Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-02-02
2003-07-08
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S530000, C514S058000, C514S922000, C514S929000, C514S946000, C514S947000
Reexamination Certificate
active
06589990
ABSTRACT:
TECHNICAL FIELD
The invention relates to the use of misoprostol, as well as its metabolites, misoprostol acid, for methods and compositions for topical use for the purpose of treating erectile dysfunction (ED).
BACKGROUND
A current pharmaceutical treatment for ED comprises oral administration of sildenafil (Viagra®), a treatment counter indicated for subjects who are: allergic to this material; or are concurrently being treated with a nitrate medicine such as nitroglycerin; a transdermal nitrate; isosorbide nitrate (Imdur®); cimetidine (Tagamet®); mibefradil (Posicor®); or an anti-infective such as erythromycin, ketoconazole, itraconazole, or rifampin. Subjects suffering with ED due to hormonal insufficiency can be treated with suitable steroid hormone substitution therapy. Other current non-oral and non-steroid treatments include mainly the use of intracavernous injections consisting of direct injection of vasodilatory drugs (for example, injections Caverject®; and papaverine, phentolamine) into the corpora cavernosa of the penis (Campell's
Urology
, ed. W.B. Saunders Company, 6
th
Edition, Volume III, 3055-3057).
Although in situ injection is efficient and scientifically approved, it has serious disadvantages of form (injection) as well as route of administration (introcarvernosal). Yohimbin, an indole alkaloid which is an a
2
-adrenergic inhibitor, is administrated per os, however the efficiency of this method is questionable (Campell's
Urology
, ed. W. B. Saunders Company, 6
th
Edition, Volume III, 3053). Nitroglycerin paste has been proposed as a topical composition (Claes, H. et al., 1989 Urol. Int. 44(5): 309-312), however the method has not been developed as a therapeutic because of concerns regarding efficacy and potential serious side effects (Campell's
Urology
, 25
th
ed. W. B. Saunders Company, 6th Edition, Volume III, 3053). The topical application of prostaglandin E
1
(or alprostadil) in the form of an endourethral gel or a stick was recently proposed as a therapeutic to treat male impotence of vascular etiology (
International Journal of Impotence Research
, Stockton ed. Vol. 7, September 1995, Supplement I, 5-6 however it is considered to be of limited efficacy.
A vasodilatory drug or combination of drugs with sufficient transcutaneous absorption, or use of methods (e.g. ionophoresis) which can reinforce the penetration of such drugs through the skin of the mucosal membranes, into the corpora cavernosa of the penis, would be of interest as a potential therapeutic (Campbell's
Urology
, ed. W.B. Saunders company 6
th
ed., Vol. III, 3057).
Up to the present, the methods intended for external application share the disadvantages of low efficiency, high cost, potential serious side effects, and discomfort of routine injection. The greatest technical difficulty that must be overcome for development of a method of topical use to reverse ED, is penetration of drugs through various barriers of skin and mucosa to reach the corpora cavernosa, in sufficient concentration to be effective in producing an erection.
SUMMARY
An embodiment of the invention provides a method for treating erectile dysfunction in a subject, comprising: (a) obtaining a therapeutic formulation having an effective dose of a misoprostol compound in an excipient carrier; and (b) applying the therapeutic formulation topically to the subject, for example, to the glans penis, the mucosa, or other area of skin. According to an embodiment of this method, the misoprostol compound comprises one or more of the group of: a purified stereoisomer, a racemic mixture, a mixture of purified stereoisomers, and a racemic mixture and a purified stereoisomer. Further, the stereoisomer is selected from the group of an R form and an S form, and a (+) and a (−) enantiomer is selected from an R form and an S form. The misoprostol compound comprises a racemic mixture of (+) and (−) enantiomers of R and S stereoisomers, for example, the racemic mixture of (+) and a (−) enantiomers of R and S stereoisomers are present in substantially equal proportions. Further the stereoisomer is selected from the group of (±)-R forms and (±)-S forms at the carbon atom at position 16 of the misoprostol compound.
According to an embodiment of this method, obtaining the therapeutic formulation in (a) includes selecting a topical delivery format from the group of: a solution, an ointment, a gel, a stick, and a transdermal patch. According to a further embodiment of this method, (b) includes applying an effective dose which is substantially equivalent to about 0.05 to 0.25 ml of a 0.9 percent formulation by weight of the misoprostol compound. In an alternative embodiment, (b) includes applying an effective dose which is substantially equivalent to at least 0.25 ml of a 0.9 percent formulation by weight of the misoprostol compound.
In a further embodiment of the invention, step (a) comprises adding an agent having synergistic activity in combination with the misoprostol compound, for example, the agent having synergistic activity is a vasodilatory substance, for example, the vasodilatory substance is alprostadil. The misoprostol compound may act as a penetration enhancer for the agent. In an alternative embodiment of the method, the agent having synergistic activity in combination with the misoprostol compound is a penetration enhancer. The agent in combination with the misoprostol compound has a synergistic effect that is selected from the group of: reducing the effective dose, prolonging the therapeutic result, and reducing or eliminating a side effect of the therapeutic formulation. For example, agent is &agr;-cyclodextrin, and the &agr;-cyplodextrin reduces or eliminates a side effect of the therapeutic formulation having a dose of greater than about 2000 micrograms of the misoprostol compound.
In another embodiment of the method, formulation further comprises one or more compounds selected from the group of: &agr;-cyclodextrin, propylene glycol, hydroxypropyl methylcellulose, and glycerol. According to this embodiment, the &agr;-cyclodextrin is present in an amount of 0% to about 1.6%, the propylene glycol is present in an amount of 0% to about 10%, the hydroxypropyl, methylcellulose is present in an amount of 0% to about 2.5%, and glycerol is present in an amount of 0% to about 7.0%.
Another embodiment of the method comprises in step (b) further determining a dosage unit which is an effective dose for the subject, the dosage unit being an amount of the therapeutic formulation applied to the glans penis for an effective period of time to achieve an erection.
Another embodiment of the method comprises in step (b) further determining a dosage unit which is an effective dose for diagnosis of vascular damage in the subject, the dosage unit being an amount of the therapeutic formulation applied to the glans penis sufficient to further perform: (c) determining vascular damage by the Doppler method or cavernosometry.
An embodiment of the invention provides an erectile dysfunction therapeutic composition, comprising an effective dose of a misoprostol compound in a topical formulation. The topical formulation is selected from the group of: a solution, an ointment, a gel, a stick, and a transdermal patch. In this embodiment, the misoprostol compound comprises one or more selected from the group of: a purified stereoisomer, a racemic mixture, a mixture of purified stereoisomers, and a mixture of a racemic mixture and a purified stereoisomer. An example of this embodiment is a composition further comprising an agent having synergistic activity in combination with the misoprostol compound, for example, a composition wherein the agent having synergistic activity is a vasodilatory substance, for example, the vasodilatory substance is alprostadil.
In another embodiment, the composition comprises further a penetration enhancer. In yet another embodiment, the composition comprises further &agr;-cyclodextrin.
REFERENCES:
patent: 4696821 (1987-09-01), Belsole
patent: 5242391 (1993-09-01
Kanakaris Panagiotis
Karouzakis Petros
Bromberg & Sunstein LLP
Henley III Raymond
Jague Donna
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