WO2005011705A1

WO2005011705A1 - Enhancement of erectile function

Info

Publication number: WO2005011705A1
Application number: PCT/CA2004/001402
Authority: WO
Inventors: Kenneth W. Adams
Original assignee: Adams Kenneth W
Priority date: 2003-07-25
Filing date: 2004-07-26
Publication date: 2005-02-10

Abstract

A pharmaceutical composition for enhancing erectile function. The composition is administered locally to the cavernosal tissue and includes a pharmaceutically acceptable hormone. An adjunct that aids in sustaining and increasing the hormone in the penile and cavernosal tissue can also be administered.

Description

Enhancement of Erectile Function

This application claims the benefit of priority of United States Provisional Application Nos. 60/489,906 and 60/536,740, filed July 25, 2003 and January 16, 2004, respectively.

Field of the invention

This invention relates to enhancement of erectile function.

Background of invention

Erectile dysfunction (ED) is defined as the inability to achieve and maintain a penile erection adequate for sexual intercourse. This may be a relative term wherein the frequency of occurrences in which a patient is able to achieve and maintain a penile erection adequate for sexual intercourse has decreased over time or as a result of a medical condition. It is a male health problem which has been estimated to affect about 150 million men worldwide. Research on erectile physiology has increased the understanding of the biochemical factors and intracellμlar mechanisms responsible for corpus cavernosal smooth muscle contraction and relaxation and has led to the development of various treatments. There must be a large enough increase in blood flow for the veno-occlusive mechanism to trap and retain blood in the cavernosal tissues, which allows the inflow of fresh arterial blood to expand and pressurize the erectile tissue. In fact, the small percentage of men who fail to respond to maximal pharmacological therapy administered directly to the penis may achieve very high rates of arterial blood flow into the penis, but the veno-occlusive system does not close and their penis does not firm up. The failure of the veno-occlusive system to close means that even when sexual stimulation and or medications causes a dramatic increase in the arterial blood flow into the erectile tissue, the pressure in the cavernosal tissue may not increase adequately, and a firm erection does not develop. Current pharmacological treatments for erectile function such as phosphodiesterase 5-blockers and intracavernosally administered medications, such as the vasodilator PGE 1 alpha, may produce levels of blood flow large enough to allow the arterial inflow to sufficiently pressurize the erectile tissue and activate the veno-occlusive system tissue to produce a usable erection. But even the higher arterial flow rates into the penis induced by pharmocological treatments such as intracavernosally administered vasodilators may fail to produce adequate erections in some patients with more severe leakage. Consequently, some men fail to respond to even maximal doses of intracavernosally administered medications. Instead of the medication along with the blood being trapped by the veno-occlusive system and resulting in a firm and prolonged erection, the patient may only experience a weak and transient engorgement of the penis for a few minutes which fades as the medication is flushed out of the cavernosal tissues by the higher flow rates induced by the intracavernosally administered medications. Men who fail to respond to such pharmacotherapy may have to resort to using a pump and a very tight penile ring or undergo the surgical insertion of an implant, which may result in the irreversible destruction of the erectile tissues. A desired approach for treating ED, as expressed by the vast majority of men with this problem, would be a treatment that restores their ability to achieve and maintain adequate erections without the use of medications or devices which must be used at the time that the erection is desired.

Pharmacological treatment options for ED currently available include agents which directly or indirectly increase penile blood flow for a few minutes to several hours, including oral agents (phosphodiesterase-5 inhibitors, such as Levitra™, Viagra™, and Cialis™, dopamine agonists, such as Uprima™, and alpha-receptor blocking drugs), intracavernosally injected vasodilators (papaverine, phentolamine, prostaglandin Ei, vasoactive intestinal peptide), transurethral vasoactive agents (prostaglandin E_1} sometimes marketed as MUSE™), vacuum erection devices, vascular surgery, and penile prostheses. Each of these options has its own disadvantages. For example, only while these medications are present at therapeutic levels in the tissues where they directly exert their effects will the male be able to functionally achieve an usable erection (i.e., usable for penetration). The sometimes limited therapeutic window of the medications does not significantly reverse or restore a patient's ability to achieve non-pharmacologically induced erections. In addition, the currently available medications require that first the male has an adequate response (only approximately 50% or less of men will obtain adequate erections using oral therapies), and then these medications must be properly administered and the timing of the therapeutic effect must coincide with the timing of the desired erection.

Viagra™ is an example of an oral treatment for ED available in North America, but not all men respond in an entirely satisfactory way to Viagra treatment. A large percentage of men trying oral medications to treat their erectile problem will have no detectable response, and in many others the effect may be marginal, with variable and unpredictable responses every time they use the medication. When there is a response, there may only be a short duration of time when the pill will work, and a variable time before the onset of any significant response. As a result, patients can have difficulty predicting if and when oral medications will work.

Another disadvantage is that the onset of the therapeutic effect of the medications may vary from use to use. For instance, the effect of some oral medications can be diminished after a large meal, and the onset of the effect can be delayed by several hours, which may be inconvenient for a patient and his partner. Other treatments for ED include vacuum suction devices and penis prostheses which can be awkward and may interfere with sexual enjoyment. On a much less frequent basis, vascular surgery is indicated for men who, for example, have suffered a traumatic transaction of the penile artery requiring repair. Most men with erectile dysfunction have normal or elevated penile blood flow or nerve damage or a combination of both, hence vascular surgery is of no benefit, and would introduce further iatrogenic damage to the penis and further impair penile function.

Low androgen levels can be associated with an increased risk of developing erectile dysfunction, although it seems that most men with low androgen levels have normal erectile function. Low androgen levels can be caused by a phenomenon called "andropause" (similar to menopause experienced by females) or other medical condition. Treatment may involve androgen replacement therapy, where the androgen is administered so that the systemic androgen level is normalized. Despite the normalization of the androgen levels in men with low hormones and erectile dysfunction, however, erectile dysfunction is not always satisfactorily improved. Whatever the changes are that occur in the body and in the penis of men with chronically low androgen levels to cause erectile dysfunction, they do not seem to be reversed by treatments which restore a male patient's androgen levels to normal. If a patient requires medications to achieve adequate erections before starting hormone therapy, he generally continues to need to use these medications for erectile dysfunction after treatment and correction of the androgen deficiency. Androgen therapy may nonetheless increase libido, a sense of well being, energy levels, moods, and less frequently may cause minor recovery in spontaneous erectile activity. Numerous studies for androgen therapy do not seem to have shown any significant or sustained effective improvement in erectile function in men with originally low androgen levels. Patients with normal androgen levels seem to show no response to androgen therapy, and may actually notice a decline in erectile function, possibly due to the suppression of the pituitary - gonadal hormonal system and the functional castration that occurs when patients with functional testicles are given androgen replacement therapy.

As well, simply replacing androgens systemically by giving testosterone, which the inventor understands to be the only treatment currently being marketed in America for andropause, does not reproduce the body's own natural pulsatile diurnal production of testosterone which is coordinated with the pulsatile diurnal secretion of growth hormone and the other major diurnal hormonal systems of the body such as the adrenal gland. Growth hormone and the sex hormones are functionally interdependent. The full expression of testosterone requires adequate levels of growth hormone as well as adequate levels of thyroid and the adrenal hormones. Growth hormone cannot function properly if testosterone levels are low. The body's major hormone systems are functionally interdependent. Hence, taking physiological doses of a systemically administered exogenously derived testosterone disrupts the body's own natural sex hormone production, which is itself coordinated and functionally integrated with the other hormonal systems in the body. The inventor believes that this disruption in the body's hormonal balance is at least partially responsible for poor clinical responses that can be observed when androgen therapy gives externally applied souces of testosterone to restore the systemic testosterone level in andropausal men with declining erectile function, and why the inventor has observed a poor clinical response to these types of therapies. In contrast, the treatment disclosed herein safely allows for the administration of supra-physiologic levels of androgens locally to the penis and the erectile tissues to improve erectile function, while the systemic doses of androgens reaching the rest of the body are sufficiently low to substantially prevent, or at least significantly reduce, potential adverse effects such as suppression of the pituitary gonadal axis, and suppression of the bodies own endogenous hormone production.

Despite the failures of systemic testosterone/androgen therapies to improve erectile function, there is scientific evidence for a role of testosterone, and especially dihydrotestosterone (DHT), in the development of the male genitalia in normal fetal development. Males that inherit defective genes for the enzyme 5-alpha-reductase (which normally converts 1-3% of the body's testosterone production to DHT) and whose bodies fail to produce DHT, or alternatively men who have inherited defective androgen receptors that prevent DHT from functioning, will be born as genetic males but possess external female genitalia, undescended testicles, and at puberty will develop exaggerated female secondary sexual characteristics and body type. Males with a partial defect will develop ambiguous genitalia and a very small penis. Studies in which males with ambiguous, small genitalia were administered systemic doses of DHT showed significant penile growth of 0.5-2 cm.

As well, blockers of the enzyme 5-alpha-reductase (ie: finesteride, marketed as

Propecia™ or Proscar™) are used to treat male pattern baldness. Finesteride does not completely eliminate the formation of DHT, but generally there is approximately a 2/3 reduction in DHT levels systemically. Some men given finesteride for the treatment of prostatic enlargement or male pattern hair loss may experience an acute onset of erectile dysfunction which in many cases has been reversed upon discontinuing the use of finesteride.

Description of invention

This invention provides the use of pharmacological agents to enhance erectile function.

As used herein, "enhanced erectile function" refers to the ability to achieve and maintain a penile erection adequate for sexual intercourse more often than one was able to before the treatment presented in the instant application. Indications that this treatment is effective include the decreased or eliminated reliance on medications and/or improved response to the medications currently used to treat erectile dysfunction or aid in achieving an adequate erection, more frequent spontaneous erections, an improved ability to sustain an erection after ejaculation, a reduction in the absolute and relative refractory period after ejaculation before another erection can be achieved, and a reduced requirement for stimulation to achieve an erection. Any of these indicators, alone or in combination, can be used as a measure of effectiveness.

As used herein, "administration to the cavernosal tissue" refers to a delivery system that results in a higher localized dose of the active agents of the present invention within the cavernosal tissue (i.e., at least 50%, but more preferably at least 75%, and even up to 100% of the administered dose) compared to what would be achieved if a similar dose were to be administered systemically, for example, when administered by injection into the bloodstream, or by a patch applied to the arm.

Administration to the cavernosal tissue encompasses injections directly into the cavernosal tissue. It also encompasses injections to the connective tissues which surround the cavernosal tissue from where the active agents of the present invention, in a water-based or oil-based system, will diffuse into the cavernosal tissue. Through this route, generally less of the administered dose would be delivered to the cavernosal tissue than if it were injected directly into the cavernosal tissue. Injections may be performed by various methods including by needle, auto-injector, slow-sustained injection pump, high pressure injection device, and microinfusion pump. Other routes of administration considered to be administration to the cavernosal tissue include urethral suppositories, implantable sustained-release drugs or devices, and transdermal devices or vehicles which are directly in contact with or adhered to the penis, such as patches, creams, or lotions. Optionally, the transdermal devices or vehicles may be delivered by a condomlike device.

Androgens typically bind to the androgen receptor (AR) protein present in the cytosol and nucleus of the cell. Once the AR protein is bound to an androgen, the androgen- AR complex typically dimerizes and undergoes nuclear translocation if it is not already in the nucleus. It can then bind to specific gene-regulatory sequences called hormone response elements (HREs) to control androgen-dependent gene expression. Currently most of the effects of androgens are thought to be mediated by this mechanism. Androgens have been shown to exert direct effects on some axons mediated through a direct action on these tissues, and other direct actions of androgens in the penis itself cannot be ruled out at this time.

In one embodiment of the invention, a pharmaceutical composition is administered to the penile and cavernosal tissue of the penis of a male patient. The pharmaceutical composition comprises an androgen hormone, an agonist for an androgen receptor, or any agonistic molecule which binds to at least one androgen receptor in the penis and male genitalia, or any agent which will bind and appropriately modify the genetic expression of the androgen HRE (i.e., HRE which controls androgen-dependent gene expression) in the male genitalia, or any biomolecule which is responsible for andfogen- related activities in the penis, a derivative thereof, or a mixture of hormones, agonists, androgen receptor-binding molecules, or molecules which bind to HREs which control androgen-dependent gene expression, or molecules which bind to biomolecules responsible for androgen-related activities in the penis, or derivatives thereof, and a pharmaceutically acceptable diluent or carrier. This definition also encompasses molecules which require a cofactor to bind to an androgen receptor, HRE, or any biomolecule which is responsible for androgen-related activities in the penis. The androgen may be, but is not limited to: the naturally occurring androgens and derivatives thereof, including androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3 -acetate, androstenediol- 17- acetate, androstenediol-3, 17-diacetate, androstenediol- 17-benzoate, androstenediol-3 - acetate- 17-benzoate, androstenedione, dehydroepiandrosterone (DHEA; also termed "prasterone"), sodium dehydroepiandrosterone sulfate, 4-dihydrotestosterone (DHT; also termed "stanolone"), 17.beta.-hydroxyandrost-4-en-3-one, 5.alpha.-dihydrotestosterone, dromostanolone, dromostanolone propionate, ethylestrenol, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol and testosterone; pharmaceutically acceptable esters of testosterone and 4- dihydrotestosterone, typically esters formed from the hydroxyl group present at the C-17 position, including, but not limited to, the enanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprate esters; and pharmaceutically acceptable derivatives of testosterone such as methyl testosterone, testolactone, oxymetholone and fluoxymesterone. Testosterone and testosterone esters, such as testosterone enanthate, testosterone propionate and testosterone cypionate, may be used. The aforementioned testosterone esters are commercially available or may be readily prepared using techniques known to those skilled in the art or described in the pertinent literature.

The aforementioned androgenic agents are selected from the group consisting of naturally occurring androgens, synthetic androgens, such as methyltrienolone, and derivatives thereof. The active agents may be incorporated into the present dosage units and thus administered in the form of a pharmaceutically acceptable derivative, pharmaceutically active sequence or region, peptidomimetic, mimetic, analog, ester, salt, or amide, or the agents may be modified by appending one or more appropriate functionalities to enhance selected biological properties such as penetration through mucosal tissue. Preparation of esters, as noted in the preceding section, involves functionalization of hydroxyl and/or carboxyl groups that may be present, as will be appreciated by those skilled in the arts of pharmaceutical chemistry and drug delivery. 5 For example, to prepare testosterone esters, the 17-hydroxyl group of the testosterone molecule is generally caused to react with a suitable organic acid under esterifying conditions, such conditions typically involving the use of a strong acid such as sulfuric acid, hydrochloric acid, or the like, and a temperature sufficient to allow the reaction to proceed at reflux. Esters can be reconverted to the free acids, if desired, by using

10 conventional hydrogenolysis or hydrolysis procedures. Testosterone is the principal steroid secreted by the testes and is the primary circulating androgen found in the plasma of males. Testosterone is converted to DHT by the enzyme 5 alpha-reductase in many peripheral tissues. DHT is thus thought to serve as the intracellular mediator for most androgen actions (Zhou, et al., Molec. Endocrinol. 9:208-

15 18 (1995)). Other steroidal androgens include esters of testosterone, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, and decanoate esters, and other synthetic androgens such as 7-Methyl-Nortestosterone ("MENT"') and its acetate ester.

The pharmaceutical composition is administered to the patient in a pharmaceutically 0 acceptable sterile dosage form to the tissues of the penis, which includes the cavernosal tissue. The composition may be administered topically by transdermal vehicles or devices, such as creams, lotions, or patches. The composition may be administered by urethral suppository, or parenterally using a needle, auto-injector, slow sustained injection pump, high pressure jet injection device, microinfusion pump, or implantable 5 sustained release drug or device. Sterile dosage forms include, but are not limited to, syringes and needles, urethral suppositories, or transurethral implants, ampoules or vials, or transdermal vehicles or devices, such as creams, lotions, or patches.

The active ingredient can be delivered to the penile and cavernosal tissue transdermally. A suitable delivery vehicle or device is situated in direct contact with the skin of the 0 penis to effect delivery of the agent to the penile and cavernosal tissue. The vehicle or device may include agents which enhance the transdermal absorption rate or agents which aid in the absorption of the pharmaceutical composition into the cavernosal tissue. A particularly preferred transdermal device of the present invention is a patch. A patch is designed to adhere to or be brought into contact with the skin of the penis so that the pharmaceutical composition contained by the patch can be absorbed transdermally and into the penile and cavernosal tissue. The patch may also contain agents which enhance, control, or a combination of both, the transdermal absorption of the pharmaceutical composition and/or the absorption of the pharmaceutical composition into the penile and cavernosal tissue. Optionally, these agents can be applied in conjunction with the pharmaceutical composition, at a different time, and/or a different route of administration. The patch may also include adhesives specially designed to adhere to the often sensitive skin of the penis.

Pharmaceutical compositions of the present invention which are given as injections may be injected in an oil based carrier (depot oil) into, for instance, the connective tissue which surrounds the cavernosal tissue. This type of injection, when given as a deep intramuscular injection, usually results in a sustained release form that requires relatively infrequent injections, where usually the serum levels peak at 3-10 days, and then serum levels diminish slowly over 3-6 weeks. By way of comparison, a water-based intracavernosal injection of vasodilator will show a peak intracavernosal effect within 20 minutes and blood flow through the erectile tissue will clear most of the medication after 6 or more hours. Generally, any water based injection into the erectile or cavernosal tissues will be cleared from the penile tissues in a matter of hours versus the days required to clear an oil based depot injection into dense and relatively avascular connective tissues. Hence, a smaller amount of any medication given by intracavernosal injection, water or oil-based, into the highly vascular erectile tissues will give higher levels but will be cleared very rapidly when compared to an injection into the relatively avascular extra-cave nosal connective tissues of the penis. Thus, intracavernosal injections into the very vascular erectile tissue will require more frequent administrations of smaller amounts of medication while much larger but less frequent doses of the same medication are required to achieve the same therapeutic effect if the medication is injected into the relatively less vascular connective tissues of the penis.

The rate of clearance from an intracavernoasal injection will vary and be dependent upon the rate of blood flow through the erectile tissue and the concentration gradient, resulting in a decline of active agent, assuming a constant flow rate. The active agent, of the depot injections of the present invention can diffuse into the erectile tissues where it will tend to be similarly washed out of the erectile tissue, but because it will enter the erectile tissue continuously for several hours or days, it will maintain more continuous and prolonged levels of the active agent in the tissue of the penis. The site of depot oil injections should be varied along the shaft of the penis, and after the application, direct pressure should be applied to avoid bruising, bleeding, hematomas, etc. In addition, the injection site should be massaged to disperse the medication. Water-based pharmaceutical compositions injected into the connective tissue which surrounds the cavernosal tissue are also contemplated. As well, transdermal devices or vehicles such as patches designed to fit and adhere to the penis, topical gels/creams/ointments/pastes with or without a condom-like device, and jet injector systems are other delivery systems that could be equally effective. Patches will probably be the preferred method.

Kits comprising pharmaceutical compositions of the invention formulated in sterile unit dosage forms suitable for administration to the cavernosal tissue, which include instructions for use in written, oral, videotape, compact disc, other digital electronic form, or other recorded media, are contemplated. Conveniently, a kit wherein the sterile unit dosage forms are for oil based depot injections and instructions for use is provided.

In addition, the inventor has found that giving aromatase inhibitors, in addition to the androgen administration to the penile and cavernosal tissue of the pharmaceutical compositions of the present invention, to subjects has resulted in further enhancement of their erectile function. The aromatase inhibitors need not be administered directly to the penile or cavernosal tissues, and preferably are given systemically. By directly blocking the conversion of testosterone to estrogens, aromatase blockers reduce systemic estrogen levels. Lower systemic levels of estrogens will reduce direct effects of estrogens in the penis and reduce the inhibitory effects of estrogens on the pituitary's release of leutenizing hormones (LH) which results in increased testosterone production in the testicles and elevate the physiological levels of androgens throughout the body. Estrogen blockers such as tamoxifen at, for example, 20mg per day may also have a similar effect. The inventor measured an average rise of 25% in the free testosterone levels in the serum of these individuals taking aromatase blockers, who reported improved libido, and more frequent and more prolonged spontaneous erections associated with a reduced need or desire to use Viagra or intracavernosal injections of vasodilators when they were taking the aromatase blockers. Without being bound to any theory, the inventor theorized that the improvement in erectile function seen with aromatase blocker therapy may be due to the effects of an increase in androgen levels acting directly in the penis, or it may be due to the effects of androgens acting outside of the penis (eg: acting centrally in the brain/peripheral nervous system or at other sites outside of the penis). It is well known that androgens have effects both inside and outside the penis.

The inventor has devised a treatment in which super-physiological levels of the active agents of the pharmaceutical compositions of the present invention are administered to the penile and cavernosal tissue of the penis using as little as, for example, 1% of the usual systemic dose which the inventor estimated would produce testosterone levels 10 times above the normal physiological levels of circulating testosterone in the cavernosal tissues of the penis. The dose of active agent which absorbs into the penile or cavernosal tissue may be as high as 25% of the usual systemic dose, depending on the route of administration.

Those of skill in the art will understand that the increased percentage absorption of the active agent of the pharmaceutical compositions of the present invention into the penile and cavernosal tissue compared to that achieved from the usual administered systemic dose is because of the different route of administration. Usual systemic doses may range from around 0.5 to 160 mg/day depending on the route of administration and the reason for treatment. For example, when treating andropause the usual systemic dose for testosterone by topical administration may be 25- 50 mg/day, and for DHT it may be around 125-250 mg/day. These doses of testosterone and DHT administered topically will usually suppress the release of FSH and LH from the pituitary gland and will suppress endogenous testosterone production.

The present invention is not a pharmacological "crutch" to transiently increase penile blood flows to give improved erections, but a treatment that may restore the natural functional capacity of a male to achieve much harder, firmer erections when sexually stimulated, and may be effective for days, weeks, and possibly even months after using this treatment. Potentially, even middle aged and older men who would not be considered to be impotent, following a course of this treatment may experience a marked improvement in their ability to achieve and maintain the erections to levels that they experienced when they were much younger and in their sexual prime, without the aid of any medications currently available to treat erectile dysfunction.

Men with very severe ED who previously were not responding to other conventional treatments such as intracevernosally administered vasodilator therapy or phosphdiesterase-5 blockers may start getting spontaneous erections with this treatment. Also, the same men who previously were not responding to other treatments may start to have even stronger erectile responses to intracavernosally administered vasodilator therapy or phosphdiesterase-5 blockers after this treatment.

The appropriate dosage and frequency of treatment may vary depending upon desire or need of the degree of enhanced erectile function sought. Other health related factors would also be considered. Men without need of great enhancement of their erectile function may not need maximal treatment. The dosage can be in the range of 0.01 to 20 mg/day, more preferably the dosage is in the range of 0.1 to 10 mg/day of testosterone, or equivalent dose of DHT or other androgen, androgen receptor agonist, or molecule which binds to an androgen receptor, depending on the route of administration.

When a combination of active agents of the present invention is used, it may be necessary to vary the amount of each agent depending upon how amenable an agent is to a particular route of administration.

The frequency of administration may be in the range of two to three times a day for intercavemosal injection, more preferably from 3 to 7 times a week, or as infrequently as monthly for depot injection or topical administrations. The patient's condition should be monitored and the dosage adjusted, usually titrated upward, if enhanced erectile function is not achieved. Enhancement in erectile function may start immediately, but the major therapeutic effect may be expected to be achieved within 2 weeks to 6 months, more often within 4 weeks to 3 months. This may be followed by a maintenance phase during which there are intermittent or less frequent administrations. This may involve administrations of at least quarterly, bimonthly, biweekly, weekly injections, depending on the route of administration.

If a transdermal vehicle or device, such as a patch, is used, a dose of 0.5 mg to 50 mg of testosterone or an equivalent dose of dihydrotestosterone or other androgen, the pharmaceutical composition may be administered for anywhere from 24 to 0.5 hours. With low efficiency delivery, a higher amount of the dihydrotestosterone or other androgen would be incorporated into the patch. Preferably, a lower dose such as 0.5 to 1 mg is administered topically for a period closer to 24 hours or a higher dose such as 50 mg of testosterone or an equivalent dose of dihydrotestosterone or other androgen is administered for a shorter period about 0.5 to 3 hours.

Other embodiments of the invention include the use of pharmacological adjuncts to aid in sustaining or increasing the amount of androgen present in the cavernosal tissue. The adjuncts need not be applied directly to the penile or cavernosal tissues. Such adjuncts include aromatase inhibitors, such as natural or synthetic progesterone, tamoxifen, letrozole marketed as Femara , and anasfrozole, marketed as Arimidex or any salts, derivatives, mimetics, or mixtures thereof, or agents which increase the ratio of testosterone to estrogen, such as chrysin. The adjuncts can be administered by such routes as oral administration, injection, topical application (creams, lotions, patches etc.), subdermal implants, etc. For example, Femara™ may be administered orally at doses ranging from 0.1 to 10 mg daily, more preferable at doses ranging from 1 to 2.5 mg daily, Arimidex™ may be administered orally at doses ranging from 0.02 to 10 mg daily, more preferably at doses ranging from 0.25 to 1 mg a day, and chrysin may be administered orally at doses ranging from 500 to 5000 mg/day, optionally in divided doses, more preferably at doses ranging from 1500 to 3000 mg/day, optionally in divided doses (such as divided into 3 portions a day) for the treatment period. The adjuncts may be administered locally to the cavernosal tissue, in conjunction with the pharmaceutical composition or separately.

The following experimental examples are illustrative of the feasibility of the use of this invention.

Example 1

One 44 year old subject, with marked erectile dysfunction after using finesteride for over one year to prevent male pattern baldness, received 0.5 mg of testosterone by intracavernosal injection 3-4 times per week for a period of two weeks. The subject developed a full recovery of his erectile problems, and the effect persisted for several weeks after stopping the therapy. Therapy was then resumed several weeks later using bi-weekly depot injections of 4 mg for a total of 5 injections and the patient continued to experience improvements in erectile function, such as improved nocturnal and morning erections, the ability to achieve an erection easily and fully minutes after ejaculating, and the ability to have multiple strong erections and ejaculations in a 12 hour period weeks after stopping the treatment. After stopping the treatment for 6 weeks, a gradual decline in erectile function occurred. The patient resumed treatment with ANDRODERM™ a 24.3 mg testosterone patch applied for 0.5 to 2 hours every 2 to 3 days for a total of 4 applications, which then restored the patient's erectile function to levels reported earlier.

Example 2

A 31 year old subject did not recall ever experiencing spontaneous erections with masturbation or nocturnal or morning erections. The patient's best erectile response of a 50-60% erection was experienced with an injection of maximal dose intracavernosal medication containing prostaglandin El alpha, papavarine, chlorpromazine and atropine, followed by 100 mg of Viagra™ taken 40 to 60 minutes before the intracavernosal injection plus the use of a tight penile ring and adding sexual stimulation. Combining and maximizing these traditional methods failed to treat erectile dysfunction in the subject and did not allow him to achieve a functional erection. The subject was administered direct subcutaneous penile injections of 6 mg testosterone biweekly for 4 weeks, then increasing to 10 mg every 2 days for another 6 weeks. After 2 weeks, the subject began to report spontaneous and morning erections for the first time in his life. He has now been able to have intercourse with traditional medication or a ring, occasionally without medication or a ring. The subject has, for example, started to develop a very strong response to Viagra™ where, prior to hormone treatment, there was no noticeable response to Viagra™ alone.

Example 3

A 67 year old subject experienced profound erectile dysfunction for 10 years and failed to respond to treatment with maximal doses of phosphodiesterase-5 blockers alone and in combination with intracavernosal injections of protstaglandinEl alpha, papavarine, atropine and chlorpromazine. These medications did not improve his condition. The subject was started on 6 mg of testosterone subcutaneously injected directly into the penis biweekly for 3 applications. He started to develop improved spontaneous and morning erections, and had a very hard sustained erection with Viagra™ in the first week of treatment. The subject then went away on holidays for 2 weeks. Treatment was resumed at 10 mg of testosterone 2 to 3 times a week for 4 weeks and patient began to develop some spontaneous erections without other medications. Since then he has tried a testosterone patch directly to the penile shaft with ANDRODERM™ a 24.3 mg applied 3 times a week for 1 to 2 hours per day. After 5 applications of the patch, he noted sustained improvements in erectile function.

While preferred embodiments of the invention have been illustrated and described, it will be appreciated that various changes and modifications can be made therein without departing from the spirit and scope of the invention as defined by the following claims.

Although various examples of combined elements of the invention have been described, it will also be understood that these are not intended to be exhaustive and features of one embodiment may be combined with those of another, and such other combinations are contemplated to be within the scope of the invention disclosed herein.

All publications and other documents mentioned herein are hereby incorporated by reference into this document as though the entire contents thereof were reproduced herein.

Claims

1. A pharmaceutical composition formulated in a sterile unit dosage form suitable for administration locally to the cavernosal tissue comprising a pharmaceutically acceptable hormone.

2. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable diluent or carrier.

3. The pharmaceutical composition of claims 1 or 2, wherein the hormone is an androgen, an agonist for an androgen receptor, or any agonistic molecule which binds to the androgen receptor and forms a complex that can then interact with a HRE in the nucleus which will induce the correct modulation of androgen-dependent gene expression, or a biomolecule which is responsible for androgen-related activities in the penis, including androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3 -acetate, androstenediol- 17-acetate, androstenediol-3, 17-diacetate, androstenediol- 17- benzoate, androstenediol-3-acetate- 17-benzoate, androstenedione, dehydroepiandrosterone (DHEA; also termed "prasterone"), sodium dehydroepiandrosterone sulfate, 4-dihydrotestosterone (DHT; also termed "stanolone"), 17.beta.-hydroxyandrost-4-en-3-one, 5.alpha.-dihydrotestosterone, dromostanolone, dromostanolone propionate, ethylestrenol, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol and testosterone, pharmaceutically acceptable esters of testosterone and 4-dihydrotestosterone, including esters formed from the hydroxyl group present at the C-17 position, including, but not limited to, the enanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate, cyclopentylpropionate, isocarponate, heptanoate, decanoate, undecanoate, caprate and isocaprate esters, pharmaceutically acceptable derivatives of testosterone such as methyl testosterone, testolactone, oxymetholone and fluoxymesterone; synthetic androgens, and 7-Methyl-Nortestosterone ("MENT¹") and its acetate ester, and salts, derivatives, precursors, pharmaceutically active sequences or regions, peptidomimetics, mimetics, and mixtures thereof.

4. The pharmaceutical composition of claim 3, wherein the hormone is testosterone.

5. The pharmaceutical composition of claim 3, wherein the hormone is dihydrotestosterone.

6. The pharmaceutical composition of any of claims 1 to 5, formulated for administration locally to the cavernosal tissue, by needle, auto-injector, slow sustained injection pump, high pressure injection device, microinfusion pump, urethral suppository, implantable sustained release drug or device, or transdermal vehicle or device such as a cream, lotion, or patch.

7. The pharmaceutical composition of claim 6, formulated for administration by needle.

8. The pharmaceutical composition of claim 6, formulated for administration by patch.

9. The pharmaceutical composition of any of claims 6 to 8, wherein a formulation is administered to the connective tissues which surround the cavernosal tissues of the penis.

10. The pharmaceutical composition of any of claims 1 to 9, further comprising an adjunct which aids in sustaining and increasing the hormone in the penile and cavernosal tissue.

11. The pharmaceutical composition of claim 10, wherein the adjunct is administered separately from the composition.

12. The pharmaceutical composition of claim 10, wherein the adjunct is administered in conjunction with the composition.

13. The pharmaceutical composition of any of claims 10, 11, or 12, wherein the adjunct is an aromatase inhibitor or estrogen blocker.

14. The pharmaceutical composition of claim 13, wherein the aromatase inhibitor or estrogen blocker is natural or synthetic and selected from a group comprising progesterone, tamoxifen, letrozole, or anasfrozole, or salts, derivatives, mimetics, or mixtures thereof.

15. The pharmaceutical composition of claims 10, 11, or 12, wherein the adjunct enhances the ratio of testosterone to estrogen.

16. The pharmaceutical composition of claim 15, wherein the adjunct is chrysin.

17. The pharmaceutical composition of any of claims 10 to 16, wherein the the adjunct is formulated for administration by intracavernosal injection, a urethral or rectal suppository, an implantable sustained release device, oral administration, intravenous administration, injection into the dorsal suspensory ligament or connective tissues of the penis, or topical administration.

18. The pharmaceutical composition of claim 17, wherein the adjunct is formulated for oral administration.

19. The pharmaceutical composition of claim 18, wherein letrozole is administered orally at a dose ranging from 0.5 to 5 mg/day.

20. The pharmaceutical composition of claim 18, wherein anasfrozole is administered orally at a dose ranging from 0.25 to 2 mg/day.

21. The pharmaceutical composition of claim 18, wherein chrysin is administered orally at a dose ranging from 500 to 5000 mg/day, optionally in divided doses.

22. The pharmaceutical composition of claim 16, wherein the adjunct is formulated for topical administration by a transdermal vehicle or device in the form of a patch, cream or lotion optionally administered by a condom-like device.

23. The pharmaceutical composition of claim 22, wherein the adjunct is administered in the form of a patch.

24. Use of a pharmaceutical composition of any of claims 1 to 23 comprising a pharmaceutically acceptable hormone for enhancing erectile function, wherein the pharmaceutical composition is administered locally to the cavernosal tissue of a male patient

25. The use of claim 24, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable diluent or carrier.

26. The use of claims 24 or 25, wherein the hormone is an androgen, an agonist for an androgen receptor, or any agonistic molecule which binds to the androgen receptor and forms a complex that can then interact with a HRE in the nucleus which will induce the correct modulation of androgen-dependent gene expression, or a biomolecule which is responsible for androgen-related activities in the penis, including androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3-acetate, androstenediol- 17-acetate, androstenediol-3 , 17-diacetate, androstenediol- 17-benzoate, androstenediol-3 - acetate- 17-benzoate, androstenedione, dehydroepiandrosterone (DHEA; also termed "prasterone"), sodium dehydroepiandrosterone sulfate, 4-dihydrotestosterone (DHT; also termed "stanolone"), 17.beta.-hydroxyandrost-4-en-3-one, S.alpha.- dihydrotestosterone, dromostanolone, dromostanolone propionate, ethylestrenol, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol and testosterone, pharmaceutically acceptable esters of testosterone and 4-dihydrotestosterone, including esters formed from the hydroxyl group present at the C-17 position, including, but not limited to, the enanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate, cyclopentylpropionate, isocarponate, heptanoate, decanoate, undecanoate, caprate and isocaprate esters, pharmaceutically acceptable derivatives of testosterone such as methyl testosterone, testolactone, oxymetholone and fluoxymesterone; synthetic androgens, and 7-Methyl-Nortestosterone ("MEN ") and its acetate ester, and salts, derivatives, precursors, pharmaceutically active sequences or regions, peptidomimetics, mimetics, and mixtures thereof.

27. The use of claim 26, wherein the hormone is testosterone.

28. The use of claim 26, wherein the hormone is dihydrotestosterone.

29. The use of any of claims 24 to 28, wherein the pharmaceutical composition is formulated for administration locally to the penile and cavernosal tissue, by needle, auto-injector, slow sustained injection pump, high pressure injection device, microinfusion pump, urethral suppository, implantable sustained release drug or device, or transdermal vehicle or device such as a cream, lotion, or patch.

30. The use of claim 29, wherein the pharmaceutical composition is formulated for administration by needle.

31. The use of claim 29, wherein the pharmaceutical composition is formulated for administration by patch.

32. The use of any of claims 29 to 31 , wherein the pharmaceutical composition is administered to the connective tissues which surround the cavernosal tissues of the penis.

33. The use of any of claims 24 to 32, further comprising an adjunct which aids in sustaining and increasing the hormone in the cavernosal tissue.

34. The use of claim 33, wherein the adjunct is administered separately from the composition.

35. The use of claim 33, wherein the adjunct is administered in conjunction with the composition.

36. The use of any of claims 33, 34, or 35, wherein the adjunct is an aromatase inhibitor.

37. The use of claim 36, wherein the aromatase inhibitor is natural or synthetic and selected from a group comprising progesterone, tamoxifen, lefrozole, or anasfrozole, or salts, derivatives, mimetics, or mixtures thereof.

38. The use of claims 33, 34, or 35, wherein the adjunct enhances the ratio of testosterone to estrogen.

39. The use of claim 38, wherein the adjunct is chrysin.

40. The use of any of claims 33 to 39, wherein the the adjunct is formulated for administration directly into the penis by intracavernosal injection, urethral or rectal suppository, an implantable sustained release device, oral administration, intravenous administration, injection into the tissue of the penis, or topical administration.

41. The use of claim 40, wherein the adjunct is formulated for oral administration.

42. The use of claim 41, wherein lefrozole is administered orally at a dose ranging from 0.5 to 5 mg/day.

43. The use of claim 41, wherein anasfrozole is administered orally at a dose ranging from 0.25 to 2 mg/day.

44. The use of claim 41, wherein chrysin is administered orally at a dose ranging from 500 to 5000 mg/day, optionally in divided doses.

45. The use of claim 40, wherein the adjunct is formulated for topical adminisfration by a transdermal vehicle or device in the form of a patch, cream or lotion optionally administered by a condom-like device.

46. The use of claim 45, wherein the adjunct is formulated for administration in the form of a patch.

47. The use of any of claims 24 to 46, wherein the pharmaceutical composition is administered to the patient at least 1 time per week for a period of at least 2 weeks.

48. The use of any of claims 24 to 47, wherein said pharmaceutical composition is administered to the patient at least twice a day for a period of at least 1, 2, 3, 4, 5, or 6 months.

49. A method for providing enhanced erectile function comprising the step of administering a pharmaceutical composition of any of claims 1 to 23 locally to the penile and cavernosal tissue of a male patient.

50. The method of claim 49, further comprising a pharmaceutically acceptable diluent or carrier.

51. The method of claims 49 or 50, wherein the hormone is an androgen, an agonist for an androgen receptor, or any agonistic molecule which binds to the androgen receptor and forms a complex that can then interact with a HRE in the nucleus which will induce the correct modulation of androgen-dependent gene expression, or a biomolecule which is responsible for androgen-related activities in the penis, including androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3 -acetate, androstenediol- 17-acetate, androstenediol-3 , 17-diacetate, androstenediol- 17-benzoate, androstenediol-3 - acetate- 17-benzoate, androstenedione, dehydroepiandrosterone (DHEA; also termed "prasterone"), sodium dehydroepiandrosterone sulfate, 4-dihydrotestosterone (DHT; also termed "stanolone"), 17.beta.-hydroxyandrost-4-en-3-one, 5.alpha.- dihydrotestosterone, dromostanolone, dromostanolone propionate, ethylestrenol, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol and testosterone, pharmaceutically acceptable esters of testosterone and 4-dihydrotestosterone, including esters formed from the hydroxyl group present at the C-17 position, including, but not limited to, the enanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate, cyclopentylpropionate, isocarponate, heptanoate, decanoate, undecanoate, caprate and isocaprate esters, pharmaceutically acceptable derivatives of testosterone such as methyl testosterone, testolactone, oxymetholone and fluoxymesterone; synthetic androgens, and 7-Methyl-Nortestosterone ("MENT"') and its acetate ester, and salts, derivatives, precursors, pharmaceutically active sequences or regions, peptidomimetics, mimetics, and mixtures thereof.

52. The method of claim 51, wherein the hormone is testosterone.

53. The method of claim 51, wherein the hormone is 4-dihydrotestosterone.

54. The method of any of claims 49 to 53, wherein the pharmaceutical composition is formulated for administration by locally to the penile and cavernosal tissue, by needle, auto-injector, slow sustained injection pump, high pressure injection device, microinfusion pump, urethral suppository, implantable sustained release drag or device, or transdermal vehicle or device such as a cream, lotion, or patch.

55. The method of claim 54, wherein the pharmaceutical composition is inserted through a needle inserted into the cavernosal tissue.

56. The method of claim 54, wherein the pharmaceutical composition is administered with a patch.

57. The method of any of claims 54 to 56, wherein the pharmaceutical composition is administered to the connective tissues which surround the cavernosal tissues of the penis.

58. The method of any of claims 49 to 57, further comprising an adjunct which aids in sustaining and increasing the hormone in the penile and cavernosal tissue.

59. The method of claim 58, wherein the adjunct is administered separately from the composition.

60. The method of claim 58, wherein the adjunct is administered in conjunction with the composition.

61. The method of any of claims 58, 59, or 60, wherein the adjunct is an aromatase inhibitor.

62. The method of claim 61, wherein the aromatase inhibitor is natural or synthetic and selected from a group comprising natural or synthetic progesterone, tamoxifen, lefrozole, or anasfrozole, or salts, derivatives, mimetics, or mixtures thereof.

63. The method of any of claims 58, 59, or 60, wherein the adjunct enhances the ratio of testosterone to estrogen.

64. The method of claim 63, wherein the adjunct is chrysin.

65. The method of any of claims 58 to 64, wherein the adjunct is formulated for adminisfration by intracavernosal injection, urethral or rectal suppository, an implantable sustained release device, oral adminisfration, intravenous adminisfration, injection into the tissues of the penis, or topical adminisfration.

66. The method of claim 65, wherein the adjunct is formulated for oral administration.

67. The method of claim 66, wherein lefrozole is administered orally at a dose ranging from 0.5 to 5 mg/day.

68. The method of claim 66, wherein anasfrozole is administered orally at a dose ranging from 0.25 to 2 mg/day.

69. The method of claim 66, wherein chrysin is administered orally at a dose ranging from 500 to 5000 mg/day, optionally in divided doses.

70. The method of claim 65, wherein the adjunct is formulated for topical administration by a transdermal vehicle or device in the form of a patch, cream or lotion optionally administered by a condom-like device.

71. The method of claim 70, wherein the adjunct is administered in the form of a patch.

72. The method of any of claims 49 to 71, wherein the pharmaceutical composition is administered to the patient at least 1 time per week for a period of at least 2 weeks.

73. The method of any of claims 49 to 72, wherein said pharmaceutical composition is administered to the patient at least twice daily for a period of at least 1, 2, 3, 4, 5, or 6 months.

74. A kit comprising a composition of any of claims 1 to 23 and instructions for administering the composition to a human male according to a method of any of claims 49 to 73 which may lead to enhanced penile function.

75. The kit of claim 74, wherein the instructions are provided in written form.

76. The kit of claim 74, wherein the instructions are provided orally by a health professional.

77. The kit of claim 74, wherein the instructions are provided on a videotape, compact disc or other electronically recordable media.

78. The kit of any of claims 74 to 77, further comprising an adjunct which aids in sustaining and increasing the hormone in the cavernosal tissue.

79. Use of a hormone of claim 3, 4 or 5 for the preparation of a medicament for enhancing erectile function.

80. Use of claim 79, further comprising use of an adjunct of any of claims 10 and 13 to 23 for the preparation of the medicament.

81. Use of claim 80, wherein the adjunct is for administration separately from the hormone.