Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-12-10
2003-04-15
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S258100
Reexamination Certificate
active
06548490
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to methods and pharmaceutical compositions for treating erectile dysfunction; more particularly, the invention relates to transmucosal (e.g., buccal, sublingual and transrectal), administration of phosphodiesterase inhibitors to treat erectile dysfunction.
BACKGROUND
Impotence is the consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse. It has recently been estimated that approximately 10 million American men are impotent (R. Shabsigh et al., “Evaluation of Erectile Impotence,” Urology 32:83-90 (1988); W. L. Furlow, “Prevalence of Impotence in the United States,”
Med. Aspects Hum. Sex
. 19:13-6 (1985)). Impotence is recognized to be an age-dependent disorder, with an incidence of 1.9 percent at 40 years of age and 25 percent at 65 years of age (A. C. Kinsey et al., “Age and Sexual Outlet,” in
Sexual Behavior in the Human Male
; A. C. Kinsey et al., eds., Philadelphia, Pa.: W. B. Saunders, 218-262 (1948)). In 1985 in the United States, impotence accounted for more than several hundred thousand outpatient visits to physicians (National Center for Health Statistics, National Hospital Discharge Survey, 1985, Bethesda, Md., Department of Health and Human Services, 1989 DHHS publication no. 87-1751). Depending on the nature and cause of the problem, treatments include psychosexual therapy, hormonal therapy, administration of vasodilators such as nitroglycerin and &agr;-adrenergic blocking agents (“&agr;-blockers”), oral administration of other pharmaceutical agents, vascular surgery, implanted penile prostheses, vacuum constriction devices and external aids such as penile splints to support the penis or penile constricting rings to alter the flow of blood through the penis.
A number of causes of impotence have been identified, including vasculogenic, neurogenic, endocrinologic and psychogenic. Vasculogenic impotence, which is caused by alterations in the flow of blood to and from the penis, is thought to be the most frequent organic cause of impotence. Common risk factors for vasculogenic impotence include hypertension, diabetes, cigarette smoking, pelvic trauma, and the like. Neurogenic impotence is associated with spinal-cord injury, multiple sclerosis, peripheral neuropathy caused by diabetes or alcoholism and severance of the autonomic nerve supply to the penis consequent to prostate surgery. Erectile dysfunction is also associated with disturbances in endocrine function resulting in low circulating testosterone levels and elevated prolactin levels.
Impotence can also be a side effect of various classes of drugs, in particular, those that interfere with central neuroendocrine control or local neurovascular control of penile smooth muscle. Krane et al.,
New England Journal of Medicine
32:1648 (1989). Penile erection requires (1) dilation of the arteries that regulate blood flow to the lacunae of the corpora cavemosum, (2) relaxation of trabecular smooth muscle, which facilitates engorgement of the penis with blood, and (3) compression of the venules by the expanding trabecular walls to decrease venous outflow.
Trabecular smooth muscle tone is controlled locally by adrenergic (constrictor), cholinergic (dilator) and nonadrenergic, noncholinergic (dilator) innervation, and by endothelium-derived vasoactive substances such as vasoactive intestinal polypeptide (VIP), prostanoids, endothelin and nitric oxide. High sympathetic tone (noradrenergic) is implicated in erectile dysfunction, and, in some patients, the disorder can be successfully treated with noradrenergic receptor antagonists. See, e.g., Krane et al., supra.
There is also evidence that dopaminergic mechanisms are involved in erectile function. For example, pharmacologic agents that elevate the level of brain dopamine or stimulate brain dopamine receptors increase sexual activity in animals (see, e.g., Gessa & Tagliamonte,
Life Sciences
14:425 (1974); Da Prada et al.,
Brain Research
57:383 (1973)).
Administration of L-DOPA, a dopamine precursor, enhances sexual activity in male rats. L-DOPA has been used in the treatment of Parkinsonism and is known to act as an aphrodisiac in some patients (Gessa & Tagliamonte, supra; Hyppa et al.,
Acta Neurologic Scand
. 46:223 (Supp. 43, 1970)). Specific dopamine agonists have been studied for their effects on erectile function. Apomorphine, (n-propyl)norapo-morphine, bromocryptine, amantidine, fenfluramine, L-DOPA and various other pharmacological activators of central dopaminergic receptors have been found to increase episodes of penile erection in male rats (Benassi-Benelli et al.,
Arch. int. Pharmacodyn
. 242:241 (1979); Poggioli et al.,
Riv. di Farm
. &
Terap
. 9:213 (1978); Falaschi et al.,
Apomorphine and Other Dopaminomimetics
, 1:117-121 (Gessa & Corsini, Eds., Raven Press, N.Y.)). In addition, U.S. Pat. No. 4,521,421 to Foreman relates to the oral or intravenous administration of quinoline compounds to treat sexual dysfunction in mammals.
The currently available dopamine agonists, with few exceptions, have found limited use in the treatment of erectile dysfunction because of their peripheral side effects. These effects include nausea and vomiting, postural hypotension, arrhythmias, tachycardia, dysphoria, psychosis, hallucinations, drowsiness and dyskinesias (See, e.g., Martindale
The Extra Pharmacopoeia
, 31st Ed., pages 1151-1168).
The invention described herein provides a means to avoid the above-mentioned problems encountered with previously known methods for treating erectile dysfunction. Specifically, the invention relates to methods and formulations for effectively treating erectile dysfunction by transmucosally, e.g., buccally, sublingually or transrectally, administering a selected active agent, wherein the active agent is an inhibitor of a phosphodiesterase.
Phosphodiesterases are a class of intracellular enzymes involved in the metabolism of the second messenger nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) (see, e.g., Doherty, “Oral, Transdermal, and Transurethral Therapies for Erectile Dysfunction” in
Male Infertility and Dysfunction
, Helistrom, ed., Chapter 34 (New York, N.Y.: Springer-VerlagHellstrom, 1997)). Numerous phosphodiesterase inhibitors have previously been described in the literature for a variety of therapeutic uses, including treatment of obstructive lung disease, allergies, hypertension, angina, congestive heart failure and depression (see, e.g., Goodman and Gilman's
The Pharmacological Basis of Therapeutics
Ninth Edition, Chapter 34). Oral and parenteral administration of phosphodiesterase inhibitors, as alluded to above, have also been suggested for the treatment of erectile dysfunction (Doherty, supra; see also PCT Publication Nos. WO 96/16644, and WO 94/28902). The phosphodiesterases have been classified into seven major families, Types I-VII, based on amino acid or DNA sequences. The members of the family vary in their tissue, cellular and subcellular distribution, as well as their links to cAMP and cGMP pathways. For example, the corpora cavernosa contains: Type III phosphodiesterases, which are cAMP-specific cGMP inhibitable; Type IV phosphodiesterases, the high affinity, high-specificity cAMP-specific form; and Type V phosphodiesterases, one of the cGMP-specific forms.
The invention, as noted above, is directed to transmucosal administration of pharmacologically active agents to treat erectile dysfunction. The agents are preferably, although not necessarily, Type III, Type IV or Type V phosphodiesterase inhibitors. Surprisingly, it has now been found by the inventors herein that transmucosal and particularly buccal, sublingual or transrectal administration of these phosphodiesterase inhibitors as disclosed herein is highly effective in treating erectile dysfunction, including vasculogenic impotence. Transmucosal and particularly buccal, sublingual or transrectal administration of phosphodiesterase inhibitors to treat erectile dysfunction accordingly represents an important adv
Doherty, Jr. Paul C.
Place Virgil A.
Smith William L.
Reamer James H.
Reed Dianne E.
Reed & Associates
Vivus Inc.
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