Angiogenesis promotion by prostaglandin compositions and methods

• US 20040241243A1
• Filed: 03/16/2004
• Published: 12/02/2004
• Est. Priority Date: 03/21/2003
• Status: Abandoned Application

• Current Assignee: Nexmed Holdings
• Original Assignee: Nexmed Holdings
• Inventors: Lin, Guiting, Mo, Y. Joseph, Lu, Mingqi, Guo, Yinglu
• Application Number:
  US10/803,101
• Publication Number:
  US 20040241243A1
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• 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 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The present invention provides compositions and methods for promoting the recovery of vascular function in erectile dysfunction associated with vasculopathy by administering a composition comprising a vasoactive prostaglandin and a biocompatible polymer. In preferred embodiments, the prostaglandin composition is a topical composition comprising prostaglandin E₁, a biocompatible polymer and a penetration enhancer and the topical composition is applied to the meatus at the tip of the penis. In another embodiment, the invention provides a method for increasing microvascular outgrowth at a targeted arterial segment comprising administering a prostaglandin E₁ composition to produce an extracellular prostaglandin E₁ concentration of about 1 micromolar to about 10 micromolar adjacent to the targeted arterial segment for about four days.

Claims

1. A composition comprising

between 0.001 weight percent and 1 weight percent of a vasoactive prostaglandin selected from the group consisting of prostaglandin E₁, prostaglandin E₂, a pharmaceutically acceptable salt thereof, a lower alkyl ester thereof and mixtures thereof, based on the total weight of the composition;

a biocompatible polymer;

a lipophilic component selected from the group consisting of a C₁ to C₈ aliphatic alcohol, a C₈ to C₃₀ aliphatic ester, a liquid polyol and a mixture thereof;

water; and

a buffer that provides a buffered pH value for the composition in the range of about 3 to about 7.4.

2. The composition of claim 1 wherein the vasoactive prostaglandin is 0.05 to 1 weight percent prostaglandin E₁, based on the total weight of the composition.

3. The composition of claim 1 wherein the biocompatible polymer is selected from the group consisting of a silastic elastomer, a biodegradable polymer and a shear-thinning polymeric thickener.

4. The composition of claim 3 wherein the biodegradable polymer is selected from the group consisting of a polylactide, a poly(lactide-co-glycolide), a polyorthoester, a polyphosphazene, a polyanhydrides, and a polyphosphoester.

5. The composition of claim 3 wherein the biodegradable polymer is a biodegradable triblock copolymer selected from the group consisting of a poly(lactide-co-glycolide)-polyethylene glycol-poly(lactide-co-glycolide) copolymer, a polylactide-polyethylene glycol-polylactide copolymer, a polyethylene glycol-poly(lactide-co-glycolide)-polyethylene glycol copolymer and a polyethylene glycol-polylactide-polyethylene glycol copolymer.

6. The composition of claim 1 wherein the shear-thinning polymeric thickener selected from the group consisting of a shear-thinning polysaccharide gum and a shear-thinning polyacrylic acid polymer.

7. The composition of claim 1 wherein the liquid polyol is a polyethylene glycol selected from the group consisting of polyethylene glycol 200, polyethylene glycol 400 and polyethylene glycol 600.

8. The composition of claim 1 further comprising a penetration enhancer selected from the group consisting of an alkyl-(N-substituted amino) alkanoate, an alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol alkanoate, pharmaceutically acceptable salts thereof and mixtures thereof.

9. The composition of claim 1 further comprising an emulsifier.

10. The composition of claim 1 further comprising a fragrance.

11. The composition of claim 1 further comprising a topical anesthetic.

12. A method of promoting the recovery of vascular function in a subject having erectile dysfunction comprising the step of administering a composition comprising a vasoactive prostaglandin selected from the group consisting of prostaglandin E₁, prostaglandin E₂, pharmaceutically acceptable salts thereof, lower alkyl esters thereof, mixtures thereof, a biocompatible polymer and a buffer that provides a buffered pH value for the composition of about 3 to about 7.4, wherein vascular recovery is demonstrable by objective measures or by clinical findings.

13. The method of claim 12 wherein the biocompatible polymer is selected from the group consisting of a silastic elastomer, a biodegradable polymer and a shear-thinning polymeric thickener.

14. The method of claim 12 wherein the vasoactive prostaglandin is between 0.001 weight percent and 1 weight percent of the total weight of the composition.

15. The method of claim 12 wherein the composition further comprises a penetration enhancer is selected from the group consisting of an alkyl-(N-substituted amino) alkanoate, an alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol alkanoate, pharmaceutically acceptable salts thereof and mixtures thereof.

16. The method of claim 12 wherein the composition further comprises a lipophilic component that is selected from the group consisting of an aliphatic C₁ to C₈ alcohol, an aliphatic C₈ to C₃₀ ester, and a mixture thereof;

and water.

17. The method of claim 12 wherein vascular recovery is demonstrable by objective measures of microvascular outgrowth or penile microcirculation.

18. The method of claim 12 wherein vascular recovery is demonstrable by clinical findings of penile tumescence or erection.

19. A method of causing microvascular sprouting in a targeted arterial segment comprising contacting the targeted segment with a solution comprising about 1 micromolar to about 100 micromolar of a vasoactive prostaglandin selected from the group consisting of prostaglandin E₁ and prostaglandin E₂.

20. The method of claim 19 wherein the solution comprises about 1 micromolar to about 60 micromolar prostaglandin E₁.

21. The method of claim 19 wherein the solution comprises about 1 micromolar to about 30 micromolar prostaglandin E₁.

22. The method of claim 19 wherein the solution in contact with the targeted arterial segment is in fluid communication with a composition comprising 0.001 weight percent to 1 weight percent of a vasoactive prostaglandin selected from the group consisting of prostaglandin E₁, prostaglandin E₂, a pharmaceutically acceptable salt thereof, a lower alkyl ester thereof and mixtures thereof, based on the total weight of the composition and a biocompatible polymer selected from the group consisting of biocompatible polymer is selected from the group consisting of a silastic elastomer, a biodegradable polymer and a shear-thinning polymeric thickener.

23. The method of claim 22 wherein the biodegradable polymer is selected from the group consisting of a polylactide, a poly(lactide-co-glycolide), a polyorthoester, a polyphosphazene, a polyanhydrides, and a polyphosphoester.

24. The method of claim 22 wherein the biodegradable polymer is a biodegradable triblock copolymer selected from the group consisting of a poly(lactide-co-glycolide)-polyethylene glycol-poly(lactide-co-glycolide) copolymer, a polylactide-polyethylene glycol-polylactide copolymer, a polyethylene glycol-poly(lactide-co-glycolide)-polyethylene glycol copolymer and a polyethylene glycol-polylactide-polyethylene glycol copolymer.

25. The method of claim 22 wherein the shear-thinning polymeric thickener is selected from the group consisting of a shear-thinning polysaccharide gum and a shear-thinning polyacrylic acid polymer.

26. The method of claim 19 wherein the targeted arterial segment is a segment of a helicine artery, a cavernosal artery, a dorsal penile artery, an internal pudendal artery or an iliac artery.