Suspending vehicles and pharmaceutical suspensions for drug dosage forms

• US 20060216242A1
• Filed: 01/30/2006
• Published: 09/28/2006
• Est. Priority Date: 02/03/2005
• Status: Abandoned Application

• Current Assignee: DURECT Corporation
• Original Assignee: DURECT Corporation
• Inventors: Weeks, Eric William, Rohloff, Catherine Manya, Berry, Stephen Andrew
• Application Number:
  US11/342,445
• Publication Number:
  US 20060216242A1
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00

Abstract

Suspending vehicles and pharmaceutical suspensions that include a biocompatible polymer that can be combined with a hydrophobic solvent and a hydrophilic solvent to provide vehicles and suspensions that are substantially free of stiff gels upon contact with an aqueous medium are provided. Vehicles and suspensions remain flowable out of a pump-driven dosage form over the life of the dosage form. Such vehicles and suspensions are also biocompatible, suitable for creating and maintaining drug suspensions, and capable of providing stable drug formulations.

Claims

1. A suspending vehicle in a pump-driven dosage form comprising a hydrophobic solvent, a hydrophilic solvent, and a biocompatible polymer, wherein the suspending vehicle is substantially free of stiff gels upon contact with an aqueous medium.

2. The suspending vehicle of claim 1, wherein the polymer is a polyester, a pyrrolidone, an ester of unsaturated alcohols, an ether of unsaturated alcohols, a polyoxyethylenepolyoxypropylene block copolymer, or combinations thereof.

3. The suspending vehicle of claim 2 wherein the polymer comprises polyvinyl pyrolidone (PVP).

4. The suspending vehicle of claim 1 wherein a weight ratio of the hydrophobic solvent to the hydrophilic solvent is from about 50:

50 to about 99;

1.

5. The suspending vehicle of claim 4 wherein the weight ratio of the hydrophobic solvent to the hydrophilic solvent is from about 50:

50 to about 90;

10.

6. The suspending vehicle of claim 1 wherein a weight ratio of a combination of the hydrophilic solvent and the hydrophobic solvent to the polymer is from about 30:

70 to about 70;

30.

7. The suspending vehicle of claim 6 wherein the weight ratio of a combination of the hydrophilic solvent and the hydrophobic solvent to the polymer is from about 40:

60 to about 55;

45.

8. The suspending vehicle of claim 1 wherein the hydrophilic solvent comprises benzyl alcohol, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl phosphate, diethyl phthalate, diethyl tartrate, polybutene, silicone fluid, glycerine, ethylene glycol, polyethylene glycol, octanol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, glycofurol, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, 1-dodecylazacyclo-heptan-2-one, polysorbate 80, tetraglycol, or combinations thereof.

9. The suspending vehicle of claim 1 wherein the hydrophobic solvent comprises a carboxylic acid ester, a polyhydric alcohol, a polymer of a polyhydric alcohol, a fatty acid, an oil, propylene carbonate, an ester of a polyhydric alcohol, a triethylglyceride, or combinations thereof.

10. The suspending vehicle of claim 1 wherein the hydrophobic solvent comprises benzyl benzoate, lauryl alcohol, decyl alcohol, lauryl lactate, myristyl lactate, myristyl alcohol, decyl lactate, Ceraphyl®

31, ethyl oleate, ethyl hexyl lactate, a vegetable oil, vitamin E, oleic acid, a mineral oil, or combinations thereof.

11. The suspending vehicle of claim 1 wherein the suspending vehicle has a viscosity of from about 500 poise to about 70,000 poise at 37°

C.

12. The suspending vehicle of claim 11 wherein the suspending vehicle has a viscosity of from about 5,000 poise to about 25,000 poise at 37°

C.

13. A kit comprising the suspending vehicle of claim 1 and instructions for suspending or dispersing a pharmaceutically active agent therein to create a pharmaceutical suspension.

14. The kit of claim 13 further comprising a pump-driven dosage form and instructions for loading the dosage form with the pharmaceutical suspension.

15. A pharmaceutical suspension comprising a pharmaceutically active agent and a suspending vehicle, wherein the pharmaceutically active agent is suspended or dispersed in the suspending vehicle, wherein the suspending vehicle comprises a hydrophobic solvent, a hydrophilic solvent, and a biocompatible polymer and the suspending vehicle is substantially free of stiff gels upon contact with an aqueous medium.

16. The suspension of claim 15, wherein the polymer is a polyester, a pyrrolidone, an ester of unsaturated alcohols, an ether of unsaturated alcohols, a polyoxyethylenepolyoxypropylene block copolymer, or combinations thereof.

17. The suspension of claim 16 wherein the polymer comprises polyvinyl pyrolidone (PVP).

18. The suspension of claim 15 wherein the hydrophilic solvent comprises benzyl alcohol, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl phosphate, diethyl phthalate, diethyl tartrate, polybutene, silicone fluid, glycerine, ethylene glycol, polyethylene glycol, octanol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, glycofurol, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, 1-dodecylazacyclo-heptan-2-one, polysorbate 80, tetraglycol, or combinations thereof.

19. The suspension of claim 15 wherein the hydrophobic solvent comprises a carboxylic acid ester, a polyhydric alcohol, a polymer of a polyhydric alcohol, a fatty acid, an oil, propylene carbonate, an ester of a polyhydric alcohol, a triethylglyceride, or combinations thereof.

20. The suspension of claim 15 wherein the hydrophobic solvent comprises benzyl benzoate, lauryl alcohol, decyl alcohol, lauryl lactate, myristyl lactate, myristyl alcohol, decyl lactate, Ceraphyl®

31, ethyl oleate, ethyl hexyl lactate, a vegetable oil, vitamin E, oleic acid, a mineral oil, or combinations thereof.

21. The suspension of claim 15 wherein the pharmaceutically active agent comprises ω

-interferon, α

-interferon, β

-interferon, γ

-interferon, erythropoietin, granulocyte macrophage colony stimulating factor (GM-CSF), human growth hormone releasing hormone (huGHRH), insulin, desmopressin, infliximab, an antibody, an agent conjugated to a targeting ligand, bone morphogenic proteins, adrenocorticotropic hormone, angiotensin I, angiotensin II, atrial natriuretic peptide, bombesin, bradykinin, calcitonin, cerebellin, dynorphin N, alpha endorphin, beta endorphin, endothelin, enkephalin, epidermal growth factor, fertirelin, follicular gonadotropin releasing peptide, galanin, glucagon, glucagon-like peptide-1 (GLP-1), gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide, histrelin, human growth hormone, insulin, leuprolide, LHRH, motilin, nafarerlin, neurotensin, oxytocin, relaxin, somatostatin, substance P, tumor necrosis factor, triptorelin, vasopressin, nerve growth factor, blood clotting factors, ribozymes, antisense oligonucleotide, or combinations thereof.

22. The suspension of claim 15 wherein the pharmaceutically active agent comprises risperidone, paliperidone, or combinations thereof.

23. A dosage form comprising:

a first wall that maintains its physical and chemical integrity during the life of the dosage form and is substantially impermeable to a pharmaceutical suspension;

a second wall that is partially permeable to an exterior fluid;

a compartment defined by the first wall and the second wall;

a pharmaceutical suspension that is positioned within the compartment and comprises a hydrophobic solvent, a hydrophilic solvent, a biocompatible polymer, and a pharmaceutically active agent, wherein the suspending vehicle is substantially free of stiff gels upon contact with an aqueous medium;

a pump in communication with the first wall, the second wall, and the compartment; and

an exit port in communication with the compartment.

24. The dosage form of claim 23 wherein the pump comprises an osmotic pump.

25. The dosage form of claim 23 wherein upon contact with an aqueous medium, the pharmaceutical suspension is flowable through the exit port under a force exerted by the pump under normal operating conditions.

26. The dosage form of claim 23 wherein the pharmaceutical suspension is substantially homogeneous for at least 3 months at 37°

C.

27. A method comprising administering the dosage form of claim 23 to a mammal.

28. A kit comprising a dosage form of claim 23 and instructions for administering the dosage form.

29. A method comprising:

identifying a hydrophobic solvent;

identifying a hydrophilic solvent;

identifying a biocompatible polymer; and

mixing the hydrophilic solvent, the hydrophobic solvent, and the biocompatible polymer to create a suspending vehicle;

wherein the suspending vehicle is substantially free of stiff gels upon contact with an aqueous medium.

30. The method of claim 29 further comprising adding a pharmaceutically active agent to the suspending vehicle to create a pharmaceutical suspension.

31. The method of claim 30 further comprising adding the pharmaceutical suspension to a dosage form.

32. The method of claim 31 wherein the dosage form comprises a first wall that maintains its physical and chemical integrity during the life of the dosage form and is substantially impermeable to a pharmaceutical suspension;

a second wall that is partially permeable to an exterior fluid;

a compartment defined by the first wall and the second wall;

a pump in communication with the first wall, the second wall, and the compartment; and

an exit port in communication with the compartment; and

wherein the pharmaceutical suspension is positioned within the compartment.