Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-12-10
2001-03-13
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
Reexamination Certificate
active
06200591
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method for greatly accelerating the rate of delivery of sildenafil, and derivatives thereof, to the central nervous system by administration via the nasal route to provide extremely rapid response in the treatment of erectile dysfunction in a patient in need of such prevention or treatment. This method provides response in less than five minutes, compared with 60 minutes or more required by the currently used oral route of administration.
2. Description of the Related Art
Male sexual dysfunction, or impotence, may be manifested in various ways: loss of desire, inability to obtain or maintain an erection, premature ejaculation, absence of emission, inability to achieve orgasm. The organic causes of erectile impotence can be grouped into endocrine, drug, local, neurologic, and vascular causes. Vascular insufficiency causes impotence because blood flow into the vascular network of the penis is insufficient to obtain (or maintain) the erect state. Likewise, occlusion in smaller vessels supplying the penis can also lead to impotence. Together with neuropathy, vascular insufficiency contributes to the impotence in many men with diabetes mellitus.
Erectile impotence or dysfunction may be defined as an inability to achieve or sustain an erection adequate for intercourse. Its prevalence is claimed to be between 2 and 7% of the human male population as a whole, and the incidence increases with age up to 50 years. Between 18 and 75% of the male population between 55 and 80 years of age are impotent. In the USA alone, for example, it has been estimated that there are up to 10 million impotent males, with the majority suffering from problems of organic rather than psychogenic origin.
Medical therapy with androgens offers little more than placebo benefit except in hypogonadal men. Surgical therapy may be useful in the treatment of decreased potency related to aortic obstruction; however, potency can be lost rather than improved after aortic operation if the autonomic nerve supply to the penis is damaged. A useful surgical technique for improvement of potency in refractory patients such as individuals with diabetic neuropathy is the implantation of a penile prosthesis, e.g., the insertion within the corpora of a small, blunt, Silastic® rod. The patient must be made aware that full erection is not produced and that the device only prevents buckling during intercourse. Furthermore, the complication rate is high in some patients. Alternatively, an inflatable prosthetic device has been devised for implantation on either side of the corpora. A connecting reservoir of material is placed in the perivesicular space and pumps are located in the scrotum. By means of these pumps the penis can be made to become nearly fully erect at the appropriate time and to relax after intercourse.
Prostaglandin E-1 (PGE-1; Alprostadil) has been employed successfully in the treatment of erectile dysfunction. Injections of 10 to 60 &mgr;g of PGE-1 directly into the corpora cavernosa of the penis have been found to be effective in producing erections sufficient to allow intercourse. The erections are reported to last 30 minutes to one hour, but the dangers associated with self-injection, e.g., infection, trauma, etc. make this treatment method highly undesirable.
PGE-1 has also been administered by placing a pellet containing 125 to 1000 &mgr;g of the drug into the male urethra using a specially-designed device. This approach, while avoiding the dangers of self-injection, still involves the danger of producing a urethral infection. Other drawbacks include difficulty in adjusting the dose, trauma to the urethra, and vaginal burning in the female partner.
Medical treatment of erectile dysfunction has been attempted using intracavernosal (i.c.) injection of vasoactive substances, and good results have been claimed with phenoxybenzamine, phentolamine, papaverine, and prostaglandin E
1
, either alone or in combination; however, pain, priapism, and fibrosis of the penis are associated with the i.c. administration of some of these agents. Potassium channel openers (KCO) and vasoactive intestinal polypeptide (VIP) have also been shown to be active i.c., but cost and stability issues could limit development of the latter. An alternative to the i.c. route is the use of glyceryl trinitrate (GTN) patches applied to the penis, which has been shown to be effective but produces side-effects in both patient and partner.
Sublingual administration of apomorphine has been reported to restore normal erectile function through its effect on brain chemistry. However, the response requires 20 to 40 minutes following administration, and apomorphine was found to be effective in returning sexual potency only to about 70% of men whose dysfunction had psychological origins.
It has recently been discovered that inhibitors of cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs) such as sildenafil are useful in the treatment of erectile dysfunction. As disclosed in PCT Publication WO 94/28902, the disclosure of which is hereby incorporated by reference, these compounds may be administered orally, thereby obviating the disadvantages associated with i.c. administration. However, the time to onset of action of periorally administered drugs is long and highly variable, due to differences in absorption based on a wide variety of factors, from the size and age of the patient to the interval since, and size and composition of, the last meal consumed by the patient. Currently, sildenafil must be administered orally about one hour prior to intercourse. This is a major drawback in situations where a rapid, reliable onset of effect is highly desirable for treatment to be considered optimal. Also, the long delay may lead to overdoses if the patient becomes impatient and decides to consume additional tablets in order to produce the desired effect.
Therefore, in view of the aforementioned deficiencies attendant with prior art methods of treatment of erectile impotence, it should be apparent that there still exists a need in the art for a rapid, reliable, safe and convenient method of inducing an erection in a patient in need of such treatment.
SUMMARY OF THE INVENTION
Accordingly, a major object of the present invention is to provide a method for safely and conveniently administering sildenafil to a patient in need of treatment for erectile dysfunction in order to produce a reliable response in less than five minutes. The method comprises the intranasal administration of an effective amount of sildenafil to rapidly produce an erection sufficient to allow intercourse.
The objective of the present inventors is to improve the rate of delivery of sildenafil to the systemic circulation by administering sildenafil via the nasal route in order to speed the onset of effect and reduce the dose required for its beneficial effect. According to the method of the present invention, sildenafil, or derivatives thereof, may successfully be administered five to ten minutes prior to intercourse.
Practice of the method of the present invention will also result in lower plasma concentrations of metabolites of sildenafil, and derivatives thereof, and therefore fewer side effects. Intranasal delivery will improve drug bioavailability by direct absorption into the systemic circulation, thereby avoiding extensive hepatic and/or gut wall first-pass metabolism which may significantly lower the plasma concentrations of sildenafil when it is administered orally. As a result, small doses of sildenafil, or derivatives thereof, can be administered which will result in fewer side effects, and the drug will be more tolerable and more effective in patients suffering from erectile impotence. Most importantly, since sildenafil is effective immediately following intranasal administration, the patient is able to titrate himself until he achieves the desired response, rather than overdosing himself by swallowing an excessive number of tablets.
Intranasal dosage forms containing sildenafil in co
Dittert Lewis W.
Hussain Anwar A.
Azpuru Carlos A.
Burns Doane Swecker & Mathis L.L.P.
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