Formulation for lipophilic agents

• US 20040053894A1
• Filed: 09/18/2002
• Published: 03/18/2004
• Est. Priority Date: 09/18/2002
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Bone Care International LLC
• Inventors: LeVan, Leon W., Goldensoph, Creighton Reed, Driscoll, Jeffrey W., Mazess, Richard B.
• Granted Patent: US 7,148,211 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61K 31/592 9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• 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 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/18 of the parathyroid hormones

Abstract

The invention relates to pharmaceutical formulations of lipophilic therapeutic agents in which such agents are solubilized in largely aqueous vehicles, and processes for preparing and using the same.

Claims

1. A formulation, comprising a lipophilic drug, a non-ionic solubilizer, a lipophilic antioxidant and an aqueous vehicle.

2. A formulation as set forth in claim 1, wherein the non-ionic solubilizer includes polyoxyalkylenes, polysorbates, fatty acid esters of glycerol, cyclodextrins, dextrans, fatty alcohol ethers of oligoglucosides and polyoxyethylene type compounds.

3. A formulation as set forth in claim 1, wherein the lipophilic antioxidant includes butylated hydroxytoluene (BHT), lipoic acid, lycopene, lutein, lycophyll, xanthophyll, carotene, zeaxanthin or vitamin E and esters thereof.

4. A formulation as set forth in claim 1, wherein the lipophilic antioxidant is present in a concentration of 20 to 2000 ppm.

5. A formulation as set forth in claim 1, wherein the non-ionic solubilizer is present in a concentration of 0.05 to 5% w/w.

6. A formulation as set forth in claim 1, wherein the lipophilic drug includes analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β

-blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine H₁ and H₂ receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, nutritional agents and fat-soluble vitamins, opioid analgesics, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional agents anti-benign prostate hypertrophy agents, and mixtures thereof.

7. A formulation as set forth in claim 1, wherein the formulation is suitable for parenteral administration.

8. A formulation as set forth in claim 1, further comprising an optional agent which is an organic solvent, a preservative or both.

9. A formulation as set forth in claim 8, wherein the optional agent includes benzyl alcohol and ethanol.

10. A formulation as set forth in claim 9, wherein the optional agent includes ethanol.

11. A formulation as set forth in claim 9, wherein the optional agent includes benzyl alcohol.

12. A formulation as set forth in claim 9, wherein the optional agent is present in a concentration of 0 to 30% w/w.

13. A formulation as set forth in claim 12, wherein the optional agent is present in a concentration of 0% to about 10% w/w.

14. A formulation as set forth in claim 12, wherein the optional agent is present in a concentration of about 1% to about 3% w/w.

15. A parenteral formulation, comprising a lipophilic drug agent, 0.05 to 5% w/w non-ionic solublizer and 20 to 2000 ppm lipophilic antioxidant.

16. A formulation as set forth in claim 15, further comprising an optional agent.

17. A formulation as set forth in claim 16, wherein the non-ionic solubilizer includes 0.5%-2.5% w/w TWEEN™

-20, the lipophilic antioxidant includes 20 ppm BHT and the optional agent includes 2.5% w/w ethanol.

18. A formulation as set forth in claim 16, wherein the non-ionic solubilizer includes 0.5%-2.5% w/w TWEEN™

-20, the lipophilic antioxidant includes 20 ppm BHT and the optional agent includes 2.5% w/w benzyl alcohol.

19. A formulation, comprising a vitamin D compound which includes an active vitamin D, a non-ionic solubilizer, a lipophilic antioxant and an aqueous vehicle.

20. A formulation as set forth in claim 19, wherein the vitamin D includes doxercalciferol, seocalcitol, calcitriol, calcipotriol, maxacalcitol, falecalcitriol and paricalcitol.

21. A formulation as set forth in claim 20, wherein the vitamin D compound includes doxercalciferol.

22. A formulation as set forth in claim 20, wherein the vitamin D compound includes seocalcitol.

23. A formulation as set forth in claim 20, wherein the vitamin D compound includes calcitriol.

24. A formulation as set forth in claim 20, wherein the vitamin D compound includes paricalcitol.

25. A formulation as set forth in claim 20, wherein the vitamin D compound includes calcipotriol.

26. A formulation as set forth in claim 20, wherein the vitamin D compound includes maxacalcitol.

27. A formulation as set forth in claim 20, wherein the vitamin D compound includes falecalcitriol.

28. A formulation as set forth in claim 19, wherein the vitamin D compound is present at a concentration of 2-10 μ

g/mL.

31. A method of lowering elevated or maintaining lowered blood parathyroid hormone level comprising, parenterally administering to a subject suffering therefrom the formulation of claim 19.

32. A method as set forth in claim 31, where is the elevated blood parathryroid level is due to hyperparathyroidism.

33. A method as set forth in claim 32, wherein the hyperparathyroidism is secondary hyperparathyroidism.

34. A method of inhibiting growth of hyperproliferative cells, comprising treating the cells with an effective growth-inhibiting amount of the formulation of claim 19.

35. A method as set forth in claim 34, wherein an amount of the formulation of claim 19 is administered to a human patient in need thereof which is effective to inhibit growth of the hyperproliferative cells.

36. A method as set forth in claim 35, wherein the amount is administered parenterally.

37. A method as set forth in claim 35, wherein the cells include cells of cancers of the breast, colon, prostate and pancreas.

38. A method as set forth in claim 35, wherein the cells are due to psoriasis.

39. A method of treating disorders of calcium metabolism, comprising parenterally administering to a subject suffering therefrom the formulation of claim 19.

29. A formulation suitable for treatment of secondary hyperparathyroidism comprising 2-10 μ

g/mL of an active vitamin D compound, 0.5%-2.5% w/w TWEEN™

-20, 20 ppm BHT and 2.5% w/w ethanol.

30. A formulation suitable for treatment of neoplastic disease comprising 10-100 μ

g/mL of an active vitamin D compound, 0.5%-2.5% w/w TWEEN™

-20, 20 ppm BHT and 2.5% w/w benzyl alcohol.