Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-04-10
2002-11-05
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C424S430000, C424S449000
Reexamination Certificate
active
06476074
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the treatment of impotence or erectile dysfunction, and more particularly to a novel prostaglandin based composition therefore and the use thereof for treating impotence or erectile dysfunction.
BACKGROUND OF THE INVENTION
Erectile dysfunction is a disorder characterized by the inability of the male to develop and maintain erection for satisfactory sexual intercourse. Erectile dysfunction is a frequent disorder particularly amongst elderly men which may lead to reduced quality of life and psychological problems. It is estimated that there may be as many as 10-20 million people in the United States suffering from erectile dysfunction, and an estimated 30 million males with at least partial erectile dysfunction (NIH Consensus Conference 1993). The prevalence of erectile dysfunction has been reported to be about 5% at age 40, and up to 25% at age 65 or older. Thus erectile dysfunction is a major clinical challenge of increasing importance with the increased standard of living and demand of a better quality of life.
The ethiology of erectile dysfunction may be psychogenic or organic. The latter seems to account for the majority of cases. Such organic causes include vascular, endocrinological, and neurological diseases as well as trauma. Patients suffering from diabetes are typically at risk. While in many cases erectile dysfunction caused by, psychogenic factors may be reversible, impotence caused by organic factors needs adequate therapy. Such therapy comprises surgical intervention, devices and medical treatment. With more effective and better tolerated drugs there is a clear tendency towards medical therapy in the treatment of erectile dysfunction. The main modalities of medical therapy consist of systemic medication, usually peroral, and local medication in the genitourinary tract. Typical drugs given orally include e.g. yohimbine, an alpha-2 adrenergic antagonist, and testosterone, the male sex hormone. Furthermore bromocriptine has also been used, as well as antiserdtoninergic agents such as trazodone, ketanserin and mianserin. Recently, a selective type 5-phosphodiesterase inhibitor sildenafil (Viagra™) has been approved for clinical use. In addition there are many other drugs that have been tested and used for the treatment of erectile dysfunction. Drugs given locally include e.g. papaverine, a smooth muscle relaxing agent, and phentol amine, an alpha-adrenergic antagonist as well as prostaglandins, particularly prostaglandin E
1
(PGE
1
; alprostadil).These drugs relax smooth muscle, thus promoting the development of erection, and are given by local injection into the cavernous tissue of the penis. Formulations for intraurethral (transurethral) administration of prostaglandins have also been developed (Wolfson et al., 1993; Bradley et al., 1996) and are described in several patents and patent applications, for instance in WO 93/00894, WO 91/16021 and EP-A-357581.
It is a clear advantage to administer the drug locally into the diseased or dysfunctional organ since a better effect is achieved, and usually less systemic side-effects are induced. However, the local side-effects, mainly pain and priapism, may constitute a problem. The latter meaning prolonged erection which potentially can lead to necrosis and irreversible damage to the reproductive organ has been minimized by the use of prostaglandins, above all PGE
1
. However, PGE
1
, given by intracavemous injection or transurethrally causes local pain in as many as 10-30% of the patients. In a recently published study transurethral administration of PGE
1
resulted in pain sensation in about 35% of the patients, and 11% of the patients reported pain after every treatment with alprostadil (Padma-Nathan et al., 1997). It is thus obvious that local pain constitutes one of the most significant side-effects of PGE
1
, and prostaglandin analogues without pain inducing effect would be desirable for clinical use.
SUMMARY OF THE INVENTION
We have now unexpectedly found that certain prostaglandin analogues of the E-type , more specifically agonists of the EP
2
prostanoid receptor, exert good relaxant effect in the penile cavernous tissue, and in blood vessels while exhibiting markedly reduced pain inducing effect. In particular we have found that PGE
2
analogues substituted in carbon 18, 19 or 20 with hydroxyl (OH) exert beneficial effects, and especially one analogue, namely 19R-OH-PGE
2
, exhibited a surprisingly advantageous effect with respect to relaxation of penile cavernous tissue and blood vessels without inducing pain as studied in an animal model.
Thus, in a first aspect, the present invention provides a composition for the treatment of impotence or erectile dysfunction, comprising a prostaglandin which is a selective EP
2
or EP
4
receptor agonist, or an active derivative including the free acid, a salt or an ester thereof, optionally together with a physiologically acceptable carrier or vehicle.
In a second aspect, the invention provides a method of treating impotence or erectile dysfunction, which method comprises administering a therapeutically active and physiologically acceptable amount of the composition to an individual in need thereof.
In a third aspect, the invention provides the use of a selective EP
2
or EP
4
receptor agonist, or an active derivative including the free acid, a salt or an ester thereof, for the preparation of a medicament for the treatment of impotence or erectile dysfunction.
In still another aspect, the invention provides a method for eliminating or at least considerably reducing side effects, such as pain and irritation, observed in connection with the use of prostaglandin derivatives for treatment of impotence.
REFERENCES:
patent: 4190670 (1980-02-01), Marx et al.
patent: 6031001 (2000-02-01), Stjernschantz et al.
patent: WO 39/00894 (1993-01-01), None
patent: WO 9300894 (1993-01-01), None
patent: WO 9632141 (1996-10-01), None
Resul Bahram
Stjernschantz Johan
Dinsmore & Shohl LLP
Ghali Isis A. D.
Page Thurman K.
Synphora AB
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