EP1220666A2 - Methodes permettant de moduler la reponse sexuelle chez les humains - Google Patents

Methodes permettant de moduler la reponse sexuelle chez les humains

Info

Publication number
EP1220666A2
EP1220666A2 EP00921760A EP00921760A EP1220666A2 EP 1220666 A2 EP1220666 A2 EP 1220666A2 EP 00921760 A EP00921760 A EP 00921760A EP 00921760 A EP00921760 A EP 00921760A EP 1220666 A2 EP1220666 A2 EP 1220666A2
Authority
EP
European Patent Office
Prior art keywords
administration
improvement
amount administered
minutes
phentolamine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00921760A
Other languages
German (de)
English (en)
Inventor
Andrian Di Zorgniotti
Joseph S. Podolski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Repros Therapeutics Inc
Original Assignee
Zonagen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zonagen Inc filed Critical Zonagen Inc
Publication of EP1220666A2 publication Critical patent/EP1220666A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the application is directed to improved methods for modulating the human sexual response by administering vasodilator agents to the circulation of a human via transmucosal, including but not limited to, administration through the vaginal mucosa, transdermal, intranasal or rectal routes of administration.
  • the human sexual response in both males and females results from a complex interplay of psychological, hormonal, and other physiological influences.
  • One important aspect of human sexual response that is common to both men and women is the erectile response which itself results from an interplay between the autonomic nervous system, the endocrine system, and the circulatory system.
  • Impotence Failure of the erectile response is most common in men and is referred to as impotence. Impotence is the inability of a male to achieve or sustain a penile erection sufficient for vaginal penetration and intercourse. Numerous approaches have been taken in attempts to treat impotence. These approaches include the use of external or internally implanted penile prosthesis. (See, e.g., U.S. Patent No. 5,065,744, to Zumanowsky). A variety of drugs and methods for administering drugs have also been used in attempts to treat impotence. For example, U.S. Patent No.
  • 3,943,246 to St ⁇ rmer addresses treatment of impotence in men by buccal and peroral administration of daily doses of 300-1500 international units (I.U.) of oxytocin or daily divided doses of 150-250 I.U. of desamino-oxytocin.
  • the patent states that the buccal administration of 100 I.U. three times a day for 14 days results in improvement of impotentia erectionis in 12 of the 16 patients treated.
  • U.S. Patent No. 4,530,920 to Nestor et al. suggests the possibility that administration of nonapeptide and decapeptide analogs of luteinizing hormone releasing hormone agonists may be useful in the induction or enhancement of sexual behavior or therapy for impotence or frigidity.
  • Nestor et al. suggest numerous routes of administration of the analogs including buccal, sublingual, oral, parenteral (including subcutaneous, intramuscular, and intravenous administration), rectal, vaginal, and others.
  • U.S. Patent No. 4,863,911 to Anderson et al. addresses methods for treating sexual dysfunction in mammals using a biooxidizable, blood-brain barrier penetrating estrogen derivative.
  • One of the purported objects of the Anderson et al. invention is the treatment of "psychological impotence" in males. Test results showed that the drugs used in the study stimulated mounting behavior, intromission, and mount latency in castrated rats.
  • vasodilators for the treatment of impotence in males. Attempts to utilize vasodilators for the treatment of impotence were prompted because a significant percentage of cases of impotence were noted to be vasculogenic, i.e., resulting from vascular insufficiency.
  • Voss et al. U.S. Patent No. 4,801 ,587, issued January 31 , 1989, addresses the use of an ointment containing a vasodilator and a carrier agent for topical application to the penis of impotent men.
  • the Voss et al. patent also describes application of such an ointment into the urethra of the penis using a catheter as well as a multi-step regimen for applying a vasodilator to the skin of the penis.
  • Voss et al. U.S. Patent No. 4,801 ,587, issued January 31 , 1989, addresses the use of an ointment containing a vasodilator and a carrier agent for topical application to the penis of impotent men.
  • the Voss et al. patent also describes application of such an ointment into the urethra of the penis using a catheter as well as a multi-step regimen for applying
  • Vasodilators suggested for use by Voss et al. include papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, and phentolamine.
  • the Voss et al. patent provides no information regarding the actual efficacy of the treatments proposed or the nature of the response to such treatments.
  • Latorre 4,127,1 18 to Latorre describes treating male impotence by directly injecting the vasodilating drugs into the corpus cavernosum and the corpus spongiosum of the penis using a syringe and one or more hypodermic needles. More particularly, the Latorre patent proposes the intracavemosal and intraspongiosal injection of sympathomimetic amines such as nylidrin hydrochloride, adrenergic blocking agents such as tolazoline hydrochloride, and direct acting vasodilators such as isoxsuprine hydrochloride and nicotinyl alcohol.
  • sympathomimetic amines such as nylidrin hydrochloride
  • adrenergic blocking agents such as tolazoline hydrochloride
  • vasodilators such as isoxsuprine hydrochloride and nicotinyl alcohol.
  • intracavemosal injection may be useful for inducing erections in impotent men
  • the technique has numerous drawbacks. Obvious drawbacks include pain, risk of infection, inconvenience and interference with the spontaneity of the sex act. Priapism (prolonged and other painful erection) also appears to be a potential problem when using injection methods. See, e.g. Brindley, (1986).
  • Another problem arising in some cases of intracavemosal injection involves the formation of fibrotic lesions in the penis. See, e.g., Corriere, et al., J. Urol. 140:615- 617 (1988) and Larsen, et al., J. Urol. 137:292-293 (1987).
  • Phentolamine which has been shown to have the potential to induce erection when injected intracavernosally, has also been the subject of oral administration to test its effects in men having non-specific erectile insufficiency (Gwinup, Ann. Int. Med. 15 July 1988, pp. 162-163).
  • Eleven of the 16 patients (including three placebo-treated patients) became tumescent, became more responsive to sexual stimulation, and were able to achieve an erection sufficient for vaginal penetration after waiting 1.5 hours to attempt intercourse. Sonda et al. J. Sex & Marital Ther.
  • lollipop-administered drugs may improve cardiovascular function including drugs exhibiting direct vasodilating effects, calcium channel blockers, ⁇ - adrenergic blocking agents, serotonin receptor blocking agents, angina blocking agents, other anti-hypertensive agents, cardiac stimulating agents, and agents which improve renal vascular function.
  • the present invention provides improved methods for modulating the human sexual response by administering a vasodilator agent to the circulation in an amount effective to increase blood flow to the genitalia.
  • modulation of male and female human sexual response is provided on demand by administering an effective vasodilating amount of the agent by a route selected from the group consisting of transmucosal, including vaginal mucosal, transdermal, intranasal and rectal.
  • Vasodilating agents useful in the present invention include, but are not limited to, the group consisting of phentolamine, phentolamine mesylate, phentolamine hydrochloride, apomorphine, phenoxybenzamine, yohimbine, organic nitrates (e.g. nitroglycerin), thymoxamine, imipramine, verapamil, isoxsuprine, naftidrofuryl, tolazoline and papaverine.
  • the presently preferred agent is phentolamine mesylate.
  • the presently preferred administrative route is transmucosal, especially through the vaginal mucosa.
  • the present invention is specifically directed to improved methods for treating male impotence by administering a vasodilator agent in an amount effective to increase blood flow to the penis wherein erectile ability on demand is permitted by administering the agent by an administrative route selected from the group consisting of transmucosal, transdermal, intranasal, and rectal.
  • the amount of vasodilating agent used in the practice of the invention for treatment of male impotence is effective to improve erectile ability in from about 1 minute to about 60 minutes following administration of the agent.
  • the invention is also specifically directed to methods for modulating the excitation and plateau phases of the female sexual response on demand by transmucosal, including vaginal mucosal, transdermal, intranasal, or rectal administration of an effective amount of vasodilator agent.
  • transmucosal administration in the female is by addition of an effective amount of the vasodilating agent to vaginal suppository formulations well known in the art
  • vasodilating agent can be administered transmucosally using creams, gels, tablet inserts and solution formulations
  • the methods of the present invention are also useful in preparation for sexual intercourse by virtue of the ability to modulate the sexual response in both males and females
  • the present invention is also directed to the use of a drug having vasodilator activity for the manufacture of a medicament for transmucosal, including vaginal mucosal, transdermal, intranasal, and rectal administration to modulate sexual response in a human
  • Vasodilator drugs useful for manufacturing the medicament include, but are not limited to, phentolamine mesylate, phentolamine hydrochloride, phenoxybenzamine yohimbine, organic nitrates, thymoxamine, imipramine, verapamil, isoxsupnne, naftidrofuryl, tolazo ne, and papaverine
  • the human sexual response in both the male and female involves a complex interplay between endocrine, neurological and psychological components which result in certain physiological and anatomical responses in both men and women
  • erectile response While there are obvious differences in the sexual response between men and women, one common aspect of the sexual response is the erectile response.
  • the erectile response in both males and females is result of engorgement of the erectile tissues of the genitalia with blood in response to sexual stimulation (physical, psychological, or both).
  • the vasculature which serves erectile tissue in both men and women is similar.
  • the arterial circulation to the erectile tissues of the genitalia derives from the common iliac artery which branches from abdominal aorta.
  • the common iliac artery bifurcates into the internal and external iliac arteries.
  • the internal pudic artery arises from the smaller of two terminal branches of the anterior trunk of the internal iliac artery.
  • the internal pudic artery branches into the superficial perineal artery which supplies the labia pudenda.
  • the internal pudic artery also branches into the artery of the bulb which supplies the bulbi vestibuli and the erectile tissue of the vagina.
  • the artery of the corpus cavernosum another branch of the internal pudic artery supplies the cavernous body of the clitoris. Still another branch of the internal pudic artery is the arteria dorsalis clitoridis which supplies the dorsum of the clitoris and terminates in the glans and membranous folds surrounding the clitoris which correspond to the prepuce of the male.
  • the internal pudic artery branches into the dorsal artery of the penis (which itself branches into a left and right branch) and the artery of the corpus cavernosum, all of which supply blood to the corpus cavernosum.
  • the dorsal artery of the penis is analogous to the artery dorsalis clitoridis in the female, while the artery of the corpus cavernosum in the male is analogous to the artery of the same name in the female.
  • the male erectile response is regulated by the autonomic nervous system which controls blood flow to the penis via the interaction of peripheral nerves associated with the arterial vessels in and around the corpus cavernosum.
  • the arteries serving the corpus cavernosum are maintained in a relatively constricted state, thereby limiting the blood flow to the corpus cavernosum
  • the smooth muscles associated with the arteries relax under the influence of catecholamines and blood flow to the corpus cavernosum greatly increases, causing expansion and rigidity of the penis Brindley, supra (1986) hypothesizes that smooth muscle contraction opens valves through which blood can flow from the corpus cavernosum into the extracavernosal veins According to Brindley (1986), when the relevant smooth muscles relax, the valves close diminishing venous outflow from the corpus cavernosum When accompanied by increased arterial blood flow into the corpus cavernosum, this results in engorgement of the corpus cavernos
  • the pre-orgasmic sexual response in females can be broken down into distinct phases Both the excitement phase and the plateau phase involve vasodilation and engorgement (vasocongestion) of the genitalia with arterial blood in a manner analogous to the male erectile response
  • the excitement phase of the female sexual response is characterized by vasocongestion in the walls of the vagina which leads to the transudation of vaginal fluids and vaginal lubrication Further, the inner one-third of the vaginal barrel expands and the cervix and the body of the uterus become elevated This is accompanied by the flattening and elevation of the labia majora and an increase in c toral size [Kolodny et al , Textbook of sexual Medicine, Little and Brown, Boston, MA (1979)]
  • the plateau phase follows the excitement phase in the female sexual response and is characterized by prominent vasocongestion in the outer one-third of the vagina, causing a narrowing of the opening of the vagina and a retraction of the shaft and the glans of the clitoris against the symphysis pubis
  • These responses are also accompanied by a marked vasocongestion of the labia [Kolodny, supra
  • Endocrine related impotence can result from primary gonadal failure, advanced diabetes mellitus, hypothyroidism, and as one of the secondary sequelae of pituitary adenoma, idiopathic or acquired hypogonadism, hyperprolactinemia and other endocrine abnormalities.
  • Neurogenic impotence arising in the central nervous system can be caused by temporal lobe disorders caused by trauma, epilepsy, neoplasms and stroke, intramedullary spinal lesions, paraplegia, and demyelinating disorders.
  • Neurogenic causes of impotence arising in the peripheral nervous system include somatic or autonomic neuropathies, pelvic neoplasms, granulomas, trauma, and others.
  • Urologic causes of impotence include complete prostatectomy, local trauma, neoplasms, Peyronie's disease, and others.
  • the present invention is designed to modify the circulatory aspects of the erectile response using vasoactive agents administered to the circulation by a route selected from the group consisting of transmucosal, including vaginal mucosal, transdermal, intranasal, and rectal.
  • vasoactive agents may be used in the practice of the present invention based on demonstrated systemic efficacy as vasodilators.
  • Useful vasodilating drugs include those generally classified as ⁇ -adrenergic antagonists, sympathomimetic amines and those agents which exhibit direct relaxation of vascular smooth muscle.
  • Exemplary - adrenergic antagonists include phentolamine, phentolamine hydrochloride, phentolamine mesylate, apomorphine, phenoxybenzamine, tolazoline, dibenamine, yohimbine, and others.
  • Phentolamine mesylate is a preferred ⁇ -adrenergic agent vasodilator for use preferred practice of the present invention.
  • An exemplary sympathomimetic amine contemplated for use in the method of the present invention is nylidrin and use of other sympathomimetic amines having vasodilating activity is also contemplated.
  • Nicotinic acid has a direct vasodilating activity useful in the practice of the present invention.
  • papaverine a non-specific smooth muscle relaxant which possesses vasodilating activity and which has been used to treat male impotence by direct injection into the corpus cavernosum either alone or in combination with other drugs such as phentolamine.
  • Organic nitrates such as nitroglycerine and amyl nitrate have pronounced vasodilating activity by virtue of their ability to relax vascular smooth muscle and are thus contemplated for use according to the invention.
  • Other vasoactive drugs useful in the practice of the present invention include, without limitation, thymoxamine, imipramine, verapamil, naftidrofuryl, and isoxsup ne.
  • vasoactive agents are administered by the transmucosal, including vaginal mucosal, intranasal, transdermal, or rectal routes of administration such that the agent is conveyed in circulation to the site of action prior to entering portal circulation.
  • Oral administration of a drug in an attempt to effect delivery to a specific site within circulation may have several drawbacks First, drug absorption is limited by gastrointestinal transit time and thus, the rapidity of onset of drug action may be limited Second, the drug may be inactivated (e.g by hydrolysis) in the low pH environment of the stomach and or by other chemical or biochemical interactions in the intestines
  • Transmucosal including vaginal mucosal, transdermal, intranasal, and rectal routes of administration of vasodilators according to the present invention allows administration of the vasodilator a short time prior to the projected initiation of intercourse ("on demand") and eliminating the need for repeated administration of the drug
  • Methods of the present invention are thus more convenient and help minimize any side-effects that can arise as a result of continuous or daily administration of the drugs
  • methods of the present invention allow more spontaneity in sexual activity than allowed by other methods such as intracavemosal injection of vasodilators
  • transmucosal delivery generally refers to delivery of the drug to the vaginal mucosa, the oral or pharyngeal mucosa and includes buccal delivery, subhngual delivery, and delivery to the pharyngeal mucosa, but not to the stomach
  • buccal delivery may be accomplished by preparing a tablet or lozenge comprising, for example, compressed lactose and an effective amount of one or more vasodilators
  • suitable tablet compositions include, but are not limited to, a combination of an effective dose of a vasodilator, and carrier substances, tablet-binding compounds and flavoring agents such as those described in U S Patent No 3,943,246 to Sturmer, which is incorporated herein by reference
  • Vasoactive agents may also be compounded with a variety of pharmaceutical excipients including binders such as gelatin and/or corn starch or
  • transdermal delivery systems are well known in the art and involve what are sometimes referred to as transdermal "patches"
  • exemplary transdermal patches typically comprise (1 ) a impermeable backing layer which may be made up of any of a wide variety of plastics or resins, e.g aluminized polyester or polyester alone or other impermeable films, and (2) a drug reservoir comprising, for example, a vasodilator in combination with mineral oil, polyisobutylene, and alcohols gelled with USP hydroxymethylcellulose
  • Other exemplary drug reservoir layers may comprise, for example, acrylic-based polymer adhesives with resinous cross-linking agents which provide for diffusion of the drug from the reservoir to the surface of the skin
  • the transdermal patch may also have a delivery rate-controlling membrane such as a microporous polypropylene disposed between the reservoir and the skin Ethylene- vinyl acetate copolymers and other microporous membranes may also be used
  • an adhesive layer is provided which may comprise an adhesive formulation
  • Vasodilating drugs for use in transmucosal including vaginal mucosal, transdermal, intranasal, or rectal delivery may be chemically modified by methods well known in the art to improve their o lipid solubility and thus their ability to penetrate skin or mucosal surfaces.
  • Rectal and vaginal suppositories are well known in the art and also useful in the practice of the present invention.
  • Exemplary suppositories comprise a vasodilating drug combined with glycerin, glycerol monopalmitate, glycerol, monostearate, hydrogenated palm 5 kernel oil and fatty acids.
  • Another exemplary suppository formulation includes ascorbyl palmitate, silicon dioxide, white wax, and cocoa butter in combination with an effective amount of a vasodilating drugs.
  • nasal sprays for the administration of the vasodilators.
  • exemplary nasal spray o formulations comprise a solution of vasodilating drug in physiologic saline or other pharmaceutically suitable carrier liquids.
  • Nasal spray compression pumps are also well known in the art and can be calibrated to deliver a predetermined dose of the vasodilator solution.
  • Phentolamine can exist in unsolvated as well as solvated 0 forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention. Phentolamine can form pharmaceutically acceptable salts with organic and inorganic acids.
  • suitable acids for salt formation are hydrohamic acids such as hydrochloric and hydrobromic; as well as other acids such as sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, toluenesulfonic, and other mineral and carboxylic acids known to those skilled in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base form for purposes of this invention.
  • Phentolamine can also form crystalline polymorph forms or crystalline forms thereof using suitable or conventional crystallization procedures.
  • Example 1 describes the effect of transmucosally administered phentolamine mesylate on penile arterial velocity.
  • Examples 2 and 3 describe the effect of buccally administered phentolamine mesylate on erectile ability in impotent men.
  • Example 4 describes the use of a variety of vasodilators in the practice of the present invention.
  • Example 5 addresses practice of the present invention in modulating erectile response in females.
  • penile arterial velocity was measured close to the base of the right branch of the dorsal artery of the penis by doppler ultrasound velocimetry using a Diasonics 400 DRF (Diasonics, Milpitas, CA). Settings, incidence of doppler beam, and angle correction were maintained to achieved maximum velocity readings on each subject.
  • the dorsal artery was selected for measurement because it was more accessible than the artery of the corpus cavernosum.
  • Velocities were measured before the transmucosal (buccal) administration of phentolamine mesylate (20 mg) and at 5, 15, 45 and 60 minutes after administration of the drug. Mean initial velocity was 10.4 cm/sec.
  • the data shown in Figure 1 shows the percentage increase in penile artery velocity versus time after administration of phentolamine mesylate and represent the mean of triplicate readings in six impotent subjects.
  • vascular status was determined by measuring brachial and penile systolic closing pressures and calculating a penile brachial index (PBI).
  • PBI penile brachial index
  • PBI was calculated by dividing the penile systolic pressure by the brachial systolic pressure.
  • Plethysmographic crest times (CT) were measured with a Penilab IV plethysmograph (Parkes, Aloha WA). Crest time is the time in seconds from the trough of the penile blood pressure curve to the next peak. The normal range of crest times is from about 1 second to about 1.8 seconds.
  • a PBI of >0.9 is considered normal while a PBI of ⁇ 0.6 indicates vascular insufficiency.
  • the patients were identified as having normal vascularity if both PBI and CT were in the normal range.
  • Patients having both CT and PBI in the abnormal range were identified as having marked vascular insufficiency.
  • Patients having one parameter in the abnormal range were identified as having moderate vascular insufficiency.
  • Age and diagnosis were generally not a factor in admission to the study, although patients with extreme age or severe penile vascular insufficiency were excluded.
  • Patients having vascular or non-specific causes of impotence were admitted to the trial, as were patients having diabetes mellitus.
  • Mean age of patients was 57.5 years (range: 25-74 years).
  • 1 indicates a report of erection and vaginal penetration
  • 2 indicates reported failure to achieve erection
  • 3 indicates report of a partial erection.
  • Table 1 illustrates that buccal administration of 20 mg of phentolamine mesylate resulted in improved erectile ability within 10 minutes to 20 minutes after buccal administration of the drug.
  • the response was characterized by improved erectile ability upon sexual stimulation and thus, the response closely mimicked the normal sexual response in men.
  • the fact that the effect of the drug was seen within 10- 20 minutes after a single administration can be characterized as a response occurring "on demand" in that multiple doses and/or a long waiting time before onset of improved erectile ability were not required.
  • the rapid increase in penile artery velocity within five minutes of administration of phentolamine mesylate suggests that improve erectile ability may actually occur sooner than 10 minutes after administration.
  • the "on demand" aspect of the method of the present invention allows a more natural and more spontaneous approach to intercourse and eliminates the need for multiple doses, and thus, reduces the frequency of undesirable side effects.
  • a 20 mg dose of phentolamine mesylate was used in the present study, doses from about 5 mg to about 80 mg of phentolamine mesylate are within the scope of the present invention as individual responsiveness to the drug may vary e.g. , on the basis of total body weight and degree of vascular insufficiency.
  • the data set out in Table 1 was further analyzed to determine if the vascular status of the patients had any predictive value with respect to the efficacy of phentolamine mesylate in improving the erectile ability in impotent patients.
  • the analysis showed that, of 16 total patients with normal vascular status, seven were successfully treated with phentolamine mesylate, six failed to respond, and three achieved partial erection. Of the 49 patients with vascular insufficiency, 15 were successful in achieving erection sufficient for vaginal penetration, while 29 failed. Five patients with vascular insufficiency achieved partial erection.
  • the side effects seen in this study were infrequent and include, stuffy nose (6%), faintness or dizziness (2.3%) (relieved by lying down for 10-15 minutes) and vomiting 0.05%.
  • vasodilators such as phentolamine mesylate when administered via a transmucosal route of administration is effective in improving the onset of erectile ability in a significant percentage of impotent men and more particularly in men having psychogenic.
  • arteriogenic, or combined psychogenic/arteriogenic impotence the subpopulation of patients comprising the majority of cases of male impotence.
  • the present invention is also useful in improving erectile ability in non- impotent men. It is well known that as men age, erectile ability may be altered.
  • the method of the present invention provides a means for improving erectile ability in non- impotent men by increasing blood flow to the penis, and thereby minimizing the erectile angle. It should also be noted that filter strips impregnated with phentolamine mesylate lost their potency after several months of storage at room temperature in a paper bag.
  • vasoactive agents may be used in the practice of the present invention based on their demonstrated efficacy as vasodilators.
  • Useful vasodilating drugs include those generally classified as ⁇ -adrenergic antagonists, sympathomimetic amines and those agents which exhibit direct relaxation of vascular smooth muscle.
  • Exemplary ⁇ -adrenergic antagonists include phentolamine hydrochloride, phentolamine mesylate, phenoxybenzamine, tolazoline, dibenamine, yohimbine, and others. Phentolamine mesylate is preferred in the practice of the present invention.
  • An exemplary sympathomimetic amine contemplated for use in the method of the present invention is nylidrin although other sympathomimetic amines having vasodilating activity are also comprehended by the invention.
  • Nicotinic acid (or nicotinyl alcohol) has a direct vasodilating activity which is useful in the practice of the present invention.
  • Papaverine is also non-specific smooth muscle relaxant which has vasodilating activity and has been used to treat male impotence by direct injection into the corpus cavernosum either alone or in combination with other drugs such as phentolamine.
  • Organic nitrates such as nitroglycerine and amyl nitrate also have pronounced vasodilating activity by virtue of their ability to relax vascular smooth muscle.
  • vasoactive drugs of use in the practice of the present invention include but are not limited to thymoxamine, imipramine, verapamil, naftidrofuryl, isoxsuprine, and others.
  • these vasoactive agents are administered by the transmucosal, including vaginal mucosal, intranasal, transdermal, or rectal routes of administration such that the agent reaches its site of action prior to entering the portal circulation.
  • each vasoactive agents for each route of administration are readily determined by those of ordinary skill in the art.
  • one of ordinary skill in the art may use as a starting point, the usual published dosage of the vasodilator.
  • the usual oral doses for commercially available vasodilators can be found in the Physician's Desk Reference published annually by Medical Economic Data, Montvale New Jersey, and in the available medical literature.
  • Pavabid® oral papaverine hydrochloride is available from Marion Merrell Dow and is normally administered at 150 mg every 12 hours to achieve its vasodilating effects.
  • Calon® vehicle hydrochloride
  • Yohimbine hydrochloride available as Daytohimbin®
  • Yocon® (Palisades Pharmaceuticals), and Yohimex® (Kramer) are all administered orally as 5.4 mg three times a day.
  • Imipramine hydrochloride is available as Tofranil® from Geigy and is administered orally 4 times a day for a total dose ranging from 50 mg to about 150 mg per day.
  • Imipramine pamoate also available from Geigy is administered in oral maintenance doses of 150 mg/day.
  • the optimal dosage for the specific route of administration can be determined by measuring baseline arterial blood flow in genital circulation of the patient prior to administration of the drug using a doppler ultrasound velocimeter as described in Example 1. Other methods such as thermography, plethysmography, radiomet c or scintigraphic methods, and other methods well known in the art may also be utilized to assess blood flow in the genitalia. Having established base line blood flow, various dosages of the respective vasodilators may be administered by the routes of administration encompassed by the present invention and their effect on blood flow may be measured. The magnitude of the increase in blood flow necessary to modulate or enhance the sexual response in humans may vary from individual to individual, but is readily determined as described below. In addition, individual patients may be titrated with various dosages of the respective vasodilators until the optimum dosage is determined.
  • Vascular flow studies may also be coupled with assessments of sexual responsiveness as evidenced by the improvement of erectile ability in response to sexual stimulation.
  • EXAMPLE 5 MODULATION OF THE FEMALE SEXUAL RESPONSE
  • the methods of the present invention may be used to improve or enhance the erectile response in women whose sexual response is impaired as evidenced by diminished capacity to produce sufficient vaginal lubrication to facilitate comfortable penile penetration and by other symptoms of impaired sexual responsiveness that may be correlated with the erectile response.
  • the methods of the present invention may be used to enhance the normal female sexual response.
  • the "on demand" aspect of the present invention will allow a more rapid response to sexual stimulation along with heightened sensation associated with excitement and plateau stages of the female sexual response by virtue of the increased blood flow to the genitalia.
  • An effective vasodilating dose of a vasodilating agent is administered to a woman via the transmucosal, including but not limited to, through the vaginal mucosa, transdermal, intranasal, or rectal routes of administration.
  • the appropriate doses of the particular vasodilating agent may be readily determined using methods described in Example 4.
  • Exemplary vasodilators useful in the practice of the present invention are set out in Example 4 and include those generally classified as ⁇ - adrenergic antagonists, sympathomimetic amines and those agents which exhibit direct relaxation of vascular smooth muscle.
  • the female response may be measured using methods described in Masters, W.H.
  • Methods for measuring blood flow including doppler ultrasonic velocimetry, thermography using for example an isothermal blood flow transducer, radioscintigraphic methods, photoplethysmography may be used as well as other methods well known in the art.
  • measuring the contraction of the distal 1/3 as is characteristic of the plateau phase of female sexual response of the vagina may be measured using methods and equipment well known in the art including but not limited to strain gauges or other devices for measuring muscular contraction or muscle tension.
  • enhanced sexual response may be measured in a more subjective manner by simply asking the female subject to describe any change in sensation brought about by administration of the vasodilator by the methods of the present invention.
  • Appropriate placebo controls should also be conducted to ascertain whether or not the effort is directly attributable to the administration of the vasodilator.
  • a preferred embodiment of the present invention involves the transmucosal administration of from about 5 mg to about 150 mg of phentolamine mesylate, preferably from about 15 mg to about 100 mg of phentolamine mesylate, more preferably from about 25 mg to about 80 mg of phentolamine mesylate, and most preferably 40 mg of phentolamine mesylate from about 1 minute to about 1 hour prior to, and in preparation for, intercourse.
  • the amount of vasodilating agent used in the practice of the invention for the improvement of the female sexual response is effective to improve sexual response from about 1 minute to about 1 hour after administration.
  • the amount of vasodilating agent used is effective to improve female sexual response from about 5 minutes to about 45 minutes after administration. It is also preferable that the amount of vasodilating agent used is effective to improve female sexual response from about 15 minutes to about 30 minutes after administration. Other vasodilating agents and other routes of administration included within the scope of the present invention are also contemplated.
  • vaginal suppositories are well known in the art and are available in a variety of physical forms. Most commonly known are suppositories or pessaries which are globular or oviform and weigh about 5 g each. More recently, creams, gels or liquids which depart from the classical concept of suppositories have become available and are useful in the practice of the present invention.
  • Compositions for vaginal administration can also be supplied as vaginal tablets, or inserts prepared by encapsulation in soft gelatin. Additionally, compositions for vaginal administration can be prepared as solutions which are then lyophilized. When water is added to the lyophilized solutions before administration, lyophilized solutions provide an effective means of administration. All of these physical forms are contemplated.
  • An exemplary vaginal suppository contains a mixture of approximately 86% poyethylene glycol 1000 NF, 10% polyethylene glycol
  • vaginal suppository provides an effective vehicle for delivering a dose of phentolamine mesylate through the vaginal mucosa.
  • An exemplary 40 mg phentolamine mesylate tablet insert contains a mixture of approximately 61 % microcrystalline cellulose, NF; 30% hydrogenated vegetable oil, NF; 4% croscarmellose sodium, NF; 4% phentolamine mesylate; 0.5% magnesium stearate, NF; and, .04% colloidal silicon dioxide.
  • the mixture is pressed into a tablet form and the resulting tablet inserts are then encapsulated in soft gelatin by methods commonly known in the art.
  • the encapsulated insert is then administered to a woman through the vaginal mucosa.
  • An exemplary vaginal gel for administration of the present invention includes a mixture of approximately 75% water, 15% glycerin, 7% phentolamine mesylate and less than 1 % hydroxyethylcellulose, methylparaben and glucono- ⁇ -lactone.
  • the resulting vaginal gel provides an effective vehicle for delivering a dose of phentolamine mesylate through the vaginal mucosa.
  • An exemplary solution for lyophilization includes phentolamine mesylate, citric acid, sodium bicarbonate, mannitol, and magnesium stearate. After lyopholization, water was added to re-hydrate before administering to a woman through the vaginal mucosa.
  • Another exemplary solution comprises a mixture of approximately 83% potable water, 13% phentolamine mesylate and 4%
  • the resulting solution provides another effective vehicle for delivering a dose of phentolamine mesylate through the vaginal mucosa.
  • Additional suppository, gel, cream, solution or insert formulations are also included within the scope of the present invention. While this invention has been described by way of preferred embodiments, the examples set out herein are not intended to limit the scope of the invention which contemplates the use of any pharmacologic vasodilating drug capable of absorption into the systemic circulation upon administration of the drug via the transmucosal, including vaginal mucosal, transdermal, intranasal, or rectal routes of administration.

Abstract

L'invention concerne des méthodes perfectionnées permettant de moduler la réponse sexuelle chez les humains grâce à l'administration d'un vasodilatateur dans le système circulatoire par administration transmuqueuse et notamment, entre autres, par voie d'administration vaginale, transdermique, intranasale ou rectale.
EP00921760A 1999-04-06 2000-04-06 Methodes permettant de moduler la reponse sexuelle chez les humains Withdrawn EP1220666A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US12791099P 1999-04-06 1999-04-06
US127910P 1999-04-06
PCT/US2000/009112 WO2000059491A2 (fr) 1999-04-06 2000-04-06 Methodes permettant de moduler la reponse sexuelle chez les humains

Publications (1)

Publication Number Publication Date
EP1220666A2 true EP1220666A2 (fr) 2002-07-10

Family

ID=22432589

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00921760A Withdrawn EP1220666A2 (fr) 1999-04-06 2000-04-06 Methodes permettant de moduler la reponse sexuelle chez les humains

Country Status (10)

Country Link
EP (1) EP1220666A2 (fr)
JP (1) JP2002541100A (fr)
KR (1) KR20020015310A (fr)
CN (1) CN1374861A (fr)
AU (1) AU4203600A (fr)
BR (1) BR0009583A (fr)
CA (1) CA2366903A1 (fr)
MX (1) MXPA01010021A (fr)
NO (1) NO20014827L (fr)
WO (1) WO2000059491A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8939889B1 (en) 2013-08-22 2015-01-27 Coloplast A/S Pump bulb for an implantable penile prosthetic

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0130704D0 (en) * 2001-12-21 2002-02-06 Glaxo Group Ltd New use

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1221826B (it) * 1988-06-08 1990-07-12 Medico Harvey Srl Centro Preparato per uso topico per il trattamento terapeutico dell impotentia coeundi
US5565466A (en) * 1993-08-13 1996-10-15 Zonagen, Inc. Methods for modulating the human sexual response
US5731339A (en) * 1995-04-28 1998-03-24 Zonagen, Inc. Methods and formulations for modulating the human sexual response
US6251436B1 (en) * 1995-09-29 2001-06-26 L.A.M. Pharmaceutical Corporation Drug preparations for treating sexual dysfunction
US5952006A (en) * 1995-09-29 1999-09-14 L.A.M. Pharmaceuticals, Llc Drug preparations for treating impotency
WO1998052569A1 (fr) * 1997-05-19 1998-11-26 Zonagen, Inc. Therapie combinatoire permettant de moduler la reponse sexuelle chez un patient
WO1999027905A1 (fr) * 1997-12-02 1999-06-10 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Compositions pour administration nasale
US6011043A (en) * 1998-06-19 2000-01-04 Schering Corporation Combination of phentolamine and apomorphine for the treatment of human sexual function and dysfunction
US6486207B2 (en) * 1998-12-10 2002-11-26 Nexmed (Holdings), Inc. Compositions and methods for amelioration of human female sexual dysfunction

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0059491A2 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8939889B1 (en) 2013-08-22 2015-01-27 Coloplast A/S Pump bulb for an implantable penile prosthetic
USD739530S1 (en) 2013-08-22 2015-09-22 Coloplast A/S Pump bulb with multi-concavity faces for an implantable penile prosthetic

Also Published As

Publication number Publication date
CN1374861A (zh) 2002-10-16
NO20014827L (no) 2001-12-04
BR0009583A (pt) 2002-06-11
WO2000059491A3 (fr) 2002-05-02
CA2366903A1 (fr) 2000-10-12
JP2002541100A (ja) 2002-12-03
AU4203600A (en) 2000-10-23
NO20014827D0 (no) 2001-10-04
MXPA01010021A (es) 2002-07-30
WO2000059491A2 (fr) 2000-10-12
KR20020015310A (ko) 2002-02-27

Similar Documents

Publication Publication Date Title
US5565466A (en) Methods for modulating the human sexual response
US5981563A (en) Methods and formulations for modulating the human sexual response
EP0996447B1 (fr) Therapie combinatoire permettant de moduler la reponse sexuelle chez un patient
EP1220666A2 (fr) Methodes permettant de moduler la reponse sexuelle chez les humains
AU696815C (en) Methods for modulating the human sexual response
AU723242B2 (en) Methods for modulating the human sexual response
US20100311785A1 (en) Combination Therapy For Modulating The Human Sexual Response

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20011102

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20021128

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20030611