JP2002541100A - Methods for modulating human sexual response - Google Patents

Abstract

  (57) [Summary] The present invention relates to improved methods for modulating human sexual response by administering vasodilators to the circulation by transmucosal. Such transmucosal administration includes, but is not limited to, vaginal mucosal, transdermal, intranasal, or rectal administration. The method of the invention is a method for modulating a sexual response in a human by administering a vasodilator to the blood circulation in an amount effective to increase blood flow to the genital tract, wherein the sexual response is Amelioration involves modulating the sexual response on demand by administering an effective amount of the agent transmucosally.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] This application relates to improvements in methods for modulating human sexual response by administering vasodilators to the human circulation by transmucosal. As this transmucosal administration,
Include, but are not limited to, vaginal mucosal, transdermal, intranasal, or rectal routes of administration.

BACKGROUND OF THE INVENTION [0002] Human sexual response in both men and women results from a complex interaction of psychological, hormonally influenced, and other physiological effects. One important aspect of the human sexual response common to both men and women is the erectile response, which itself results from interactions between the autonomic nervous system, the endocrine system, and the circulatory system .

[0003] Failure of the erectile response is most common in men and is referred to as impotence. The impotence is that men cannot achieve or sustain penile erections sufficient for vaginal insertion and sexual intercourse. Neurological approaches have been taken in an attempt to treat impotence. These approaches involve the use of externally or internally implanted penile prostheses. (See, for example, US Pat. No. 5,065,
744 (Zumanowsky)). Various drugs and drug administration methods have also been used in attempts to treat impotence. For example, U.S. Pat. No. 3,943,246 (Sturmer) states that daily doses are 300-400.
1500 international units (IU) of oxytocin or 15 divided doses daily
0-250I. U. Has addressed the treatment of impotence in men by oral and oral administration of desamino-oxytocin. This patent is issued 100 times three times a day.
I. U. For 14 days, resulting in an improvement in impotentia erectionis in 12 of the 16 patients treated.

[0004] US Pat. No. 4,530,920 (Nestor et al.) Discloses that administration of nonapeptide and decapeptide analogs of luteinizing hormone-releasing hormone agonists is useful in inducing or enhancing sexual behavior, or treating impotence or insensitivity. Implies the possibility that Nestor et al. Suggest a number of routes of administration of the analogs, including buccal, sublingual, oral, parenteral (including subcutaneous, intramuscular, and intravenous), rectal, vaginal, and the like. .

[0005] US Pat. No. 4,139,617 (Grunwell et al.) Discloses 19-oxygenated-an for endocrine.
It is suggested that the buccal route of drost-5-ene) and other routes of administration mediated enhanced libido in humans.

[0006] US Pat. No. 4,863,911 (Anderson et al.) Addresses a method for treating sexual dysfunction in mammals using biooxidizable blood-brain barrier permeable estrogen derivatives. One of the intended purposes of the Anderson et al. Invention is to treat "psychological impotence" in men. The test results showed that the drugs used in this study stimulated riding behavior, insertion and mount latency in castrated rats.

[0007] Many publications have proposed the use of various vasodilators to treat impotence in men. Attempts have been made to use vasodilators to treat impotence. This is because a significant proportion of impotence cases were referred to as vascular (ie, resulting from vascular dysfunction).

[0008] Voss et al. (US Pat. No. 4,801,587, issued Jan. 31, 1989)
Addresses the use of ointments containing vasodilators and carrier agents for topical application of impotence to the penis in men. The Voss et al patent also describes applying such an ointment to the corpus cavernosum using a catheter, as well as a multi-step regimen for applying a vasodilator to penile skin. Furthermore, V
proposes to surgically remove a portion of the fibrous sheath surrounding the corpus cavernosum, thereby facilitating the penetration of ointments containing vasodilators into the corpus cavernosum. V
Vasodilators suggested for use by oss et al. include papaverine, hydrazine, sodium nitroprusside, phenoxybenzamine, and phentolamine. However, the Voss et al. Patent does not provide information on the actual efficacy of the proposed treatment, nor on the nature of the response to such treatment.

US Pat. No. 4,127,118 (Latorre) treats male impotence by injecting vasodilator drugs directly into the corpus cavernosum and penis corpus cavernosum using a syringe and one or more hypodermic needles. It is described. More specifically,
Latorre's patent is directed to sympathomimetic amines such as nylidrin hydrochloride, adrenergic blockers such as tolazoline hydrochloride, and direct acting vasodilators such as isoxsuprine hydrochloride and nicotinyl alcohol.
g vasodilator in the intracavernosa
And intraspongiosal injections have been proposed.

[0010] Blindley, G .; S. (Br. J. Pharmac. 87: 495-5).
00,1986) show that certain smooth muscle relaxants, including phenoxybenzamine, phentolamine, thymoxamine, imipramine, verapamil, papaverine, and naftidrofuryl, cause erections when injected directly into the corpus cavernosum using a hypodermic needle. Indicated. The study noted that "injection of the appropriate dose of phenoxybenzamine or papaverine is followed by a persistent erection lasting several hours." Injections of the other drugs studied induced an erection lasting from about 11 minutes to about 6.5 hours. Zo
rgniotti et al. Urol. 133: 39-41 (1985) reported that intracavernous injection of a combination of papaverine and phentolamine could cause erection in men with impotence that were not. Similarly, Althof et al. S
ex. Marital. Ther. 17 (2): 101-112 (1991) reported that intracavernous injection of papaverine hydrochloride and phentolamine mesylate resulted in improved erectile capacity in about 84% of injected patients. However, the dropout rate was 57% in that study, and 26% of patients had fibrotic nodules.
Nodule) occurred, 30% of patients had abnormal liver function values, and 19% of patients had bruises.

Other studies describing intracavernous injection of drugs using hypodermic needles to treat impotence include the following: Blindley, J. et al. Physi
ol. 342: 24P (1983); Blindley, Br. J. Psych
iatr. 143: 312-337 (1983); Virag, Lancet.
ii: 978 (1982); and Virag et al., Angology 35:
79-87 (1984).

Although intracavernous injection may be useful in inducing erections in men with impotence, this technique has many disadvantages. Obvious disadvantages include pain, risk of infection, inconvenience and spontaneous interference with sexual activity. Priapism (prolonged other painful erections) also appears to be a potential problem when using the injection method. See, for example, Blindley (1986). Another problem that occurs in some cases of intracavernous injections is the formation of fibrotic lesions in the penis. See, for example, Corriere et al. Urol. 140: 615
-617 (1988) and Larsen et al. Urol. 137: 292-
293 (1987).

[0013] Phentolamine, which has been shown to have the potential to induce erection when injected into the cavernous sinus, is also administered orally to test its effects in men with non-specific erectile dysfunction (Gwinup, Ann. Int. M.
ed. 15 July 1988, 162-163). 16 in that study
Name patients received either placebo or a 50 mg oral dose of phentolamine. 11 of 16 patients (including 3 placebo-treated patients)
Had an erection, became more responsive to sexual stimuli, and after waiting 1.5 hours, could achieve intercourse with sufficient erection for vaginal insertion.

Sonda et al. Sex & Martial Ther. 16 (1):
From 15 to 21 (years), yohimbine intake was increased in 38 of treated impotence males.
% Produced a subjective improvement in erectile performance, but only 5% of treated patients
Reported that they reported complete satisfaction.

Of interest in the context of the present invention are Stanley et al., US Pat.
No. 885,173, which has cardiovascular or renal vascular activity through the use of lollipops, which articulately enhance the absorption of drugs through the mucosal tissues of the mouth, pharynx, and esophagus. Work on methods for non-invasive administration of drugs. The Stanley et al. Patent discloses that a number of lollipop-administered drugs provide cardiovascular functions, including direct vasodilatory effects of the drug, calcium channel blockers, β-adrenergic blockers, serotonin receptor blockers, angina blockers, and others. It is suggested that antihypertensives, cardiostimulants, and drugs that improve renal vascular function can be improved.

US Pat. No. 5,059,603 to Rubin et al. Describes the topical administration of isoxpurine and caffeine, and nitroglycerin and caffeine to the penis, together with suitable carrier compounds for the treatment of impotence. .

There remains a need in the art for effective means to modulate human sexual response and, in particular, to increase erectile capacity in men with impotence. Ideally, such a means would be convenient and simple to use, would not require a constant dosing regimen or even multiple doses to achieve the desired result, would be non-invasive, Enables a quick and predictable ability to initiate erectile function in response to normal sexual stimulation.

SUMMARY OF THE INVENTION The present invention provides an improved method for modulating human sexual response by administering to the circulation a vasodilator in an amount effective to increase blood flow to the genital tract. Provide a way. In accordance with the present invention, the modulation of the sexual response in male and female humans is controlled by the route selected from the group consisting of transmucosal (including vaginal mucosa), transdermal, intranasal and rectal Provided on demand by administering a vasodilator dose. Vasodilators useful in the present invention include, but are not limited to, phentolamine, phentolamine mesylate, phentolamine hydrochloride, apomorphine, phenoxybenzamine, yohimbine, organic nitrates (eg, nitroglycerin), thymoxamine , Imipramine, verapamil, isoxuprine, naftidrofuryl, trazoline, and papaverine. The currently preferred drug is phentolamine mesylate. The currently preferred route of administration is transmucosal, especially by vaginal mucosa.

The present invention specifically relates to an improved method for treating male impotence by administering a vasodilator in an amount effective to increase blood flow to the penis, wherein the method comprises: Erectile capacity at times is tolerated by administering the drug by an administrative route selected from the group consisting of transmucosal, transdermal, intranasal, and rectal.

Preferably, for the treatment of male impotence, the amount of vasodilator used in the practice of the present invention is effective to improve erectile capacity for about 1 minute to about 60 minutes following administration of the drug. It is a target.

The invention also specifically relates to transmucosal (including vaginal mucosa) effective amounts of a vasodilator,
It relates to a method for modulating the excitement and plateau phase of a female sexual response on demand by transdermal, intranasal or rectal administration. A preferred form of transmucosal administration in women is by adding an effective amount of a vasodilator to vaginal suppository formulations well known in the art.

Other preferred embodiments include, but are not limited to, improving the sexual response of a woman by administering an effective amount of a vasodilator. Vasodilators can be administered transmucosally using creams, gels, tablet inserts and solution formulations.

The methods of the present invention are also useful in preparations for sexual intercourse with the ability to modulate sexual response in both men and women.

The invention also relates to a method for the manufacture of a medicament for transmucosal (including vaginal mucosal), transdermal, intranasal and rectal administration to modulate sexual response in humans. , The use of drugs having vasodilatory activity. Vasodilators useful for making the medicament include phentolamine mesylate, phentolamine hydrochloride, phenoxybenzamine, yohimbine, organic nitrates, timoxamine, imipramine, verapamil, isoxuprine, naftidrofuryl, trazoline, and papaverine. It is not limited to.

[0025] Numerous other advantages of the present invention are apparent from the following detailed description of the invention, including the appended examples and the appended claims.

DETAILED DESCRIPTION Human sexual response in both men and women involves a complex interaction between endocrine, neurological, and psychological elements, It produces specific physiological and anatomical responses in both men and women.

Although there are clear differences in the sexual response between men and women, one common aspect of sexual response is the erectile response. The erectile response in both men and women is the result of redness of the genital erectile tissue with blood in response to sexual stimuli (physical, psychological, or both).

The vasculature that serves erectile tissue in both men and women is similar. In particular, in both men and women, arterial circulation to the genital erectile tissue is derived from the common iliac arteries, which branch off from the abdominal aorta. The common iliac artery bifurcates into the internal and external iliac arteries. The pudendal artery originates from the smaller of the two terminal branches of the anterior branch of the internal iliac artery. In women, the pudendal artery branches to the superficial perineal artery, which supplies the labia. The vulvar arteries also branch to the aortic sphere,
Provides vestibular bulb and vaginal erectile tissue. The corpus cavernosum (another branch of the internal pudendal artery) supplies the clitoral corpus cavernosum. Yet another branch of the pudendal artery is the dorsal clitoral artery (art
eria dorsalis clitoridis, the dorsal artery of the clitoris supplies to the back of the clitoris and terminates in the glans and membrane folds surrounding the clitoris (corresponding to the male foreskin).

In men, the pudendal artery branches into the dorsal penile artery (which itself branches into the left and right branches) and the arteries of the corpus cavernosum, all of which supply blood to the corpus cavernosum. . The dorsal penile artery resembles the female clitoral dorsal artery, while the male penile cavernous artery resembles the female artery of the same name.

The erectile response in men is regulated by the autonomic nervous system, which controls blood flow to the penis through the interaction of peripheral nerves associated with arterial vessels in and around the corpus cavernosum I do. In a non-aroused or non-erected state, the arteries supplying the corpus cavernosum remain relatively constricted, thereby limiting blood flow to the corpus cavernosum. However, in the excited state, the smooth muscle associated with the arteries relaxes under the influence of catecholamines, greatly increasing blood flow to the corpus cavernosum, causing penile swelling and stiffening. Blindley, supra (1986)
Indicates that smooth muscle contraction causes blood to flow from the corpus cavernosum to the extrasinus vein (extracavernosa).
Assume that a valve is opened that can flow to 1 vein). Blindley (1986)
According to, when the associated smooth muscle relaxes, the valve closes and reduces venous ejection from the corpus cavernosum. When accompanied by increased arterial blood flow to the corpus cavernosum, this results in corpus cavernosum hyperemia and erection.

Pre-orgasmic sexual response in women can be classified in another phase. Both the excitement and plateau phases involve genital vasodilation and distension (vascular hyperemia) by arterial blood in a manner similar to male erectile responses.

The excitement phase of the female sexual response is characterized by vascular hyperemia in the vaginal wall,
This leads to vaginal fluid and vaginal fluid transmission. In addition, one third of the interior of the vaginal barrel expands, and the cervix and uterine body become elevated. This is accompanied by flattening and raising of the labia majora and an increase in clitoris size. [Kolodny et al., Textbook of Sexual Medicine, Little and Brown, Boston, Mass. (1979)].

The plateau phase following the excitement phase in the female sexual response is characterized by pronounced vascular hyperemia in the external third of the vagina, narrowing of the vaginal opening, and the long trunk and glands of the clitoris to the pubis Bring about involution. These responses are also accompanied by marked vascular hyperemia of the labia. [Kolodny, supra (1979)].

The vascular hyperemia phase of a woman's sexual response often also causes isola tonicity to the extent that it covers the preceding nipple erection, usually associated with the arousal phase.

Defects in the erectile response in men to the extent that vaginal insertion and intercourse cannot be achieved are called impotence. Impotence has many possible causes that can be categorized into several general categories. Endocrine-related impotence results from gonadal deficiency, progressive diabetes, hyperthyroidism, and as one of the secondary sequelae of pituitary adenoma, idiopathic or acquired hypogonadism, hyperprolactinemia and other endocrine disorders. obtain.

[0036] Chronic systemic diseases such as cirrhosis, chronic renal failure, malignancies and other systemic diseases can also cause impotence. Neural impotence occurring in the central nervous system can be caused by trauma, epilepsy, neoplasms and seizures, spinal cord injury in the bone marrow, paraplegia, and temporal lobe disorders caused by demyelinating diseases. Neural causes of impotence occurring in the peripheral nervous system include somatic or autonomic disorders, pelvic neoplasms, granulomas, trauma and others. Urological causes of impotence are:
Includes total prostatectomy, local trauma, neoplasms, Peyronie's disease, and others.

[0037] Half of the causes of impotence in men can be mental. Because there is no readily identifiable underlying cause of the disease. Mental factors play a role in the disease, even when there seems to be an underlying cause of impotence.

The present invention modifies 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 mucosa, transdermal, intranasal, and rectal. Designed to be.

Many vasoactive agents can be used in the practice of the present invention based on the indicated systemic efficacy as vasodilators. Useful vasodilator drugs include sympathomimetic amines and drugs that exhibit a direct relaxation of vascular smooth muscle, generally classified as alpha-adrenergic antagonists. Exemplary alpha-adrenergic antagonists include phentolamine, phentolamine hydrochloride, phentolamine mesylate, apomorphine, phenoxybenzamine, tolazoline, diben, dimenamine, yohimbine, and others. Phentolamine mesylate is a preferred alpha adrenergic drug vasodilator for preferred use in the practice of the present invention. An exemplary sympathomimetic amine envisioned for use in the methods of the present invention is niridrin, and the use of other sympathomimetic amines having vasodilator activity is also contemplated.

[0040] Nicotinic acid (or nicotine alcohol) has direct vasodilator activity useful in the practice of the present invention. A nonspecific smooth muscle relaxant that possesses vasodilator activity, either alone or in combination with other drugs, such as phenanthramine, which increases male impotence by direct injection into the clitoral corpus cavernosum. Use of papaverine, which has been used to treat, is also anticipated. Other nitrates, such as nitroglycerin and amyl nitrate, have a remarkable vasodilator activity due to their ability to relax vascular smooth muscle, and are therefore contemplated for use according to the present invention. Other vasoactive drugs useful in the practice of the present invention include, without limitation, thymoxamine, imipramine,
Including verapamine, naftidrofuryl, and isoxpurine.

In the practice of the present invention, the vasoactive drug is delivered to the site of action by the transmucosal, including the vaginal, intranasal, transdermal, or rectal routes of administration, before the drug enters the portal circulation. Is administered to be transported to the circulation.

[0042] Oral administration of a drug in an attempt to perform delivery to a particular site in the circulation can have several disadvantages. First, drug absorption may be limited by gastrointestinal transit time, and therefore, the onset of drug action may be limited. Second, the drug can be inactivated (eg, by hydrolysis) in the low pH environment of the stomach and / or by other chemical or biochemical interactions in the intestine.

The transmucosal, including vaginal mucosal, transdermal, intranasal, and rectal routes of administration according to the present invention may be administered with a vasodilator shortly before (on demand) the estimated onset of sexual intercourse. And eliminates the need for repeated dosing of the drug. Thus, the methods of the present invention are more convenient and help to minimize any side effects that may result from continuous or daily administration of the drug. Further, the methods of the present invention allow for more spontaneity in sexual activity than is possible with other methods, such as intracavernous injection of vasodilators.

Formulations for effecting transmucosal delivery of a vasodilator according to the present invention are well known in the art. For the purposes of the present invention, "transmucosal delivery" generally refers to drug delivery to the vaginal, buccal, or pharyngeal mucosa, and includes buccal, sublingual, and pharyngeal mucosa But not to the stomach. Oral delivery can be achieved, for example, by preparing tablets or lozenges containing compressed lactose and an effective amount of one or more vasodilators. Other suitable tablet compositions include an effective dose of a vasodilator and U.S. Pat. No. 3,943,24 to Sturmer, which is incorporated herein by reference.
No. 6, including but not limited to combinations with carrier substances, tablet binding compounds and artificial sweeteners as described in No. 6. The vasoactive agent may also be mixed with various pharmaceutical excipients, including binders such as gelatin and / or corn starch, or pharmaceutically acceptable gums such as tragacanth gum. Vasoactive agents can also be combined in hard candies (which can be dissolved in the mouth) or in chewing gum to provide buccal or sublingual delivery to the oral mucosa.

A vasodilator may also be administered transmucosally by impregnating a filter paper strip or filter paper disc with an effective amount of a vasodilator. Then
The filter paper strip or disc may be placed between the cheek and gum (on the cheek) for delivery to the vasculature. Other transmucosal delivery systems, such as lollipops (as described in US Pat. No. 4,885,173 to Stanley) or vaginal suppositories, are well known and are expected to be useful in the practice of the present invention. You.

Transdermal delivery systems are well-known in the art, and are often referred to as transdermal “patches”. Exemplary transdermal patches typically include: (1) an impermeable backing layer or other impermeable film that can be made from any of a wide variety of plastics or resins, such as, for example, aluminized polyester or polyester And (2) a drug reservoir comprising, for example, a vasodilator in combination with mineral oil, polyisobutylene, and alcohol gelled with USP hydroxymethylcellulose. Other exemplary drug reservoir layers may include, for example, an acrylic-based polymer adhesive with a resin crosslinker that provides diffusion of the drug from the reservoir to the surface of the skin. Transdermal patches can also have a rate-controlling membrane, such as microporous polypropylene, disposed between the reservoir and the skin. Ethylene vinyl acetate copolymer and other microporous membranes can also be used. Typically, an adhesive layer is provided, which may include an adhesive formulation such as mineral oil and polyisobutylene in combination with a vasoactive agent.

Other exemplary transdermal patches include three layers: (1) an outer layer comprising a laminated polyester film; (2) a central layer comprising a rate controlling adhesive, a structural non-woven material and a vasodilator; and ( 3) It may include a disposable liner to be removed before use.
Transdermal delivery systems can also include the incorporation of highly lipid-soluble carrier compounds, such as dimethyl sulfoxide (DMSO), to facilitate skin penetration. Other exemplary carriers include lanolin and glycerin.

Vasodilator drugs for use in vaginal mucosa, transdermal, intranasal, or transmucosal, including rectal delivery, improve their lipid solubility and therefore their ability to penetrate skin or mucosal surfaces To do so, they can be chemically modified by methods well known in the art.

Rectal and vaginal suppositories are well known in the art and are also useful in the practice of the present invention. Exemplary suppositories include vasodilators in combination with glycerin, glycerol monopalmitate, glycerol, monostearate, hydrogenated coconut oil and fatty acids. Another exemplary suppository formulation, combined with an effective amount of a vasodilator,
Contains ascorbyl palmitate, silicon dioxide, white wax, and cocoa butter.

The present invention also relates to the use of a nasal spray for the administration of a vasodilator. An exemplary nasal spray formulation comprises a solution of a vasodilator drug in saline or other pharmaceutically suitable carrier fluid. Nasal spray compression pumps are also well known in the art and can be calibrated to deliver a predetermined dose of a vasodilator solution.

The examples presented below are intended to be illustrative of the present invention and are not intended to limit the scope of the present invention as set forth in the appended claims. The present invention is illustrated in the following examples with reference to phentolamine as a vasodilator and in particular to phentolamine mesylate.

[0052] Phentolamine can exist in unsolvated and solvated forms, including, for example, hydrated forms of the hemihydrate. Generally, solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to unsolvated forms for the purposes of the present invention. Phentolamine can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrogen halides such as hydrogen chloride and hydrogen bromide;
And sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic,
Toluenesulfonic acid and other acids such as mineral and carboxylic acids known to those skilled in the art. 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 form can be regenerated by treating the salt with a suitable dilute base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and bicarbonate. This free base form differs somewhat from their individual salt forms in certain physical properties, such as solubility in polar solvents, but otherwise, the salts are useful for the purposes of the present invention. Equivalent to the free base form. Phentolamine may also form its crystalline polymorph or crystalline form using appropriate or conventional crystallization procedures.

Example 1 describes the effect of transmucosally administered phentolamine mesylate on penile artery velocity. Examples 2 and 3 describe the effect of orally administered phentolamine mesylate on erectile performance in impotence males. Example 4 describes the use of various vasodilators in the practice of the present invention. Example 5
Are directed to the practice of the present invention in modulating erectile response in women.

Example 1 Effect of Transmucosal Administration of Phentolamine Mesylate on Penile Artery Velocity To evaluate whether orally administered phentolamine mesylate could alter blood flow in the penis. Diasonics 400 DRF (Diasonics
s, Milpitas, CA), the penile artery velocity was measured by Doppler ultrasound velocimetry close to the base of the right branch of the penile dorsal artery. Settings, Doppler beam frequency, and angle correction were maintained to achieve maximum velocity readings for each subject. The dorsal artery was selected for measurement because it was more accessible than the clitoral cavernous artery.

The rates were determined prior to transmucosal (oral) administration of phentolamine mesylate (20 mg),
And at 5, 15, 45 and 60 minutes after administration of the drug. The average initial speed was 10.4 cm / sec. The data shown in FIG. 1 shows the percent increase in penile artery velocity versus time after administration of phentolamine mesylate, and represents the average of three readings in six impotence patients.

The results show that within 5 minutes of placing the tablet between the cheek and gum, the arterial velocity increased by more than 50% above the baseline velocity. Within 25 minutes, arterial velocities peaked above 100% above baseline velocities, after which velocities began to fall and reached pre-treatment levels one hour later. Thus, buccal administration of 20 mg phentolamine mesylate is shown to provide a suitable means for rapidly modifying penile arterial blood flow.

Example 2: Effect of transmucosal (oral) administration of phentolamine mesylate on male erectile performance Oral administration of 20 mg phentolamine mesylate as in Example 1
The fact that it caused a rapid increase in penile artery velocity supported the utility of this route of administration of vasodilators by improving erectile performance in impotence men. Accordingly, studies were performed to determine the effect of transmucosal administration of phentolamine mesylate on erectile performance in impotence males.

All patients involved in this study were either obstructed vaginal insertions or were unable to maintain an erection without ejaculation at the onset of vaginal insertion He complained of erectile dysfunction. The duration of impotence was in this patient population in the range of 0.5 to 35 years and the average duration was 3.4 years.

Prior to administration of phentolamine mesylate or placebo, genital examinations were performed and penile vascular status was determined, taking into account the medical history. Vascular status was measured by measuring arm and penile systolic closing pressure, and penile brachia index (penile brachia).
l index) (PBI). PBI was calculated by dividing penile closure pressure by arm closure. Pulse wave inspection peak time (CT)
Measured on a Penilab IV plethysmograph (Parkes, Aloha WA). The peak time is the time in seconds from the valley of the penile blood pressure curve to the next peak. A typical range for the peak time is from about 1 second to about 1.8 seconds. PBI is 0
. Above 9 is normal, while PBI less than 0.6 indicates vascular dysfunction.

For the purposes of this study, patients were identified as having normal vascularity when both PBI and CT were in the normal range. Patients with abnormal CT and PBI in both areas were identified as having significant vascular dysfunction. Patients with one parameter in the abnormal range were identified as having moderate vascular dysfunction.

[0061] Patients with extreme age or severe penile vascular dysfunction were excluded, but in general,
Age and diagnosis were not factors in the approval of this study. Patients with a vascular or non-specific cause of impotence were entered into the study, as were patients with diabetes. The average age of the patients was 57.5 years (range: 25-74 years).

A single blind study was performed to test the performance of phentolamine mesylate on erectile performance. Each patient received two tablets; a placebo tablet containing only lactose, and a second lactose tablet containing 20 mg phentolamine mesylate.

The patient was required to place one tablet between cheek and gum (in the mouth) 10-20 minutes before attempting sexual intercourse. Oral administration was used as a paradigm for transmucosal delivery. This appears to be all routes of delivery useful in the practice of the invention, resulting in the drug reaching the target (genital) vasculature before passing through the liver. One or more days after using the first tablet, the patient repeated the process with the second tablet. Patients were warned not to take tablets or drink alcohol before using the tablets and were told not to want an erection without sexual stimulation.

Tell the patient which tablets may prove beneficial, and maintain a partial erection in terms of erection and vaginal insertion, or an erection sufficient to allow insertion Told to report failure. The patient was instructed to report any side effects as well. The results of this study are illustrated in Table 1, which shows the effect of phentolamine mesylate on age, vascular status and erectile performance in disabled men. Table 1
In the column to the right of, the number 1 indicates a report of erection and vaginal insertion, 2 indicates a failure to report a successful erection, and 3 indicates a report of a partial erection.

[0065]

[Table 1] The data in Table 1 illustrates that buccal administration of 20 mg of phentolamine mesylate results in improved erectile performance within 10-20 minutes after administration of the drug. This response was characterized by improved erectile ability upon sexual stimulation, and thus closely mimicked normal sexual response in men. The fact that the effect of this drug was seen within 10 to 20 minutes after a single dose was attributed to the "demand-type", which did not require multiple doses and / or long waiting times before the onset of improved erectile abilities Can be characterized as producing a response. 5 of administration of phentolamine mesylate
A rapid increase in penile arterial velocity within minutes (represented in Example 1) suggests that an improvement in erectile capacity may actually occur earlier than 10 minutes after administration. The "demand-based" aspect of the method of the present invention allows for a more natural and more spontaneous approach to intercourse and eliminates the need for multiple doses, thereby reducing the frequency of unwanted side effects . In this study, 20 mg phentolamine mesylate was used, but doses of about 5 mg to about 80 mg phentolamine mesylate are within the scope of the invention. Because, for example, an individual's responsiveness to a drug can vary based on total body weight and the degree of vascular insufficiency.

The data described in Table 1 is further analyzed to determine whether the patient's vascular status has any predictive value for the effect of phentolamine mesylate in improving erectile performance in disabled patients. did. This analysis shows that out of a total of 16 normal vascular conditions, 7 were successfully treated with phentolamine mesylate, 6 failed to respond, and 3 reached partial erections. Was. Of 49 patients with vascular insufficiency, 15 succeeded in achieving sufficient erection for vaginal insertion, but 29 failed. Five patients with vascular insufficiency achieved partial erection.
Side effects seen in this study are rare and these include nasal congestion (6%
), Syncope or dizziness (2.3%) (released after 10-15 minutes) and 0.05% vomiting.

Example 3 Effect of Oral Phentolamine Mesylate and Disability of Various Pathogens To further evaluate the efficacy of phentolamine administered orally in ameliorating erectile dysfunction, various pathogens were Another single blind study was performed in men with erectile dysfunction.

A mixed population of men with erectile dysfunction of various etiologies received three filter paper strips and three placebo strips impregnated with 20 mg of phentolamine mesylate. These patients were not told which strip contained the drug and which was a placebo. 10-20 attempts to reach erection in patient
One minute before, a piece of filter paper was instructed to be placed between the cheeks and gums. The procedure was considered successful if sufficient erection was achieved to affect vaginal insertion. Table 2 shows the results.

[0069]

[Table 2] Table 2 continued ^* Prior to describing this study, patient numbers 7-11 were on a program of intracavernous self-injection using 20 μg of PGE-1 with full efficacy. These patients also
She had severe cardiovascular disease. 1 = erection and vaginal insertion 2 = cannot achieve sufficient erection for vaginal insertion.

The results of this study indicate that orally administered phentolamine mesylate (20 mg)
Established improved erectile performance in 36% of the reported patients (excluding a total of two placebo responders). This result was most pronounced in patients with a diagnosis of psychogenic impotence, where five out of five patients reported achieving an erection sufficient to penetrate the vagina. Of the patients diagnosed as having arterial impotence, 3 out of 7 patients showed improved erectile performance, where one of these patients also responded to placebo . Two out of three patients diagnosed with complex psychogenic / arterial impotence show improved erectile performance, where one of these patients also , Responded to placebo. Of the five patients for whom self-injection of PGE-1 did not show complete efficacy, none showed any improvement in erectile performance with orally administered phentolamine mesylate.

These results, combined with the results shown in Example 2, show that when a vasodilator (eg, phentolamine mesylate) is administered via transmucosal route administration, men with impotence, and More specifically, the development of erectile abilities in men with a psychogenic, arterial, or complex psychogenic / arterial impotence (sub-population of patients, including most cases of male impotence) , Indicating that it is effective to improve by a significant percentage.

While useful for treating impotence in males, the present invention is also useful for improving erectile abilities in non-impotent males. It is well known that erectile abilities can change as men age. One sign of this decrease in erectile capacity is
The angle of erection (erection angle) defined by the dorsal aspect and the belly of an erect penis increases with age. The method of the present invention provides a means for improving the erection performance of non-impotent males by increasing blood flow to the penis and thereby minimizing erection angles.

It should also be noted that filter strips impregnated with phentolamine mesylate lose their efficacy after several months of storage at room temperature in paper bags.

Example 4: Vascular Agents Useful in Modulating Human Sexual Response Many other vasoactive agents have been identified in the practice of the present invention based on their demonstrated efficacy as vasodilators. Can be used. Useful vasodilators include alpha-adrenergic antagonists, drugs classified as sympathomimetic amines, and drugs that exhibit direct relaxation of vascular smooth muscle.

Exemplary α-adrenergic antagonists include phentolamine hydrochloride, phentolamine mesylate, phenoxybenzamine, tolazoline, dibenamine, yohimbine, and the like. Phentolamine mesylate is preferred in the practice of the present invention. An exemplary parasympathomimetic amine contemplated for use in the methods of the present invention is nylidrin, but other parasympathomimetic amines having vasodilator activity are also contemplated by the present invention.

Nicotinic acid (or nicotinyl alcohol) has direct vasodilator activity useful in the practice of the present invention. Papaverine also has vasodilator activity, and to treat male impotence by injection directly into the clitoral corpus cavernosum, either alone or in combination with other drugs (eg, phentolamine). It is a non-specific smooth muscle relaxant used.

Organic nitrates (eg, nitroglycerin and amyl nitrate) also have significant vasodilator activity due to their ability to relax vascular smooth muscle. Other vasoactive drugs useful in the practice of the present invention include, but are not limited to, timoxamine, imipramine, verapamil, naftidrofuryl, isoxpurine, and the like.

In the practice of the present invention, these vasoactive agents are administered transmucosally (eg, vaginal mucosa, intranasally, transdermally, or rectally) so that the agent reaches its site of action before it enters the portal circulation. (Including the administration route).

The appropriate dose of each vasoactive agent for each route of administration is readily determined by one skilled in the art. By way of example, to determine the appropriate dose of each of the vasodilators of the present invention, one of ordinary skill in the art can use the usual published doses of vasodilators as a starting point. The usual oral dose for over-the-counter vasodilators is Medical Econ
Omic Data, Physician's Desk Reference, published annually by Montvale New Jersey, and other medical literature available.

By way of example, Pavabid® oral papaverine hydrochloride was purchased from Mario
n is available from Merrell Dow and is usually dosed at 150 mg every 12 hours to achieve its vasodilator effect.

An oral dose of Calon® (verapamil hydrochloride), available from Seale, is administered every 12 hours with 120 mg to about 240 mg of drug (a specific dose depending on the response of the individual patient to this drug) It is determined by measuring the individual patients who do.

Daytohimbin (registered trademark) (Dayton Pharmaceut)
icals), Yocon® (Palisades Pharmac)
euhimicals), and yohimbine hydrochloride, available as Yohimex® (Kramer), are all given 5.4 mg orally three times daily.

[0083] Imipramine hydrochloride is available as Tofranil® from Geigy and is administered orally four times daily, for a total dose ranging from 50 mg to about 150 mg per day.

Imipramine pamoate (also available from Geigy) contains 1
It is administered at an oral maintenance dose of 50 mg.

Using the established oral dosage as a starting point, the optimal dosage for a particular route of administration can be determined using a Doppler ultrasound velocimeter as described in Example 1 Prior to administration, it can be determined by measuring the baseline arterial blood flow in the patient's genital circulation. Other methods, such as thermography, plethysmography, dosimetry or scintigraphy and other methods well known in the art, may also be used to assess blood flow in the genital tract. With baseline blood flow established, various dosages of each vasodilator may be administered by the administration routes encompassed by the present invention, and their effect on blood flow measured. The magnitude of the increase in blood flow required to modulate or enhance a sexual response in humans can vary from individual to individual, but can be readily determined as described below. In addition, individual patients may be measured with different dosages of each vasodilator until the optimal dosage has been determined.

[0086] Blood flow studies can also be linked to assessment of sexual responsiveness as indicated by improved erectile capacity to sexual stimuli.

Example 5 Modulation of Female Sexual Response As discussed above, there is a trade-off between male and female genital vasculature and the erectile response promoted by this vasculature. There is a significant response. In both men and women, an erectile response occurs when blood flow to the genitals is increased by relaxation of smooth muscle in arteries to the genitals under physical or psychological stimuli.

[0088] Using the methods of the present invention, by reducing the ability to produce sufficient vaginal lubrication to facilitate comfortable penile penetration, and other symptoms of sexual responsiveness deficiencies that may correlate with erectile response May improve or enhance the erectile response in women whose sexual response has been impaired as indicated by.

In the absence of any clinically diagnosed dysfunction in a female erectile response, as in the case of a male sexual response, the method of the present invention may be used to enhance a female normal sexual response. Can be used for The "on demand" aspect of the present invention allows for a more rapid response to sexual stimuli, with increased excitement of the female sexual response due to increased blood flow to the genitals and increased perception associated with the plateau phase. I do.

In practice, the enhancement of female sexual response using the method of the present invention was demonstrated in Examples 2 and 3
Perform in much the same manner as described in.

An effective vasodilating dose of a vasodilator is administered transmucosally (vaginal mucosa, transdermal,
To women, including, but not limited to, via the intranasal or rectal routes of administration. The appropriate dose of a particular vasodilator can be readily determined using the method described in Example 4. Exemplary vasodilators useful in the practice of the present invention are set forth in Example 4 and are commonly used as agents that exhibit direct relaxation of alpha-adrenergic antagonists, parasympathomimetic amines and vascular smooth muscle. Includes those that are categorized. Women's response is described in Masters, W.W. H. And Johnson
, V. et al. E. FIG. , Human Sexual Response, Little, B
row, and Co. , Boston (1996), which is incorporated herein by reference. Methods for measuring blood flow (including thermography using Doppler ultrasound velocimeters, such as isothermal blood flow transducers, radiation scintigraphy, photoplethysmography, and other methods well known in the art) Can be used. In addition, distal ３ contractions, characteristic of the plateau phase of the female vaginal sexual response, can be measured by methods and devices well known in the art (such as strain gauges or other strain gauges for measuring muscle contraction or muscle tension). (Including but not limited to devices).

Furthermore, the enhancement of the sexual response can be made more substantive by simply asking a female subject to describe any changes in perception resulting from the administration of a vasodilator according to the methods of the present invention. In a simple manner. Appropriate placebo controls should also be performed to determine if this attempt is directly attributable to the administration of a vasodilator.

[0093] Preferred embodiments of the invention comprise from about 5 mg to about 150 mg phentolamine mesylate, preferably from about 15 mg to about 100 mg phentolamine mesylate, more preferably from about 25 mg to about 80 mg phentolamine mesylate, and most preferably Administering 40 mg of phentolamine mesylate transmucosally from about 1 minute to about 1 hour prior to intercourse and in preparation for intercourse. Preferably, the amount of vasodilator used in the practice of the present invention for improving female sexual response is about 1 to about 1% of administration.
Effective in improving sexual response after minutes to about 1 hour. More preferably, the amount of vasodilator used is effective to improve the female sexual response from about 5 minutes to about 45 minutes after administration. It is also preferred that the amount of vasodilator used is effective to improve the female sexual response from about 15 minutes to about 30 minutes after administration. Other vasodilators or other routes of administration within the scope of the present invention are also contemplated.

A currently preferred method of transmucosal administration is by vaginal suppository. Vaginal suppositories are well known in the art and are available in various physical forms. Suppositories or pessaries, which are spherical or ovoid and each weigh about 5 g, are most commonly known. More recently, creams, gels or liquids that overturn the classic concept of suppositories have become available and are useful in the practice of the present invention. Compositions for vaginal administration may also be supplied as vaginal tablets or as inserts prepared by encapsulation in soft gelatin. Additionally, compositions for vaginal administration can be prepared as solutions, which are then lyophilized. The lyophilized solution provides an effective means of administration when water is added to the lyophilized solution prior to administration. All these physical forms are contemplated.

An exemplary vaginal suppository is approximately 86% polyethylene glycol 1000 NF,
Contains a mixture of 10% polyethylene glycol 3350NF and 4% phentolamine mesylate. The resulting vaginal suppositories provide an effective vehicle to deliver a specific dose of phentolamine mesylate through the vaginal mucosa.

The exemplary 40 mg phentolamine mesylate tablet insert is approximately 61%
Crystalline cellulose (NF); 30% hydrogenated vegetable oil (NF); 4% croscarmellose sodium (NF); 4% phentolamine mesylate: 0.1%.
It contains a mixture of 5% magnesium stearate (NF); and 0.04% colloidal silicon dioxide. The mixture is compressed into tablet form, and the resulting tablet insert is then encapsulated in soft gelatin by methods commonly known in the art. The encapsulated insert is then administered to the woman through the vaginal mucosa.

An exemplary vaginal gel for administration of the present invention comprises approximately 75% water, 15% glycine, 7% phentolamine mesylate and less than 1% hydroxyethylcellulose, methylparaben and glucono-δ-lactone. Of mixtures. The resulting vaginal gel provides an effective vehicle for delivering a specific dose of phentolamine mesylate through the vaginal mucosa.

[0098] Exemplary solutions for lyophilization include phentolamine mesylate, citric acid, sodium bicarbonate, mannitol and magnesium stearate. After lyophilization, water was added for rehydration before administration to women through the vaginal mucosa.

Another exemplary solution comprises a mixture of approximately 83% drinking water, 13% phentolamine mesylate and 4% D-mannitol. The resulting solution provides another effective vehicle for delivering a specific dose of phentolamine mesylate through the vaginal mucosa.

Further suppository, gel, cream, solution or insert formulations are also within the scope of the invention.

Although the present invention has been described in terms of a preferred embodiment, the examples provided herein administer drugs through the transmucosal (including vaginal, transdermal, intranasal or rectal routes of administration). In doing so, it is not intended to limit the scope of the present invention, which contemplates the use of any pharmacological vasodilator drug that can be absorbed into the systemic circulation.

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Claims (100)

[Claims] 1. A method for modulating a sexual response in a human by administering a vasodilator to the blood circulation in an amount effective to increase blood flow to the genital tract, comprising the steps of: The method wherein the ameliorating comprises modulating the sexual response on demand by administering an effective amount of the agent transmucosally. 2. The group of vasodilators comprising phentolamine, phentolamine mesylate, phentolamine hydrochloride, apomorphine, phenoxybenzamine, nitroglycerin, thymoxamine, nicotinyl alcohol, imipramine, verapamil, isoxpurine, naftidrofuryl, trazoline, and papaverine. The method of claim 1, wherein the method is selected from: 3. The method according to claim 1, wherein the administration route is through the vaginal mucosa. 4. The method of claim 1 or 2, wherein the administered agent is selected from the group consisting of phentolamine, phentolamine mesylate and phentolamine hydrochloride. 5. The method of claim 3, wherein the administered agent is selected from the group consisting of phentolamine, phentolamine mesylate, and phentolamine hydrochloride. 6. The method of claim 4, wherein said administered amount is between about 5 mg to about 150 mg. 7. The method of claim 5, wherein said administered amount is about 5 mg to about 150 mg. 8. The method of claim 4, wherein said administered amount is from about 15 mg to about 100 mg. 9. The method of claim 5, wherein said administered amount is between about 15 mg to about 100 mg. 10. The method of claim 4, wherein the amount administered is about 25 mg to about 80 mg. 11. The method of claim 5, wherein said administered amount is from about 25 mg to about 80 mg. 12. The method of claim 4, wherein said administered amount is 40 mg. 13. The method of claim 5, wherein said administered amount is 40 mg. 14. The method according to claim 1, wherein the administered amount is effective to improve the female sexual response within about 1 minute to about 1 hour after administration.
The method described in the section. 15. The method of claim 3, wherein the amount administered is effective to improve the female sexual response within about 1 minute to about 1 hour after administration. 16. The method of claim 4, wherein said administered amount is effective to improve the female sexual response within about 1 minute to about 1 hour after administration. 17. The method according to claim 1, wherein the administered amount is effective to improve the female sexual response within about 5 minutes to about 45 minutes after administration.
The method described in the section. 18. The method of claim 3, wherein the amount administered is effective to improve the female sexual response within about 5 minutes to about 45 minutes after administration. 19. The method of claim 4, wherein said administered amount is effective to improve the female sexual response within about 5 minutes to about 45 minutes after administration. 20. The method according to any one of claims 1, 2 or 5 to 13, wherein the amount administered is effective to improve the female sexual response within about 15 minutes to about 30 minutes after administration. The method described in. 21. The method of claim 3, wherein the amount administered is effective to improve the female sexual response within about 15 minutes to about 30 minutes after administration. 22. The method of claim 4, wherein the amount administered is effective to improve the female sexual response within about 15 minutes to about 30 minutes after administration. 23. The administration according to claim 5, wherein said administration is in the form of a vaginal suppository.
, 16, 18, 19, 21 or 22. 24. The method of claim 3, wherein said administration is in the form of a vaginal suppository. 25. The method of claim 4, wherein said administration is in the form of a vaginal suppository. 26. The method of claim 14, wherein said administration is in the form of a vaginal suppository. 27. The method of claim 17, wherein said administration is in the form of a vaginal suppository. 28. The method of claim 20, wherein said administration is in the form of a vaginal suppository. 29. The administration according to claim 5, wherein the administration is in the form of a tablet insert.
, 16, 18, 19, 21 or 22. 30. The method of claim 3, wherein said administration is in the form of a tablet insert. 31. The method of claim 4, wherein said administration is in the form of a tablet insert. 32. The method of claim 14, wherein said administration is in the form of a tablet insert. 33. The method of claim 17, wherein said administration is in the form of a tablet insert. 34. The method of claim 20, wherein said administration is in the form of a tablet insert. 35. The method according to any one of claims 5 to 13, 15, 16, 18, 18, 19, 21 or 22 wherein said administration is in the form of a rehydrated lyophilized solution. 36. The method of claim 3, wherein said administration is in the form of a rehydrated lyophilized solution. 37. The method of claim 4, wherein said administration is in the form of a rehydrated lyophilized solution. 38. The method of claim 14, wherein said administration is in the form of a rehydrated lyophilized solution. 39. The method of claim 17, wherein said administration is in the form of a rehydrated lyophilized solution. 40. The method of claim 20, wherein said administration is in the form of a rehydrated lyophilized solution. 41. The method according to any one of claims 5 to 13, 15, 16, 16, 18, 19, 21 or 22 wherein said administration is in the form of a vaginal gel or cream. 42. The method of claim 3, wherein said administration is in the form of a vaginal gel or cream. 43. The method of claim 4, wherein said administration is in the form of a vaginal gel or cream. 44. The method of claim 14, wherein said administration is in the form of a vaginal gel or cream. 45. The method of claim 17, wherein said administration is in the form of a vaginal gel or cream. 46. The method of claim 20, wherein said administration is in the form of a vaginal gel or cream. 47. The method of claim 41, wherein said gel contains about 30 mg to about 50 mg of phentolamine mesylate. 48. The method of any one of claims 42-46, wherein the gel contains about 30 mg to about 50 mg of phentolamine mesylate. 49. The method of claim 47, wherein said gel contains 40 mg phentolamine mesylate. 50. The method of claim 48, wherein said gel contains 40 mg phentolamine mesylate. 51. A method for the manufacture of a medicament for modulating a sexual response in a human by administering a vasodilator to the blood circulation in an amount effective to increase blood flow to the genital tract. The method comprises modulating the sexual response on demand by administering an effective amount of the agent transmucosally. 52. The vasodilator comprises the group consisting of phentolamine, phentolamine mesylate, phentolamine hydrochloride, apomorphine, phenoxybenzamine, nitroglycerin, thymoxamine, nicotinyl alcohol, imipramine, verapamil, isoxsuprine, naftidrofuryl, trazoline, and papaverine. 52. The method of claim 51, wherein the method is selected from: 53. The method of claim 51 or 52, wherein the route of administration is via the vaginal mucosa. 54. The method of claim 51 or 52, wherein said administered agent is selected from the group consisting of phentolamine, phentolamine mesylate and phentolamine hydrochloride. 55. The method of claim 53, wherein said administered agent is selected from the group consisting of phentolamine, phentolamine mesylate and phentolamine hydrochloride. 56. The method of claim 54, wherein said administered amount is between about 5 mg to about 150 mg. 57. The method of claim 55, wherein said administered amount is between about 5 mg to about 150 mg. 58. The dose administered is between about 15 mg to about 100 mg.
55. The method of claim 54. 59. The dose administered is between about 15 mg to about 100 mg.
56. The method according to claim 55. 60. The method of claim 54, wherein said administered amount is about 25 mg to about 80 mg. 61. The method of claim 55, wherein said administered amount is about 25 mg to about 80 mg. 62. The method of claim 54, wherein said administered amount is 40 mg. 63. The method of claim 55, wherein said administered amount is 40 mg. 64. The method of any one of claims 51, 52 or 55-63, wherein the amount administered is effective to improve the female sexual response within about 1 minute to about 1 hour after administration. The method described in. 65. The method of claim 53, wherein the amount administered is effective to improve the female sexual response within about 1 minute to about 1 hour after administration. 66. The method of claim 54, wherein the amount administered is effective to improve the female sexual response within about 1 minute to about 1 hour after administration. 67. The method of any one of claims 51, 52 or 55-63, wherein the amount administered is effective to improve the female sexual response within about 5 minutes to about 45 minutes after administration. The method described in. 68. The method of claim 53, wherein the amount administered is effective to improve the female sexual response within about 5 minutes to about 45 minutes after administration. 69. The method of claim 54, wherein the amount administered is effective to improve the female sexual response within about 5 minutes to about 45 minutes after administration. 70. The method of any one of claims 51, 52 or 55-63, wherein the amount administered is effective to improve the female sexual response within about 15 minutes to about 30 minutes after administration. The method described in. 71. The method of claim 53, wherein the amount administered is effective to improve the female sexual response within about 15 minutes to about 30 minutes after administration. 72. The method of claim 54, wherein the amount administered is effective to improve the female sexual response within about 15 minutes to about 30 minutes after administration. 73. The administration according to claim 55, wherein said administration is in the form of a vaginal suppository.
The method according to any one of 5, 66, 68, 69, 71 or 72. 74. The method of claim 53, wherein said administration is in the form of a vaginal suppository. 75. The method of claim 54, wherein said administration is in the form of a vaginal suppository. 76. The method of claim 64, wherein said administration is in the form of a vaginal suppository. 77. The method of claim 67, wherein said administration is in the form of a vaginal suppository. 78. The method of claim 70, wherein said administration is in the form of a vaginal suppository. 79. The method of claim 55, wherein the administration is in the form of a tablet insert.
The method according to any one of 5, 66, 68, 69, 71 or 72. 80. The method of claim 53, wherein said administration is in the form of a tablet insert. 81. The method of claim 54, wherein said administration is in the form of a tablet insert. 82. The method of claim 64, wherein said administration is in the form of a tablet insert. 83. The method of claim 67, wherein said administration is in the form of a tablet insert. 84. The method of claim 70, wherein said administration is in the form of a tablet insert. 85. The method of any one of claims 55 to 63, 65, 66, 68, 69, 71 or 72, wherein said administration is in the form of a rehydrated lyophilized solution. 86. The method of claim 53, wherein said administration is in the form of a rehydrated lyophilized solution. 87. The method of claim 54, wherein said administration is in the form of a rehydrated lyophilized solution. 88. The method of claim 64, wherein said administration is in the form of a rehydrated lyophilized solution. 89. The method of claim 67, wherein said administration is in the form of a rehydrated lyophilized solution. 90. The method of claim 70, wherein said administration is in the form of a rehydrated lyophilized solution. 91. The method according to any one of claims 55 to 63, 65, 66, 68, 69, 71 or 72, wherein said administration is in the form of a vaginal gel or cream. 92. The method of claim 53, wherein said administration is in the form of a vaginal gel or cream. 93. The method of claim 54, wherein said administration is in the form of a vaginal gel or cream. 94. The method of claim 64, wherein said administration is in the form of a vaginal gel or cream. 95. The method of claim 67, wherein said administration is in the form of a vaginal gel or cream. 96. The method of claim 70, wherein said administration is in the form of a vaginal gel or cream. 97. The method of claim 91, wherein said gel contains about 30 mg to about 50 mg of phentolamine mesylate. 98. The method of any one of claims 92-96, wherein said gel contains about 30 mg to about 50 mg of phentolamine mesylate. 99. The method of claim 97, wherein said gel contains 40 mg phentolamine mesylate. 100. The method of claim 98, wherein said gel contains 40 mg phentolamine mesylate.