KR20020015310A - Methods for modulating the human sexual response - Google Patents

Abstract

The present invention relates to a method of altering the physical sexual response by supplying vasodilators to the circulatory system through the mucosa, and is not limited to the supply of the vaginal mucosa, the internal or rectal and transdermal supply pathways of the vagina. not.

Description

Methods for modulating the human sexual response

Men and women's physical sexual reactions are caused by complex interactions of psychological, hormonal and somatic effects. One important aspect of the physical sexual response common to both men and women is the erectile response resulting from the interaction between the autonomic nervous system, the endocrine system and the circulatory system. Failure of an erection reaction is the most common in men and is called erectile dysfunction. Erectile dysfunction is a man's inability to maintain or maintain a penis for vaginal insertion and intercourse. Numerous methods have been attempted to treat erectile dysfunction. These methods include penile prosthesis that is inserted externally or internally (see US Pat. No. 5,065,744, Zumanovsky). It has been used to treat various erectile dysfunctions that supply drugs and drugs. For example, U. S. Patent No. 3,943, 246 addresses the treatment of men's erectile dysfunction by supplying 300-1500 international doses of oxytocin or 150-250 international doses of desamino-oxytocin at mouth and mouth. Claim that. The patent provided 100 international standards three times a day for 14 days, with 12 out of 16 patients improving impotence.

Nestor's US Pat. No. 4,530,920 discloses that the supply of nonapeptide and diapeptide analogues of luteinizing hormone releasing hormone factors is useful in improving or inducing sexual activity or treatment for erectile dysfunction or infertility. . Nestor offers a number of analogue supply pathways, including mouth, sublingual, mouth, sublingual, mouth, rectum and vagina.

Grunwell's U.S. Patent No. 4,139,617 proposes a mouth of 19-oxygenated-androst-5-en and other feed routes for improvement by the endocrine of libido in the body.

Anderson's US Pat. No. 4,863,911 proposes methods for treating sexual disorders in mammals using biologically oxidizable cerebrovascular barrier penetrating estrogen derivatives. Anderson's purpose is to cure men's "psychological disability." Test results show that the drugs used in the experiments have improved mounting behavior, intromission and mount latency in castrated mice.

Many publications have proposed various vasodilators for the treatment of erectile dysfunction in men. Many erections become vasculogenic due to lack of blood vessels, so attempts have been made to use vasodilators for the treatment of erectile dysfunction.

US Pat. No. 4,801,587, issued Jan. 31, 1989, proposes the use of an ointment comprising vasodilators and carriers for topical application to the male penis of erectile dysfunction. Bos also describes putting this ointment into the catheter of the penis using a catheter as well as multistage therapy to supply vasodilators to the skin of the penis. Boss proposes to surgically remove a portion of the fibrous foreskin surrounding the corpus cavernosum, facilitating the insertion of an ointment containing vasodilators into the corpus cavernosum. Vasodilators proposed by Moss include papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine and phentolamine. The boss, however, does not provide information on the nature of the response to this treatment or the actual effect of the proposed treatment.

Lator's US Pat. No. 4,127,118 describes treating men's erectile dysfunction by injecting vasodilators into the corpus spongiosum and corpus cavernosum using a syringe and one or more subcutaneous injections. In particular, Lator may be used in the urethra and penis of direct acting vasodilators such as isoxsuprine hydrochloride and nicotinyl alcohol, adrenergic blocking agents such as torazoline hydrochloride, and sympathetic stimulating amines such as nydrine hydrochloride. I'm proposing.

Brindley, G. S, when injected directly into the corpus cavernosum using subcutaneous injections, phenoxybenzamine, pentoramine, thymoxamine, imipramine, verapamil, papaverine and Some muscle relaxants, including naftidrofuryl, claim to have an erection. These studies have shown that the administration of an appropriate amount of phenoxybenzamine or papaverine allows continuous erection for several hours. The addition of another drug shows that an erection is induced that lasts from 11 minutes to about 65 hours. Zornioti proved that intra-penis administration of the combination of papaverine and fentoramine causes erectile dysfunction in men with erectile dysfunction. As such, Altnov reported that intra-penal administration of papaverine acetate and pentoramine improved erection in about 84% of patients injected. However, in that report, the failure rate was 57%. Fibrous lumps occurred in 26% of patients, 30% of patients had abnormal liver function levels, and 19% of patients had wounds.

Other studies describing intranasal injection of drugs using hypodermic needles for the treatment of erectile dysfunction have been described by Brindley. J. Physiol. 342.24 ?? (1983); Brindley, Br. J. Psychiatr. 143: 312-337 (1983, Virag, Lancetii: 978 (1982); and Vilag Angiology 35: 79-87 (1984)).

Although intranasal injection is useful for inducing erectile dysfunction in men, these techniques have other drawbacks.

Obvious shortcomings include pain, risk of infection, discomfort and interference in the nature of sexual life. Priapism (long and other painful erections) is also a potential problem when using the dosing method. See Brindley (1986). Another problem that occurs in some cases when entering the penis involves fibrous wounds of the penis. Corriere. J. Urol 140: 615-617 (1988) and Larsen J. Urol. 137: 292-293 (1987).

Pentoramine has been shown to have the potential to induce erection when injected intranasally. And also in men with unspecified erectile dysfunction, it has been a drug of interval supply testing the effect. (Gwinup, Ann. Int. Med 15 July 1988, pp 162-163) In the report, 16 patients ate 50 mg of pentoramine supplied in placebo or oral cavity. Eleven of 16 patients (including three placebo-treated patients) had an erection and were more responsive to sexual arousal. After waiting 15 hours for sexual intercourse, I could get enough erection for vaginal insertion.

Hand, Sex & Marital Ther. 16 (1): 15-21 (years) reported that 38% of patients treated with yohimbine improved erection capacity. But only 55 reported complete satisfaction.

Of interest to the background of the present invention is Stanley US Pat. No. 4,885,173. This patent provides methods for non-invasively supplying drugs with cardiovascular or renal vascular activity through the use of lollipops that promote the absorption of drugs through the gonad, pharynx and esophagus. It is described. Stanley's patents include drugs that show vasodilating effects, calcium channel blockers and β-adrenergic blocking agents, serotonin receptor blocking agents, blocking agents, other stimulants, and cardiostimulants. And a number of drugs supplied to lollipop, including drugs that improve renal vascular function, have been proposed and suggested to improve cardiovascular function.

U.S. Patent 5,059,603 describes the topical supply of isoxusuprine and caffeine, and nitroglycerin and caffeine to the penis along with a suitable carrier compound for the treatment of erectile dysfunction.

In this area, there is a continuing need for effective means of altering the body's sexual response and in particular improving the erection of men suffering from erectile dysfunction. Ideally, this means is simple and simple to use. And do not require a constant dose of therapy or administration of large amounts to achieve the desired result. It is noninvasive and allows rapid and predictable function in response to sexual excitement and on demand to initiate erection.

The present application relates to a method of altering the physical sexual response by supplying vasodilators to the circulatory system through the mucosa, and is not limited to supply through the mucous membrane, the internal or rectal and transdermal supply pathways of the vagina. not.

The present invention relates to an improved method of altering human sexual response by supplying vasodilators to the blood circulation in an amount necessary to increase blood flow to the genitals. According to the present invention, changes in sexual response in men and women are made by ordering the required amount of vasodilators into the mucous membranes including vaginal mucosa, skin liver, nose and rectum. Effective vasodilators in the present invention are pentoramine, pentoramine mesylate, pentoramine hydrochloride, apomorphine, phenoxybenzamine, yohimbine, organic nitrates (e.g. nitroglycerin), thymoxamine, imipramine , But are not limited to groups consisting of verapamil, isoxsuprine, naphthydropuryl, tolazoline and papaverine. A good drug at present is pentoramine mesylate, and a good supply route is through the mucosa, in particular the vaginal mucosa.

The present invention relates to a method for treating erectile dysfunction in men by supplying vasodilators to the blood circulation system, in particular in an amount necessary to increase blood flow to the penis, which is selected from the group consisting of between mucous membranes, skin, nose and rectum. The erection is done on demand by supplying the dilator by the supply path.

The amount of vasodilator used in the embodiments of the present invention to treat erectile dysfunction in men is the amount necessary to improve the erection for about 1 minute to 60 minutes after the drug is injected.

The present invention also relates to a method of varying the excitement and elevation of the sexual response of a female as needed by the supply of the required amount of vasodilator by the mucous membrane including the vaginal mucosa, skin, nose or rectum. For women, a preferred form of mucosal supply is the addition of the required amount of vasodilator to the known vaginal suppository form.

Another preferred embodiment includes, but is not limited to, improving sexual response in women by supplying the required amount of vasodilators. Vasodilators are supplied to the mucosa using creams, gels, tablet inserts and solutions.

The methods of the present invention are also effective in preparing for sexual intercourse by the ability to alter the sexual response of both men and women.

The present invention relates to the use of a drug having vasodilator function for the manufacture of a drug for mucous membranes including the vaginal mucosa, skin, nose and rectal administration to alter the human body's sexual response. . Vasodilators useful for the preparation of the drug include pentoramine mesylate, pentoramine hydrochloride, phenoxybenzamine, yohimbine, organic nitrates, thymoxamine, imipramine, verapamil, isoxsuphrine, naphthydropuryl, tolazoline And papaverine, including but not limited to.

Numerous other advantages of the invention will be apparent from the following detailed description of the invention, including the appended claims and examples.

Men and women's physical sexual responses include complex interactions between endocrine, neurological and physiological components that produce some physiological and anatomical responses in men and women.

Although there are obvious differences in sexual response between men and women, one common aspect of sexual response is erectile response. Erectile responses in men and women are the result of sexual stimulation (physical, psychological, or both) of the genitalia's erectile tissue.

The vasculatures that serve the male and female erectile cells are identical. In particular, for men and women, the arterial circulation of the genitals to the erectile cells comes from the usual iliac artery branching from the abdominal aorta. Common iliac arteries are divided into external and internal iliac arteries. The internal pudic artery occurs in the smaller of the terminal branches of the anterior trunk of the internal iliac artery. In women, the internal vulvar arteries branch into the superficial perinea artery, which supplies blood to the labia pudena. The internal vulvar arteries also branch into arterial bulbs, providing blood flow to the bulbli vestibuli and erectile cells of the vagina. Urinary cavernous arteries and other internal vulvar arteries supply blood flow to the cavernous body of the clitoris. In addition, the other branch of the internal vulvar artery is the artery behind the clitoris (arterina dorsalis clitoris), which supplies the bloodstream to the dorsum of the clitoris, and the membranous cortex that corresponds to the glans that cover the clitoris and the male foreskin. fold).

In males, the internal vulvar arteries branch into the arteries of the dorsal artery of the penis (which bifurcates itself from side to side) and the corpus cavernosum, all of which supply blood to the urethral cavernous body. The dorsal artery of the penis is the same as the arteries behind the clitoris of the woman (arterina dorsalis clitoris), and the artery of the urethral cavernous body is like that of a woman.

Male erectile responses are controlled by the autonomic nervous system, which controls blood flow to the penis through the response of peripheral nerves associated with arterial vessels in or around the urethral cavernous body. In an erection-free state, the arteries serving the urethral cavernous body remain relatively constricted, limiting blood flow to the urethral cavernous body. However, in an erected state, the effect of catecholamines relaxes the smooth muscles associated with the arteries and rapidly increases the blood flow to the urethral cavernos, causing the penis to swell and become hard. Brindley, supra (1986) assumes that lotus root contraction opens a valve (through which blood flows from the urethral cavernos to an extra-cavernous vein). According to Brindley (1986), when the relevant smooth muscle relaxes, the plate closes, reducing the outflow of venous blood from the urethral cavernous body. When the arterial blood flow to the urethral cavernous body increases, the urethral cavernous body is congested and erected.

Women's sexual response before orgasm can be divided into several stages. In the excitement phase and in the resting phase, arterial blood vasodilation and vasocongestion are the same as the male erectile response.

The excitement phase in female sexual response is characterized by vasodilation in the vaginal wall, which induces vaginal fluid secretion. In addition, one third of the vagina expands and the cervix and body of the uterus rise. Subsequently, the labia majora flattens and rises, and the size of the clitoris increases (Kolodny et al., Textbook of Sexual Medicine, Little and Brown, Boston, MA (1979)).

The stabilization stage is the next stage of the excitation phase, characterized by marked hyperemia in the outer third of the vagina, narrowing the entrance of the vagina to the symphysis pubis and contracting the clitoris' bone and glans. Let's do it. This reaction is accompanied by noticeable congestion of the labia [Kolodny, supra].

The redness of sexual reactions in women is not limited to the genitals in that they also develop anortic engorgement, sometimes to the extent of masking the nipple erection that is usually involved in the excitement phase. .

Erectile dysfunction is a case in which a man's erectile reaction fails to prevent vaginal insertion and intercourse. There are many causes of erectile dysfunction, which can be divided by general classification. Endocrine-related erectile dysfunction is one of primary gonadal failure, progressive diabetes mellitus, thyroid dysfunction and secondary sequelae of pituitary adenoma, idiopathic or acquired dysfunction, hyperprolactinemia. And other endocrine glands.

Chronic systemic diseases such as cirrhosis, chronic renal failure, and malignancy and other systemic diseases can also cause erectile dysfunction. Cerebral erectile dysfunction in the central nervous system is caused by traumatic lobe disorders, epilepsy, neoplasms, seizures, intramedullary spinal lesions, paraplegia and demyelinating disorders. Cause. Nervous erectile dysfunction in the peripheral nervous system is caused by somatic or autonomic neuropathy, pelvic neoplasm, granulomas, trauma, and the like. Urinary causes include complete prostatectomy, local trauma, tumors, and Peyronie's disease.

Half of all male erectile tracts are psychological causes because no immediately identifiable physical cause of the disorder is known. Even if the underlying cause of erectile dysfunction is the body organs, psychological factors make up a large part of the disorder.

The present invention is to change the circulation of the erection reaction by using a vasodilator administered to the circulation by the route selected from the group consisting of permeable mucosa including the vaginal mucosa, skin permeation, nasal mucosa, rectum and the like.

Many vasodilators can be used in the practice of the present invention depending on their proven potency. Useful vasodilators include dilators that are generally classified as α-adrenergic antagonists, sympathetic stimulatory amines, and dilators that cause direct relaxation of vascular lotus roots. Exemplary α-adrenergic antagonists include phentolamine, phentolamine hydrochloride, phentolamine mesylate, apomorphine, phenoxybenzamine , Tolazoline, dibenamine, yohimbine, and the like. Pentoramine mesylate is a good α-adrenergic antagonist for the proper practice of the present invention. The sympathetic stimulatory amine contemplated for use in the method of the present invention is nylidrin, and other sympathetic stimulatory amines with vasodilation may also be used.

Nicotinic acid (nicotinyl alcohol) has direct vasodilation, useful in the practice of the present invention. In addition, the use of papaverine, an unspecified lotus root relaxant, which has been used to treat erectile dysfunction in men by having vasodilatation alone or by directly injecting into the urethral cavernous body together with drugs such as pentoramine, may be considered. Organic nitrates such as nitroglycerin and amyl nitrate are known to have vasodilatation due to their ability to relax vasculature, and contemplated use in the present invention. Other vasodilators useful in the practice of the present invention include, without limitation, thymoxamine, imipramine, verapamil, naphthydropuryl, isoxsuprin and the like.

In the practice of the present invention, vasodilators are administered by permeable mucosa, including the vaginal mucosa, nasal mucosa, permeated skin and rectal route, and are delivered to the site of action prior to entering the portal circulation.

Oral medications for transport to specific sites in the circulation present a number of problems. First, because the absorption of the drug is limited by the travel time to the stomach, there is a limit on the rate at which the drug effect occurs. Second, the drug may not be activated in a low pH environment in the stomach (by hydrolysis) or by chemical biochemical action in the intestine.

Since the vasodilator according to the present invention is administered to the root of the permeable mucosa including the vaginal mucosa, nasal mucosa, permeated skin and rectum in a short time prior to intercourse, there is no need for repeated administration. Thus, the method of the present invention is very simple and helps to minimize the side effects that can occur with continuous dosing. In addition, the method of the present invention allows for more spontaneous sexual activity than other methods such as injecting vasodilators into the nasal (intracavernosal).

Formulas for delivering vasodilators according to the present invention to permeable mucosa are well known in the art. For the purposes of the present invention, "transmucosal delivery" refers to the delivery of medicine to the vaginal mucosa, oral mucosa or pharyngeal mucosa, and to buccal delivery, sublingual delivery, pharyngeal mucosa. Includes but does not convey comfort. Buccal delivery may use tablets or lozenges (comprising compressed lactose and one or more vasodilators (effective amounts)). Other suitable tablet blends are not limited to this, and may be mixed in effective amounts as vasodilators, delivery agents, tablet binding compounds, and flavoring agents, as disclosed in US Pat. No. 3,943,246. Vasodilators may also be mixed with various pharmaceutical prostheses, including binders such as gelatin and / or corn starch or rubber (gum tragacanth, etc.) that can be used in pharmaceuticals. Vasodilators may also be combined with candy or chewing gum for buccal or sublingual movement to the oral mucosa.

Vasodilators may be administered by smearing an effective amount of vasodilators into a paper filter strip or filter paper disc. A strip of filter paper or disc is then placed between the gums and cheeks (in the cheeks) and delivered to the vasculature. Other permeable mucosal delivery systems such as lollipops (disclosed in US Pat. No. 4,885,173) or vaginal suppositories are well known in the art and are expected to be useful in the practice of the present invention.

Permeable skin transport systems are well known in the art and are often referred to as "patches" for permeable skin. Illustrative transdermal patches are typically (1) an impermeable layer made of various resins (aluminum treated polyester, polyester itself or other impermeable membranes), (2) mineral oil, polyisobutylene It consists of a drug reservoir containing polyisobutylene, USP hydroxymethylcellulose and vasodilators combined with gelled alcohol. As another example, the drug reservoir layer includes an acrylic polymerized adhesive having resinous cross-linking agents that diffuse the drug from the drug reservoir to the skin surface, for example. The permeable skin supernatant may also have a transport rate control membrane, such as microporous polypropylene, between the drug reservoir and the skin. Ethylenevinyl acetate copolymers and other microporous membranes may also be used. Typically, there is an adhesive layer in the form of an adhesive such as polyisobutylene and mineral oil that binds the vasodilator.

Other typical skin permeation agents consist of (1) an outer layer consisting of a laminated polyester film, (2) a speed control adhesive, an interlayer containing nonwovens and vasodilators, and (3) a liner to be removed before use. . Skin permeation delivery systems also include binding to highly lipid soluble carrier compounds, such as dimethylsulfoxide, which promotes skin permeation. Examples of other transporters include lanolin and glycerin.

Vasodilators used in permeable mucosa, including vaginal mucosa, nasal mucosa, penetrating skin or rectal delivery, are chemically modified by well-known methods in the art to improve lipid solubility, thereby improving the ability to penetrate the skin or mucosal surface.

Rectal and vaginal suppositories are well known and are also useful in the practice of the present invention. Exemplary suppositories are vasodilators that combine glycerin, glycerol monopalmitate, glycerol, monostearate, hydrogenated palm kernel oil and fatty acids. Other suppositories include ascorbyl palmitate, silicon oxide, white wax, cocoa butter that bind effective amounts of vasodilators.

The present invention may also use a nasal spray for vasodilator administration. Nasal sprays are solutions in which vasodilators are dissolved in saline or other delivery fluids suitable for pharmaceuticals. Nasal spray compression pumps are well known and can be adjusted to deliver an amount of vasodilator.

The examples disclosed below are intended to illustrate the invention and do not limit the scope of the invention as set forth in the claims. The present invention will be described below with reference to phentolamine (phentolamine), in particular phentolamine mesylate as a vasodilator.

Pentoramine may be present in hydrated form, such as in solvated form as well as in unsolvated form, including hemi-hydrate. In general, the solvated forms are the same as those which are not solvated for the purposes of the present invention, using solvents usable in medicine such as water, ethanol and the like. Pentoramine can form pharmaceutically usable salts using organic and inorganic acids. Examples of suitable acids for salt formation include sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic, fumaric, succinic, ascorbic acid, which are well known in the art. (ascorbic), maleic acid, methanol sulfonic acid, toluenesulfonic acid and other minerals and carboxylic acids, as well as hydrohamic acid such as hydrochloric acid and hydrobromic acd. . Salts are formed in conventional manner by contacting the free base form with a sufficient amount of the desired acid. Free base forms can be regenerated by treating the salt with a suitable dilute basic aqueous solution such as dilute aqueous sodium hydroxide solution, potassium carbonate, ammonia, sodium bicarbonate, or the like. The free base form is somewhat different from each salt form in physical properties such as solubility in polar solvents, but in all other respects the salt is identical to each free base form for the purposes of the present invention. Pentoramine may also form isomorphic forms of the crystals or crystal forms through appropriate traditional crystallization processes.

Example 1 shows the effect of pentoramine mesylate administered by mucosal permeation on the arterial velocity of the penis. Examples 2 and 3 show the effect of pentoramine administered to the oral cavity on the erectile ability of erectile dysfunction men. Example 4 illustrates the use of various vasodilators in the practice of the present invention. Example 5 illustrates the practice of the present invention in regulating female erectile response.

Example 1 Effect of Transmucosal Dosing of Phentolamine Mesylate on Penile Artery Velocity

To assess whether orally administered pentoramine mesylate can alter the rate of arterial blood flow to the penis, the penis by a Doppler ultrasound tachometer using Diasonics 400 DRF (Diasonics, Milpitas, Calif.) Penile arterial velocity was measured near the base of the right branch of the dorsal artery. Setting, incidence and angle adjustment of the Doppler beams were maintained to achieve maximum speed reading for each subject under test. The reason why the artery was used for the measurement was that the artery was easier to access than the artery of the urethral cavernous body.

Prior to mucosal (oral) dosing (20 mg) of pentoramine mesylate, the rate was also measured 5, 15, 45, 60 minutes after drug administration. The average initial velocity was 10.4 cm / sec. The data shown in FIG. 1 shows the increase in percent in penile arterial velocity after administration of pentoramine mesylate and represents the mean value of three measurements of six erectile dysfunction subjects.

According to these results, 5 minutes after placing the tablet between the cheek and the gum, the arterial velocity increased 50% more than the reference linear velocity. After 25 minutes, the arterial velocity increased to 100% higher than the reference line velocity to its maximum value, from which the arterial velocity began to fall, and after one hour it returned to the predose level. Therefore, oral administration of 20 mg of pentoramine mesylate has been found to be a suitable means for rapidly changing the penile arterial blood flow.

Example 2 Effect of Transmucosal Dosing of Phentolamine Mesylate on Male Erectile Function

Considering that the penile arterial velocity is rapidly increased by oral administration of pentoramine mesylate 20 mg as in Example 1, it is understood that this vasodilator administration method will be effective in improving the erectile function of erectile dysfunction men. Can be.

All patients in this study complained of erectile dysfunction, such as poor vaginal insertion or poor ability to sustain an erection without ejaculation at the beginning of vaginal insertion. These erectile dysfunctions occurred in the group from 0.5 to 35 years, with an average duration of 3.4 years.

Before administering this placebo or pentoramine mesylate, medical history was examined, genital examinations were performed, and penile vascular status was determined. Vascular conditions were determined by measuring systolic closing pressure of the upper arm and penis and calculating the penile brachial index (PBI). PPI was calculated by dividing the pubic contraction pressure by the brachial contraction pressure. Plethysmographic cres times (CT) were measured by Penilab IV plethysmograph (Parkes, Aloha WA). Crest time is the time (in seconds) from the trough of the penis blood pressure curve to the next peak. The typical time range for crest time is from 1 second to about 1.8 seconds. PBI above 0.9 is considered normal, whereas PBI below 0.6 indicates vascular insufficiency.

In this study, patients were considered to have normal vascular function when PBI and CT were in the normal range. Patients with abnormal ranges of both PBI and CT were considered to have significant vascular dysfunction. Patients within the abnormal range of one parameter were considered to have moderate vascular dysfunction.

In general, age and diagnosis were not considered as factors to allow participation in this study, but patients who were very old or had severe penile vascular dysfunction were excluded from the study. In addition, patients with vascular dysfunction or unspecified causes of erectile dysfunction were also allowed to participate in this trial, as are patients with diabetes mellitus. The average age of the patients was 57.5 years (25-74 years).

To test the effect of pentoramine mesylate on erectile function, a test was performed on one blind person. Each patient was given two tablets, one was a placebo tablet containing only lactose, and the second was a lactose tablet containing 20 mg of pentoramine mesylate.

Patients were asked to put a tablet between the cheek and gum 10-20 minutes before sexual intercourse. Oral dosing has been used as a mucosal permeable paradigm to allow the drug to reach the blood vessels of the destination (genital) before passing through the liver, as are all the transport routes useful in the practice of the present invention. More than one day after the first tablet was used, patients repeated this process with the second tablet. Patients were advised not to drink alcohol before swallowing or using tablets, and they were advised not to expect an erection without sexual stimulation.

Patients were advised that each of the two tablets would be beneficial, and they were asked to fail to maintain sufficient erections for vaginal insertion or to report results for erection, vaginal insertion, and partial erection. The results in Table 1 show the effects of pentoramine mesrate on the age, vascular status and erectile function of erectile dysfunction men. Number 1 in the right column of Table 1 is for reports of erection and vaginal insertion, number 2 is for reports that fail to get an erection, and number 3 is for reports of partial erection.

The data in Table 1 shows oral administration of phentolamine mesylate 20 mg, resulting in enhanced erection within 10-20 minutes after oral administration of the drug. The response is characterized by enhanced erection to sexual stimulation and, therefore, the response is similar to the normal sexual response of men. The fact that after taking one dose, within ten to twenty minutes after one dose, does not require several doses and / or long waiting periods before the onset of enhanced erection, a response that occurs every time it is needed. Can be characterized. A rapid increase in penile arterial speed within 5 minutes after taking pentoramine mesylate (shown in Example 1) indicates that enhanced erection can actually occur within 10 minutes after taking. Aspects that can be used “on demand” as the method of the present invention allow for a more natural and spontaneous access for sexual activity, eliminate the need for multiple doses, and thus reduce the frequency of unwanted side effects. A dose of pentoramine mesylate 20 mg was used in this study, but 5 mg to 80 mg pentoramine mesyl, as individual responses to the drug may vary based on, for example, total weight and the degree of vascular insufficiency. Rate taking is also within the scope of the present invention.

The data set shown in Table 1 was analyzed to detect what expected values the vascular status of these patients had regarding the efficacy of pentoramine mesylate in improving erectile dysfunction in erectile dysfunction patients. The analysis revealed that among the 16 patients with normal vascular status, 7 had a successful response to pentoramine mesylate, 6 failed to respond, and 3 had partial erection. Of 49 patients with vascular insufficiency, 15 had a successful erection sufficient for sexual activity, while 29 failed to respond. The remaining five with vascular deficiency showed partial erection. Side effects in this study are irregular and include nasal congestion (6%), dizziness and drowsiness (23%) (recovered by lying for 10 to 15 minutes).

Example 3

Effect of Oral Pentoramine Mesylate and Impotence by Various Causal Relationships

Another randomized experiment was performed on men with erectile dysfunction due to various causal relationships to evaluate the efficacy of oral pentoramine administration in improving erectile dysfunction.

A mixed causal group of men with erectile dysfunction with various causal relationships was provided with three filter paper strips containing 20 mg of pentoramine mesylate and three placebo strips. These patients were not told which strips contained the drug and which strips were the placebo. Patients were asked to bite one filter paper strip between the cheek and gum 10 to 20 minutes prior to an attempt to erect. If you have enough erections for sex, this method is a success. The results are shown in Table 2.

Continued on table 2

Prior to recording in this trial, patients (Nos. 7-11) received a program of autoinjection into the nasal cavity using 20 μg of fully effective PGE-1. These patients also have severe cardiovascular disease.

1 = Erection and Vaginal Insertion

2 = sufficient erection for vaginal insertion

The trial found 36% improvement in erectile ability in patient reports (except for a total of two placebo respondents) by buccally administrated pentoramine mesylate (20 mg). The results were most frequently reported in patients diagnosed with erectile dysfunction due to psychological causes. All five patients had sufficient erections to allow intravaginal insertion. Three of the seven patients diagnosed with erectile dysfunction were diagnosed with erectile dysfunction. Of the three patients diagnosed with erectile dysfunction due to a combination of arterial abnormalities and psychological causes, two patients with erectile dysfunction improved their erection ability. None of the five patients who showed complete effect by autoinjection of PGE-1 showed an improvement in erectile ability by pentoramine mesylate administered orally.

These results, in combination with those listed in Example 2, suggest that when vasodilators such as pentoramine mesylate are administered through the permeable mucosa, in erectile dysfunction males (especially in the population of patients that make up most cases of male erectile dysfunction). Men with erectile dysfunction by psychological factors, arterial factors, or a combination thereof) have been shown to be effective in improving the erectile ability of many.

Although the present invention is useful for treating male erectile dysfunction, it is also useful for improving erectile ability in men without erectile dysfunction. As men age, it is well known that erection declines. A clear sign of erectile decline is that the angle between the back and the abdomen of the erect penis increases with age. The method of the present invention is to increase the blood flow to the penis to provide a means for minimizing the erection angle to improve the erection even in men without erectile dysfunction.

It should be noted that filter paper strips with pentoramine mesylate lose their efficacy after 6 months at room temperature in paperback.

Example 4

Vasodilators useful for changing human sexual response

Other vasoactive agents can be practiced in the present invention based on the efficacy of being proven as vasodilators. Useful vasodilators include those such as those that are generally classified as α-adrenergic antagonists, sympathetic stimulatory amines, and drugs that indicate direct relaxation of vascular smooth muscle.

Representative α-adrenergic antagonists include pentoramine hydrochloride, pentoramine mesylate, phenoxylbenzamine, tolazoline, dibenamine, yohimbine and the like. Pentoramine mesylate is preferred for the practice of the present invention. A representative example of sympathomimetic amines contemplated for use in the methods of the present invention is nilidrin, although other sympathomimetic amines with vasotropic activity are also understood by the present invention.

Nicotinic acid (or thicotinyl alcohol) has direct vasorelaxant activity useful in the practice of the present invention.

Papaverine is also an unspecified smooth muscle relaxant with vasorelaxant activity and has been used to treat male impotence, either alone or in combination with other drugs, such as pentoramine, directly into the urethral cavernous body.

Organic nitrates, such as nitroglycerin and amyl nitrate, have also been shown to exhibit vasotropic activity by their ability to relax vascular smooth muscle. Other vasoactive agents used in the practice of the present invention include, but are not limited to, thymosamine, imipramine, verapamil, naphthydrofuryl, isoxsupurin and the like.

In the practice of the present invention, these vasoactive agents are taken by mucosal pathways, including the vaginal mucosa, nose, skin or rectal pathways to reach the site of action before the vasoactive agent enters the portal circulation.

Appropriate doses of each vasoactive agent for each route of administration are readily determined by those of ordinary skill in the art. By way of illustration, in order to determine the appropriate dose of each vasodilator of the present invention, a conventional published dose of vasodilator can be used as a self-starting point with conventional techniques of the art. Conventional dosages of commercially available vasodilators can be found in the Physician's Desk Reference, published annually by Medical Economic Data, Montvale New Jersey, and in useful medical literature.

By way of example, Fabavid Oral Papaverin Hydrochloride is useful from Marion Merel Dow and typically achieves 150 mg every 12 hours to achieve a vasorelaxant effect.

The dose of calon (verapamil hydrochloride) available from the company is determined by titrating the patient to a specific dosage depending on the individual patient's response to the drug from 120 mg to approximately 240 mg every 12 hours.

Yohimbine hydrochloride, useful as Daytohimbine (Dayton Pharmaceuticals), Yokon (Palaseide Pharmaceuticals), and Yohimex (Kramer), takes 5.4 mg three times daily.

Imipramine hydrochloride is available as Tofranil from the gauge company and is taken four times a day for a total dose of 50 mg to approximately 150 mg per day.

Also useful from gages, imipramine pamoate is taken at a sustained dose of 150 mg per day.

Using the dose set as the starting point, the optimal dose for a particular dose route can be determined by measuring the baseline arterial blood flow of the patient's genital circulation prior to taking the drug using the Doppler ultrasound rheometer described in Example 1 . Other methods well known in the art, such as thermography, flexography, radiometric or scintigraphic methods, may be used to evaluate the blood flowing to the genitals. While establishing basic blood flow, various vasodilators can be taken by the route of administration included in the present invention, and the effect on blood flow can be measured. The amount of increase in blood flow needed to control or improve sexual response in humans may vary from person to person, but is readily determined as described below. In addition, individual patients are titrated with various vasodilators at various doses until an optimal dose is determined.

Blood flow studies can be thought of as linking with the evaluation of sexual responses, as evidenced by improved erectile response to sexual stimulation.

Example 5

Changes in sexual response in women

As described above, there are similarities in the anatomy of the genitals of men and women and the erection reactions promoted by these vessels. In both men and women, erectile reactions occur under physical or psychological excitement, when blood flow to the genitals increases due to the relaxed tendon of the arteries in the genitals.

The methods of the present invention reduce the ability to produce lubricating components of the vagina that are necessary for smooth penis insertion, and in the case of women whose sexual response has been impaired by other phenomena of impaired sexual reactivity that correlate with the erection response. It can be used to improve or increase the.

As in the case of male sexual response, in the absence of any pathologically diagnosed disorder in female erectile response, the methods of the present invention can be used to increase female normal sexual response. The "as needed" feature of the present invention will result in a rapid response to sexual excitement, with heightened emotions associated with excitement and plateau stages of the female sexual response by increasing blood flow to the genitals.

Indeed, the improvement of sexual response in women using the methods of the present invention is performed by the same method as described in Examples 2 and 3.

Effective dosages of vasodilators are supplied to women by an intermucosal route including, but not limited to, the mucous membranes of the vagina, skin, nose, or rectum. Appropriate dosages of particular vasodilators can be readily determined using the methods described in Example 4.

Representative vasodilators useful in embodiments of the present invention are described in Example 4. And those generally classified as α-adrenergic antagonists, including drugs that induce sympathomimetic amines and direct relaxation of vascular tendons. do. Female reactions are included in the Masters W.H. It can be measured using the methods described in Johnson, V.E., Human Sexual Response, Little, Brown, and Co., Boston (1996). Methods of measuring blood flow, including Doppler ultrasonic velocimetry, thermography using isothermal blood transducers, radioscintigraphic methods and photoplexes Photoplethysmography can be used with other methods known in the art. In addition, measuring distal 1/3 contraction, which is characteristic of the elevated state of sexual response in women, includes but is not limited to strain gauges or devices that measure tendon contraction or tendon tension. It can be measured using methods and equipment that are not.

In addition, improved sexual response can be measured in a more subjective way by simply allowing a woman to describe any change in excitement caused by the supply of vasodilators in accordance with the present invention. Appropriate placebo control may also be performed to ascertain whether the effort is directly attributable to the supply of vasodilators.

Preferred embodiments of the invention include mucosal feeding of about 5 mg to 150 mg of pentoramine mesylate for about 1 minute to about 1 hour prior to sexual intercourse and for sexual intercourse preparation, and 15 mg of pentoramine mesylate More preferably 100 mg. And more preferably 25 mg-80 mg of pentoramine mesylate, most preferably 40 mg of pentoramine mesylate. Moreover, the amount of vasodilator used in embodiments of the present invention for improving female sexual response is effective for improving sexual response from about 1 minute to about 1 hour after feeding. More preferably, the amount of vasodilator used is effective to improve female sexual response from about 5 minutes to about 45 minutes after feeding. The amount of vasodilator used is effective to improve female sexual response from about 15 minutes to about 30 minutes after feeding. Other supply pathways and other vasodilators included within the scope of the present invention are also contemplated.

Another preferred method of transmucosal administration is by vaginal suppositories. Vaginal suppositories are known in the art and are available in a variety of physical forms. The most well known are suppositories or pessaries that are ball or egg-shaped and weigh about 5 g each. Most recently, creams, gels, or solutions that fall outside the concept of conventional suppositories are available and useful in embodiments of the present invention. Mixtures for vaginal feeding can be supplied in vaginal tablets, or the insertion can be encapsulated in soft gelatin. In addition, the mixture for vaginal feeding can be prepared as a lyophilized solution. If water is added to the freeze-dried solution before feeding, the freeze-dried solution provides an effective supply means. All these physical forms are considered.

Representative vaginal suppositories include a mixture of about 86% of polyethylene glycol 1000NF, 10% polyethylene glycol 3350 NF, and 4% phentolamine mesylate. The final vaginal suppository will provide an effective means of delivering a dose of pentoramine mesylate through the vaginal mucosa.

A 40 mg tablet insert of a representative pentoramine mesylate contains about 61% microcrystalline celluose, NF; Hydrogenated vegetable oil treated with 30% hydrogen, NF; 4% croscamellose sodium, NF; 4% pentoramine mesylate; 0.5% magnesium stearate, NF; It contains a mixture of 0.4% colloidal silicon dioxide. The mixture is compressed into tablet form and the final tablet insert is encapsulated in soft gelatin by conventional methods. Encapsulated tablets are supplied to women through the vaginal mucosa.

Representative vaginal gels for the supply of the invention include 75% water, 15% glycerin, 7% pentoramine mesylate and less than 1% hydroxyethylcellulose, methylparaben and glucono-lactone -o-lactone). The final vaginal gel will provide an effective means of delivering a dose of pentoramine mesylate through the vaginal mucosa.

Representative solutions for lyophilization include pentoramine mesylate, citric acid, sodium bicarbonate, mannitol and magnesium stearate salts. After lyophilization, water is added and re-hydrated prior to feeding the woman through the vaginal mucosa.

Another representative solution comprises about 83% drinkable water and a mixture of 13% pentoramine mesylate and 4% D-mannitol. The final solution provides another effective means of delivering a dose of pentoramine mesylate through the vaginal mucosa.

Additional suppositories, gels, creams, solutions or inserts are also included within the scope of the present invention.

Although the present invention has been described by the preferred embodiments, the examples described herein are those that can be absorbed into the circulatory system upon introduction of the drug by an intermucosal route including the supply pathways of the mucous membrane of the vagina, skin, nose, or rectum. It does not limit the scope of the invention.

The present invention relates to a method of altering the physical sexual response by supplying vasodilators to the circulatory system through the mucosa, and is not limited to supply through the mucous membrane, the internal or rectal and transdermal supply pathways of the vagina. not.

Claims (100)

In a method of altering human sexual response by supplying vasodilators to the blood circulation in an amount necessary to increase blood flow to the genitals, The method comprises changing the sexual response by supplying the required amount of vasodilator into the mucosa by order. The method of claim 1, The vasodilator is pentoramine, pentoramine mesylate, pentoramine hydrochloride, apomorphine, phenoxybenzamine, nitroglycerin, thymoxamine, nicotinyl alcohol, imipramine, verapamil, isox sprin, naphthydrofuryl , Tolazoline and papaverine. The method according to claim 1 or 2, The supply route is through the vaginal mucosa. The method according to claim 1 or 2, The vasodilator supplied is selected from the group consisting of pentoramine, pentoramine mesylate and pentoramine hydrochloride. The method of claim 3, wherein Vasodilators are selected from the group consisting of pentoramine, pentoramine mesylate and pentoramine hydrochloride. The method of claim 4, wherein The amount supplied is about 5 mg-150 mg. The method of claim 5, The amount supplied is about 5 mg-150 mg. The method of claim 4, wherein The amount supplied is about 15 mg-100 mg. The method of claim 5, The amount supplied is about 15 mg-100 mg. The method of claim 4, wherein The amount supplied is about 25 mg-80 mg. The method of claim 5, The amount supplied is about 25 mg-80 mg. The method of claim 4, wherein The amount supplied is 40 mg. The method of claim 5, The amount supplied is 40 mg. The method of any one of claims 1, 2 and 5-13, wherein The amount supplied is effective to improve the sexual response of women within about 1 minute-1 hour after feeding. The method of claim 3, wherein The amount supplied is effective to improve the sexual response of women within about 1 minute-1 hour after feeding. The method of claim 4, wherein The amount supplied is effective to improve the sexual response of women within about 1 minute-1 hour after feeding. The method of any one of claims 1, 2 and 5-13, wherein The amount supplied is effective to improve the sexual response of women within about 5 to 45 minutes after feeding. The method of claim 3, wherein The amount supplied is effective to improve the sexual response of women within about 5 to 45 minutes after feeding. The method of claim 4, wherein The amount supplied is effective to improve the sexual response of women within about 5 to 45 minutes after feeding. The method of any one of claims 1, 2 and 5-13, wherein The amount supplied is effective to improve the sexual response of women within about 15-30 minutes after feeding. The method of claim 3, wherein The amount supplied is effective to improve the sexual response of women within about 15-30 minutes after feeding. The method of claim 4, wherein The amount supplied is effective to improve the sexual response of women within about 15-30 minutes after feeding. The method of claim 5-13, 15, 16, 18, 19, 21 or 22, Supply is in the form of suppositories for the vagina. The method of claim 3, wherein Supply is in the form of suppositories for the vagina. The method of claim 4, wherein Supply is in the form of suppositories for the vagina. The method of claim 14, Supply is in the form of suppositories for the vagina. The method of claim 17, Supply is in the form of suppositories for the vagina. The method of claim 20, Supply is in the form of suppositories for the vagina. The method of claim 5-13, 15, 16, 18, 19, 21 or 22, The feeding is in the form of tablets. The method of claim 3, wherein The feed is in tablet form. The method of claim 4, wherein The feed is in tablet form. The method of claim 14, The feeding is in the form of tablets. The method of claim 17, The feeding is in the form of tablets. The method of claim 20, The feeding is in the form of tablets. The method of claim 5-13, 15, 16, 18, 19, 21 or 22, The supply is in the form of a re-hydrated lyopholized soultion. The method of claim 3, wherein Wherein the feed is in the form of a rehydrated, lyophilized solution. The method of claim 4, wherein Wherein the feed is in the form of a rehydrated, lyophilized solution. The method of claim 14, Wherein the feed is in the form of a rehydrated, lyophilized solution. The method of claim 17, Wherein the feed is in the form of a rehydrated, lyophilized solution. The method of claim 20, Wherein the feed is in the form of a rehydrated, lyophilized solution. The method of claim 5-13, 15, 16, 18, 19, 21 or 22, Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 3, wherein Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 4, wherein Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 14, Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 17, Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 20, Method in which the supply is in the form of a gel or cream of the vagina. 42. The method of claim 41 wherein Gel is composed of 30mg-50mg pentoramine mesylate. The method of claim 42-46, wherein Gel is composed of 30mg-50mg pentoramine mesylate. The method of claim 47, The gel consists of 40mg pentoramine mesylate. The method of claim 48, The gel consists of 40mg pentoramine mesylate. In the method of manufacturing a drug that changes the sexual response of humans by supplying vasodilators to the blood circulation system in an amount necessary to increase blood flow to the genital organs, The method comprises changing the sexual response by supplying the required amount of vasodilator into the mucosa by order. The method of claim 18, The vasodilator is pentoramine, pentoramine mesylate, pentoramine hydrochloride, apomorphine, phenoxybenzamine, nitroglycerin, thymoxamine, nicotinyl alcohol, imipramine, verapamil, isox sprin, naphthydrofuryl With tolazoline The method is selected from the group consisting of papaverine. The method of claim 51 or 52, The supply route is through the vaginal mucosa. The method of claim 51 or 52, The vasodilator supplied is selected from the group consisting of pentoramine, pentoramine mesylate and pentoramine hydrochloride. The method of claim 53, Vasodilators are selected from the group consisting of pentoramine, pentoramine mesylate and pentoramine hydrochloride. The method of claim 54, The amount supplied is about 5 mg-150 mg. The method of claim 55, The amount supplied is about 5 mg-150 mg. The method of claim 54, The amount supplied is about 15 mg-100 mg. The method of claim 55, The amount supplied is about 15 mg-100 mg. The method of claim 54, The amount supplied is about 25 mg-80 mg. The method of claim 55, The amount supplied is about 25 mg-80 mg. The method of claim 54, The amount supplied is 40 mg. The method of claim 55, The amount supplied is 40 mg. The method of any one of claims 51, 52 and 55-63, wherein The amount supplied is effective to improve the sexual response of women within about 1 minute-1 hour after feeding. The method of claim 53, The amount supplied is effective to improve the sexual response of women within about 1 minute-1 hour after feeding. The method of claim 54, The amount supplied is effective to improve the sexual response of women within about 1 minute-1 hour after feeding. The method of any one of claims 51, 52 and 55-63, wherein The amount supplied is effective to improve the sexual response of women within about 5 to 45 minutes after feeding. The method of claim 53, The amount supplied is effective to improve the sexual response of women within about 5 to 45 minutes after feeding. The method of claim 54, The amount supplied is effective to improve the sexual response of women within about 5 to 45 minutes after feeding. The method of any one of claims 51, 52 and 55-63, wherein The amount supplied is effective to improve the sexual response of women within about 15-30 minutes after feeding. The method of claim 53, The amount supplied is effective to improve the sexual response of women within about 15-30 minutes after feeding. The method of claim 54, The amount supplied is effective to improve the sexual response of women within about 15-30 minutes after feeding. The method according to any one of claims 55 to 63, 65, 66, 68, 69, 71 or 72, Supply is in the form of suppositories for the vagina. The method of claim 53, Supply is in the form of suppositories for the vagina. The method of claim 54, Supply is in the form of suppositories for the vagina. The method of claim 64, wherein Supply is in the form of suppositories for the vagina. The method of claim 67, Supply is in the form of suppositories for the vagina. The method of claim 70, Supply is in the form of suppositories for the vagina. The method according to any one of claims 55 to 63, 65, 66, 68, 69, 71 or 72, The feeding is in the form of tablets. The method of claim 53, The feeding is in the form of tablets. The method of claim 54, The feeding is in the form of tablets. The method of claim 64, wherein The feeding is in the form of tablets. The method of claim 67, The feeding is in the form of tablets. The method of claim 70, The feeding is in the form of tablets. The method according to any one of claims 55 to 63, 65, 66, 68, 69, 71 or 72, The supply is in the form of a re-hydrated lyopholized soultion. The method of claim 53, Wherein the feed is in the form of a rehydrated, lyophilized solution. The method of claim 54, Wherein the feed is in the form of a rehydrated, lyophilized solution. The method of claim 64, wherein Wherein the feed is in the form of a rehydrated, lyophilized solution. The method of claim 67, Wherein the feed is in the form of a rehydrated, lyophilized solution. The method of claim 70, Wherein the feed is in the form of a rehydrated, lyophilized solution. The method according to any one of claims 55 to 63, 65, 66, 68, 69, 71 or 72, Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 53, Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 54, Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 64, wherein Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 67, Method in which the supply is in the form of a gel or cream of the vagina. The method of claim 70, Method in which the supply is in the form of a gel or cream of the vagina. 92. The method of claim 91 wherein Gel is composed of 30mg-50mg pentoramine mesylate. 97. The method of any of claims 92-96, Gel is composed of 30mg-50mg pentoramine mesylate. 97. The method of claim 97, The gel consists of 40mg pentoramine mesylate. 99. The method of claim 98, The gel consists of 40mg pentoramine mesylate.