or 4 wherein said drug is griseofulvin.

11. The composition of claim 1, 2, 3 or 4 wherein said drug is griseofulvin in a concentration ranging from about 0.1% to about 90% by weight;

the concentration of the polymer is from about 5% to about 95% by weight; and

the concentration of the wetting agent in the drug-polymer mixture is from about 0.025% to about 2.0% by weight.

12. The composition of claim 1, 2, 3 or 4 wherein said drug is griseofulvin in a concentration ranging from about 50% to about 80% by weight;

the concentration of the polymer is from about 20% to about 50% by weight; and

the concentration of the wetting agent in the drug-polymer mixture is from about 0.2% to about 1.0% by weight.

15. A compressed pharmaceutical tablet comprising the composition of claim 1, 2, 3, 4, 13 or 14 wherein said drug is in the form of ultramicrocrystals and pharmaceutically acceptable excipients.

13. A pharmaceutical composition in solid form comprising a mixture of at least about 0.1% to about 90% by weight of griseofulvin;

from about 5% to about 95% by weight of a polymer selected from polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, block copolymers of ethylene oxide and propylene oxide, and polyethylene glycol; and

from about 0.025% to about 2.0% by weight of a wetting agent selected from anionic surfactants which was added to the drug-polymer mixture in dry solid form by a wet treatment from a solution comprising water;

wherein said drug polymer mixture is the product of a melt mix or of a dried solution and said composition was dried following the wet treatment.

14. The composition of claim 13 wherein the concentration of the griseofulvin is from about 50% to about 80% by weight;

from about 20% to about 50% by weight of a polymer selected from polyvinylpyrrolidone and hydroxypropyl cellulose; and

from about 0.2% to about 1.0% by weight of an anionic surfactant selected from sodium lauryl sulfate, sodium sulfate and dioctylsodium sulfosuccinate.

21. A method for treating fungal diseases in mammals which comprises orally administering to said mammal the composition of claim 13 or 14.

16. A method of preparing a pharmaceutical composition with increased bioavailability in mammals from a poorly water soluble or water insoluble drug, which comprises:

(a) forming a solution of the drug with a pharmacologically acceptable, water soluble polymer;

(b) drying the drug-polymer solution;

(c) treating the dried drug-polymer solution with a wetting sufficient amount of a solution comprising water and a wetting agent selected from anionic and cationic surfactants; and

(d) drying the mixture of step (c).

17. The method of claim 16 wherein said polymer is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyethylene glycol and block co-polymers of ethylene oxide and propylene oxide and said wetting agent is an anionic surfactant selected from sodium lauryl sulfate, sodium laurate and dioctyl sodium sulfosuccinate.

18. The method of claim 16 or 17 wherein the solution of the drug and polymer is formed in a mutual solvent;

the drug is griseofulvin and wherein the concentration of griseofulvin in the dried mixture of step (d) is from about 0.1% to about 90% by weight and the concentration of the wetting agent in the dried mixture is about 0.025-2.0% by weight.

19. The method of claim 18 wherein the grisefulvin concentration is from about 50% to about 80% and the concentration of said wetting agent is from about 0.2% to about 1.0%.

20. The product prepared by the method of claim 16 or 17.

22. The product prepared by the method of claim 18.

23. The product prepared by the method of claim 19.