Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-06-29
2001-10-23
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C514S224200, C514S224500, C514S224800, C514S284000, C514S617000, C514S646000
Reexamination Certificate
active
06306437
ABSTRACT:
FIELD OF THE INVENTION
This invention, in one aspect, relates to dosage forms and methods for ameliorating erectile dysfunction in psychogenic male patients. In another aspect this invention relates to diagnosis of erectile dysfunction. More particularly, this invention relates to the use of apomorphine-containing compositions for amelioration of erectile dysfunction in psychogenic male patients and for diagnostic purposes.
BACKGROUND OF THE INVENTION
A normal erection occurs as a result of a coordinated vascular event in the penis. This is usually triggered neurally and consists of vasodilation and smooth muscle relaxation in the penis and its supplying arterial vessels. Arterial inflow causes enlargement of the substance of the corpora cavernosa. Venous outflow is trapped by this enlargement, permitting sustained high blood pressures in the penis sufficient to cause rigidity. Muscles in the perineum also assist in creating and maintaining penile rigidity. Erection may be induced centrally in the nervous system by sexual thoughts or fantasy, and is usually reinforced locally by reflex mechanisms. Erectile mechanics are substantially similar in the female for the clitoris.
Impotence or male erectile dysfunction is defined as the inability to achieve and sustain an erection sufficient for intercourse. Impotence in any given case can result from psychological disturbances (psychogenic), from physiological abnormalities in general (organic), from neurological disturbances (neurogenic), hormonal deficiencies (endocrine) or from a combination of the foregoing.
These descriptions are not exact, however. There is currently no standardized method of diagnosis or treatment. As used herein, psychogenic impotence is defined as functional impotence with no apparent overwhelming organic basis. It may be characterized by an ability to have an erection in response to some stimuli (e.g., masturbation, spontaneous nocturnal, spontaneous early morning, video erotica, etc.) but not others (e.g., partner or spousal attention).
Various methods for the treatment of impotence have been suggested, including external devices, for example, tourniquets (see U.S. Pat. No. 2,818,855). In addition, penile implants, such as hinged or solid rods and inflatable, spring driven or hydraulic models, have been used for some time. The administration of erection effecting and enhancing drugs is taught in U.S. Pat. No. 4,127,118 to LaTorre. That patent teaches a method of treating male impotence by injecting into the penis an appropriate vasodilator, in particular, an adrenergic blocking agent or a smooth muscle relaxant to effect and enhance an erection. More recently, U.S. Pat. No. 4,801,587 to Voss et al. teaches the application of an ointment to relieve impotence. The ointment consists of the vasodilators papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or phentolamine and a carrier to assist absorption of the primary agent through the skin. U.S. Pat. No. 5,256,652 to El-Rashidy teaches the use of an aqueous topical composition of a vasodilator such as papaverine together with hydroxypropyl-&bgr;-cyclodextrin.
Recently the effect of apomorphine on penile tumescence in male patients afflicted with psychogenic impotence has been studied. These studies show that while apomorphine can indeed induce an erection in a psychogenic male patient, the apomorphine dose required to achieve a significant erectile response is usually accompanied by nausea or other serious undesirable side effects such as hypertension, flushing and diaphoresis. The specific mechanisms by which apomorphine acts to produce an erectile response in a human patient are not yet completely understood, however.
Moreover, apomorphine has been shown to have very poor oral bioavailability. See, for example, Baldessarini et al., in Gessa et al., eds.,
Apomorphine and Other Dopaminomimetics, Basic Pharmacology,
Vol. 1, Raven Press, N.Y. (1981), pp. 219-228.
Thus the search is continuing for an effective treatment of psychogenic impotence in male patients as well as for diagnostic methods that can identify such patients. It has now been found that certain delivery systems for apomorphine can provide a practical therapeutic and/or diagnostic “window” while reducing the likelihood of undesirable side effects. It has also been found that nausea side effects associated with the use of apomorphine can be substantially reduced by the pre-administration or co-administration of an antiemetic agent.
SUMMARY OF THE INVENTION
It has now been found that, for an optimal erectile response, steady state circulating serum and mid-brain tissue levels of apomorphine are to be maintained within a relatively closely defined range.
Sublingual apomorphine dosage forms, usually containing about 2.5 to about 10 milligrams of apomorphine, have been found to be effective in male patients suffering from psychogenic erectile dysfunction for the induction and maintenance of an erection sufficient for intercourse (i.e., vaginal penetration) without nausea or other undesirable side effects. The apomorphine is administered sublingually, preferably about 15 to about 20 minutes prior to sexual activity, and so as to maintain a predetermined circulating serum levels and mid-brain tissue levels of apomorphine during the period of sexual activity sufficient to induce an erection adequate for vaginal penetration but less than the amount that induces nausea. The plasma concentration of apomorphine should be maintained at no more than about 5.5 nanograms per milliliter, preferably about 0.3 to about 4 nanograms per milliliter, and more preferably about 1 to about 2 nanograms per milliliter.
The foregoing sublingual apomorphine dosage forms are also suitable for screening patients complaining of erectile dysfunction so as to identify patients of psychogenic etiology.
The nausea side effect associated with the use of apomorphine can be substantially reduced by administration of an antiemetic agent. Specifically, a method suitable for treating erectile dysfunction in a male patient comprises administering to the patient prior to sexual activity, an antiemetic agent in an amount sufficient to substantially reduce nausea associated with use of apomorphine, and apomorphine in an amount sufficient to induce and maintain an erection adequate for vaginal penetration.
The antiemetic agent is preferably co-administered with the apomorphine in a single sublingual dosage unit. Separate dosage units with differing delivery routes are also suitable for practicing the present invention, however. For example, the antiemetic agent and apomorphine may be administered to the patient sequentially by first administering a composition comprising an antiemetic agent and thereafter a composition comprising apomorphine.
A dosage unit for administering the antiemetic-apomorphine combination comprises an antiemetic agent as a relatively faster release component and apomorphine as a component released after release of the antiemetic agent has begun. This staggered release dosage unit is preferably a layered tablet having a core portion containing the apomorphine and an outer layer portion containing the antiemetic agent.
A sublingual tablet for administering the antiemetic-apomorphine combination comprises apomorphine, an antiemetic agent, an osmotic agent and a swellable hydrophilic carrier. The preferred osmotic agent is mannitol, while the preferred swellable hydrophilic carrier is microcrystalline cellulose.
The practice of this invention using apomorphine and an antiemetic agent also can be applied to the treatment of severe motor fluctuations in Parkinson's disease.
REFERENCES:
patent: 2818855 (1958-01-01), Miller
patent: 3885034 (1975-05-01), Risse et al.
patent: 3976780 (1976-08-01), Thominet
patent: 4127118 (1978-11-01), Latorre
patent: 4521421 (1985-06-01), Foreman
patent: 4543256 (1985-09-01), Neumeyer
patent: 4569940 (1986-02-01), Watts
patent: 4624965 (1986-11-01), Wenig
patent: 4687773 (1987-08-01), Neumeyer et al.
patent: 4749686 (1988-06-01), Hintze
patent: 4749700 (1988-06-01), Wenig
El-Rashidy Ragab
Ronsen Bruce
Delacroix-Muirheid C.
Jones Dwayne C.
Olson & Hierl Ltd.
Pentech Pharmaceuticals, Inc.
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