HK1068549B - Use of a tramadol material in the preparation of a medicament for delaying ejaculation - Google Patents

Description

Use of tramadol material for the preparation of a medicament for delaying ejaculation in men

Technical Field

The present invention relates to a method of delaying ejaculation. The invention particularly relates to methods of delaying ejaculation by administering a tramadol material.

Background

Premature ejaculation is a weak sexual dysfunction. This dysfunction can lead to the inability to intervene or sustain sexual intercourse and can produce psychological damage to the patient. Premature ejaculation can also impair successful reproduction.

Treatments for premature ejaculation include psychotherapy, local anesthetics, and application devices. All of these treatments have significant drawbacks. Psychotherapy is beneficial to only a small percentage of patients and requires a specific therapist who is not likely to be available to all patients. Furthermore, psychotherapy is not possible to alleviate premature ejaculation due to non-psychological causes. The anesthetic may reduce the sensitivity of the tissue, thereby reducing the pleasure of intercourse. In addition, local anesthetics may be transferred into the sexual partner and thereby reduce its sensitivity and pleasure. In terms of devices, they can be awkward, and awkward to use. The device is extremely conspicuous and shows the specific conditions that the sick partner should prefer to hide. In addition, the device may produce stimulation to one or both partners.

Methods for treating premature ejaculation by systemic administration of certain antidepressant compounds, including fluoxetine, sertraline, paroxetine, have been described. See U.S. patents US4,507,323, US4,940,731, US5,151,448 and US5,276,042 and Rosen et al j.clin.psychopharmacol, 19, 67-85 (1999). However, these antidepressants may not be effective in all patients and their side effects may prevent treatment or affect patient compliance. Disease conditions or adverse interactions with other drugs may contraindicate the use of these compounds or require lower doses, which may not be effective in delaying ejaculation.

Methods of treating premature ejaculation by administering certain 5-hydroxytryptamine agonists and antagonists are described in US6,037,360. In this patent, a 5-hydroxytryptamine agonist is defined as mimicking at least one of the receptors for 5-hydroxytryptamineA compound that blocks the effect of 5-hydroxytryptamine on at least one of its receptors and a 5-hydroxytryptamine antagonist is defined as a compound that blocks the effect of 5-hydroxytryptamine on at least one of its receptors. Preferably 5-hydroxytryptamine 5HT₃Receptor antagonists (e.g., ondansetron, ergot alkaloids, granisetron, metoclopramide, trimethobenzamide, tropisetron, dolasetron, patapride and zacopride) and 5-hydroxytryptamine 5HT₄Stimulants (e.g., cisapride and D-lysergic acid diethylamide). Unfortunately, these compounds have side effects that may prohibit their use (e.g., ergot alkaloids and D-ergot diacetyl amide) or have limited efficacy (e.g., metoclopramide et al; see PCT application WO 95/13072).

Thus, there is clearly a need for additional methods of treating premature ejaculation. There is a particular need for a method of treating premature ejaculation that does not require specific psychotherapy, can be conveniently used without difficulty, and does not include the difficulties associated with existing treatments.

Tramadol is a centrally acting synthetic analgesic compound. The mode of action is not fully understood. It appears from animal experiments that at least two complementary mechanisms can be applied: (1) the parent compound (tramadol) and the O-demethylated M1 metabolite bind to the u-opioid receptor; and (2) a weak inhibition of the reuptake of norepinephrine and 5-hydroxytryptamine. Opioid activity is due to low affinity binding of the parent compound and high affinity binding of the M1 metabolite to the u-opioid receptor. M1 was more than 6-fold more effective in producing analgesia than tramadol in animal models and more than 200-fold more potent in u-opioid binding than tramadol. Inhibition of norepinephrine and 5-hydroxytryptamine reuptake in vitro has been demonstrated because tramadol has some other opioid analgesic effect. These mechanisms can independently produce the overall analgesic profile of tramadol.

In addition to analgesia, tramadol has been described for use in the treatment of pollakiuria and urinary incontinence (see U.S. Pat. No. 6,090,856) and in the treatment of cough, bronchitis and the common cold (see U.S. Pat. Nos. 3,652,589 and 3,830,934). There is no teaching or suggestion in the prior art that tramadol could be used to delay ejaculation.

Summary of The Invention

The invention provides a method for delaying ejaculation. The method includes the step of administering to the male an effective amount of tramadol prior to intercourse.

Brief Description of Drawings

Figure 1 stereoisomers of tramadol.

Detailed description of the preferred embodiments of the invention

The term "premature ejaculation" as used herein refers to a sexual dysfunction in which a male is unable to control the ejaculatory process to a degree sufficient to satisfy a spouse. In general, premature ejaculation refers to persistent or recurrent ejaculation with minimal stimulation before or during sexual intercourse. The term includes both "congenital" or "lifelong" premature ejaculation and "primary" or "acquired" premature ejaculation. Specific definitions include: (i) performing ejaculation before insertion or performing internal ejaculation for 10-20 times by rubbing after insertion; (ii) ejaculation in less than 1-2 minutes; and (iii) if the woman is not suffering from orgasmic disorder, then ejaculation occurs 50% faster than the woman is able to achieve orgasm. See, for example: US patents US6,037,360 and US5,151,448; male preferability and Sexual Dysfunction, page 356 (Springer-Verlag 1997); the Diagnostic and statistical Manual of Mental Disorders (American Psychiatric Association 1994). However, premature ejaculation as defined may be treated by the methods of the invention.

As used herein, "delaying ejaculation" means that a male receiving tramadol material is able to control the ejaculatory process so as to prevent ejaculation for a time which is longer than the time which a male would normally experience without receiving tramadol material. In the case of men with premature ejaculation, it is expected that men will be able to control the ejaculation process to a degree sufficient to make their spouse more or fully satisfactory. "delaying ejaculation" does not mean completely preventing ejaculation.

The term "tramadol material" as used herein refers to all pharmaceutically acceptable forms and derivatives of 2- [ (dimethylamino) methyl ] -1- (3-methoxyphenyl) -cyclohexanol ("tramadol") and tramadol. The term specifically includes N-oxide derivatives ("tramadol N-oxide") and O-demethyl derivatives ("O-nortramadol"). The term also includes solvates, polymorphs and pharmaceutically acceptable acid addition salts of tramadol and its derivatives. The term further includes stereoisomers of any of the foregoing, including individual stereoisomers (including individual enantiomers) and mixtures of stereoisomers (including racemates).

The stereoisomers of tramadol are shown in figure 1. There appears to be some difference in the literature regarding the nomenclature of the individual stereoisomers of tramadol. For the purposes of this application, the "cis" and "trans" stereoisomers of tramadol are named according to the relative positions of the dimethylamino and hydroxyl groups on the cyclohexane rings within the tramadol molecule. As shown in FIG. 1, the R, R and S, S enantiomers are referred to herein as the "cis" isomers, while the R, S and S, R isomers are referred to herein as the "trans" isomers. As also shown in FIG. 1, the R, R isomer of tramadol is referred to herein as the "+" cis isomer, while the S, S isomer is referred to as the "-" cis isomer. It is presently understood that the R, S and S, R isomers are not optically active.

Tramadol and its acid addition salts, particularly the hydrochloride salt, are currently preferred. Even more preferred are (±) cis-tramadol, their acid addition salts, especially the hydrochloride salt and the individual enantiomers.

Processes for the preparation of tramadol, tramadol N-oxide and O-nortramadol are well known. See, for example: U.S. Pat. Nos. 3,652,589, 3,830,934, 5,223,541, 5,336,691, 5,723,668, 5,728,885 and 5,874,620, the disclosures of which are incorporated herein by reference in their entirety. Tramadol is also commercially available from Gruenenthal GmbH, Aschen, Germany.

Pharmaceutically acceptable acid addition salts are prepared by conventional methods well known in the art using pharmaceutically acceptable, substantially non-toxic organic and inorganic acids. Such acids include hydrochloric, nitric, sulfuric, phosphoric, hydrobromic, acetic, propionic, maleic, malonic, succinic, citric, tartaric, malic, benzoic, salicylic, phthalic, nicotinic, and the like. Hydrochloric acid is preferred and tramadol hydrochloride is the most preferred compound for carrying out the invention.

To delay ejaculation, an effective amount of a tramadol material is administered to a male prior to intercourse. By "effective amount" is meant a non-toxic amount of tramadol material that is sufficient to delay ejaculation. Effective dosage forms, modes and times of administration, and dosages may be determined empirically and making such determinations is within the purview of one skilled in the art. Preferably a single dose is administered orally shortly before sexual intercourse. In particular, it has been found that an effective dose of (±) cis-2- [ (dimethylamino) methyl ] -1- (3-methoxyphenyl) -cyclohexanol hydrochloride for delaying ejaculation is from about 10 to about 50 milligrams (mg), preferably from about 15 to about 35mg, most preferably about 25mg, administered orally from about 30 to about 60 minutes prior to intercourse. However, it will be understood by those skilled in the art that the dosage may vary with the particular form of tramadol employed, the route of administration, the timing of administration, the identity of any other drug administered, whether the male suffers from premature ejaculation and the severity of the premature ejaculation condition, the age, size and condition of the patient, and like factors well known in the medical arts. In general, a suitable dose is the amount of the compound that is the lowest dose effective to delay ejaculation without toxicity. However, the dosage, route of administration, etc., may be determined by the attending clinician within the scope of sound medical judgment.

The tramadol material may be administered by any suitable route of administration, including orally, nasally, rectally, parenterally (e.g., intravenously, subcutaneously, or intramuscularly), topically (i.e., delivery to the skin or mucosa), transdermally (i.e., delivery of the drug through the skin into the bloodstream), transmucosally (i.e., delivery of the drug through mucosal tissue into the bloodstream), intracavernosally (i.e., injection into one or both corpora cavernosa of the penis), and intraurethrally (i.e., delivery into the urethra). Oral administration is highly preferred.

Although the tramadol material can be administered alone, it is preferably administered in the form of a pharmaceutical formulation (composition). The pharmaceutical compositions comprise a tramadol material as the active ingredient in admixture with one or more pharmaceutically acceptable carriers and optionally one or more other compounds, drugs or other materials. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the male who is taking the composition. Pharmaceutically acceptable carriers are well known in the art. The active ingredient is formulated into a pharmaceutically acceptable dosage form by conventional methods well known to those skilled in the art, regardless of the route of administration chosen. See, for example: remington's pharmaceutical sciences.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, powders, granules or as aqueous or non-aqueous liquid solutions or suspensions or oil-in-water or water-in-oil liquid emulsions or elixirs or syrups or as lozenges (using an inert base such as gelatin and glycerin or sucrose and acacia) each containing a predetermined amount of the active ingredient. Preferred oral administration forms are tablets and capsules.

In the solid dosage forms of the invention (capsules, tablets, pills, lozenges, powders, granules, etc.) for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or disodium phosphate, and/or any one of the following: (1) fillers or supplements such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) adhesives, such as: for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerin; (4) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) adsorbents such as kaolin and bentonite clays; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may be employed as fillers in soft and hard gelatin capsules using such excipients as lactose and high molecular weight polyethylene glycols and the like.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agents. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or coated with coating materials and shells such as enteric coating materials and other coating materials well known in the pharmaceutical arts. They may also be formulated into sustained or controlled release formulations of the active ingredient in which, for example, hydroxypropylmethyl cellulose in varying proportions is employed to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may also be sterilized, for example, by filtration through a membrane that entraps bacteria. These compositions may optionally also contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferably, in a delayed manner, optionally, at some point in the gastrointestinal tract. Examples of embedding substances (compositions) that may be used include polymers and waxes. The active ingredient may also be in microencapsulated form.

Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, thickening and preservative agents.

Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention for rectal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature but liquid at body temperature and thereby melts in the rectum to release the active ingredient.

Dosage forms for topical, transdermal or transmucosal administration of the active ingredient include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, drops and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any buffers or propellants which may be required.

Ointments, pastes, creams and gels may contain, in addition to the active ingredient, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the active ingredient, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

The active ingredient may also be delivered through the skin using a conventional transdermal drug delivery system, i.e., a transdermal patch, wherein the active agent is typically contained within a layered structure that serves as a drug delivery device that is affixed to the skin. In such structures, the active ingredient is typically contained in a layer or "reservoir" below an upper backing layer. The layered device may contain a single reservoir or may contain multiple reservoirs. In one embodiment, the reservoir comprises a polymer matrix of a pharmaceutically acceptable contact adhesive material for immobilizing the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and the skin-contact adhesive are present as separate and distinct layers, in which case the adhesive under the reservoir may be a polymer matrix as described above or may be a liquid or hydrogel reservoir or may take other forms.

The backing layer in these layers used as the upper surface of the device serves as the main structural part of the laminate structure and provides the device with a lot of flexibility. The material selected for the backing material should be selected such that it is substantially impermeable to the active ingredient and any other substances present. The backing layer may be occlusive or non-occlusive, depending on whether hydration of the skin during drug delivery is desired. The backing layer is preferably made of a flexible sheet or film of elastomeric material. Examples of polymers suitable for the backing layer include polyethylene, polypropylene, polyesters, and the like.

During storage and prior to application, the layered structure includes a release liner. Immediately prior to application, the layer is removed from the device to expose its base surface, drug reservoir or a separate contact adhesive layer so that the system can be secured to the skin. The release liner should be made of a drug/carrier impermeable material.

Transdermal drug delivery devices may be made using conventional techniques well known in the art, for example by molding a liquid mixture of adhesive, drug and carrier onto a backing layer, followed by lamination of the release liner. Similarly, the adhesive mixture may be molded onto a release liner, followed by lamination of the backing layer. Alternatively, the drug reservoir may be prepared without the drug or excipient present and then loaded by "dipping" in the drug/carrier mixture.

The layered transdermal drug delivery system may also contain a skin permeation enhancer. That is, because the inherent permeability of the skin to certain drugs may be too low to allow therapeutic levels of the drug to pass through an appropriately sized area of unbroken skin, it is necessary to co-administer a skin permeation enhancer with such drugs. Suitable accelerators are well known in the art.

The pharmaceutical compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and aqueous salt solutions of such compositions may be prepared using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.

Preferred formulations for topical drug delivery are ointments and creams. Ointments are semisolid preparations which are generally based on petrolatum or other petrolatum derivatives. Creams containing selected active agents are viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil, as are well known in the art. Cream bases are water-fast and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes referred to as the "inner" phase, is generally composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase typically, although not necessarily, exceeds the oil phase in volume and typically contains a humectant. The emulsifier in the cream is typically a nonionic, anionic, cationic or amphoteric surfactant. As will be appreciated by those skilled in the art, the particular ointment or cream base employed is one that provides optimal drug delivery. As with the other carriers or excipients used, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration may be carried out using transmucosal delivery systems known to those skilled in the art.

Pharmaceutical compositions suitable for parenteral administration comprise the active ingredient in admixture with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders or other solid forms which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of surface coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as wetting agents, emulsifying agents and dispersing agents. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the active ingredient, it is desirable to delay the absorption of the active ingredient from subcutaneous or intramuscular injections. This is accomplished by using a liquid suspension of crystalline or amorphous material having low water solubility. The rate of absorption of the active component depends on its rate of dissolution and in turn on the grain size and crystalline form. On the other hand, delayed absorption of active ingredients for parenteral administration is achieved by dissolving or suspending the drug in an oil carrier.

Injectable sustained release formulations are prepared by forming a matrix of microcapsules of the active ingredient in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of active ingredient to polymer and the nature of the particular polymer used, the rate of release of the active ingredient can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Sustained release injectable formulations are also prepared by incorporating the active ingredient into liposomes or microemulsions which are compatible with body tissues. For example, the injectable material may be sterilized by filtration through a bacterial-resistant filter.

Intracavernosal injection may be performed by using a syringe or any other suitable device. An example of a hypodermic syringe as used herein that can be used for simultaneous injection of the corpora cavernosa is described in U.S. Pat. No. 4,127,118. Injection into the dorsal aspect of the penis is performed by placing a needle on each dorsal vein side and inserting the corpus cavernosum.

The active ingredient may be administered in the form of a pharmaceutical formulation suitable for transurethral drug delivery. The formulations contain one or more selected carriers or excipients, such as water, silicones, waxes, petrolatum, polyethylene glycol, propylene glycol, liposomes, sugars such as mannitol and lactose, and/or various other substances, with polyethylene glycol and its derivatives being particularly preferred. It is desirable to incorporate a transurethral penetration enhancer into the urethral dosage form. Examples of suitable transurethral penetration enhancers include dimethyl sulfoxide, dimethylformamide, N-dimethylacetamide, decylmethyl sulfoxide, polyethylene glycol monolaurate, glycerol monolaurate, lecithin, 1-substituted azepan-2-ones, particularly 1-N-dodecylcycloazepan-2-one (commercially available from Nelson Research & Development Co., Irvine, Calif., under the trade name Zone ®), SEPA ® (commercially available from Macrochem Co., Lexington, Mass.), alcohols (e.g., ethanol), detergents (such as Tergitol ®, Nonoxynol-9 ®, and TWEEN-80 ®), and the like. The transurethral preparation may additionally include one or more enzyme inhibitors effective to inhibit drug-degrading enzymes that may be present in the urethra. Other optional ingredients include excipients, preservatives (e.g., antioxidants), chelating agents, solubilizers (e.g., surfactants), and the like, as will be appreciated by those skilled in the art of pharmaceutical formulation and delivery.

Transurethral drug administration as explained in PCT application WO91/16021 can be carried out in a number of different ways using various urethral dosage forms. For example, the drug may be introduced into the urethra from a flexible tube, squeeze bottle, pump, or aerosol spray. The drug may also be contained in a coating, pellet or suppository that is absorbed, melted or bioerodable in the urethra. In certain embodiments, the drug is contained within a coating on the exterior surface of the penile insert body. Drug delivery devices for transurethral administration are described in US6,037,360 and PCT application WO 91/16021.

Urethral suppositories containing polyethylene glycol or polyethylene glycol derivatives can be used as urethral dosage forms and can be conveniently formulated using conventional techniques such as molding, thermoforming, and the like, as will be appreciated by those skilled in the art and as described in the relevant literature and pharmaceutical texts. For example: see Remington: the Science and practice of Pharmacy, 19 th edition (Easton, PA: Mack publishing Co., 1995), discloses a typical method for preparing pharmaceutical compositions in The form of urethral suppositories. It is also preferred that the urethral suppository contains one or more solubilizing agents (e.g., nonionic, anionic, cationic or amphoteric surfactants) effective to increase the solubility of the active ingredient in the polyethylene glycol or other transurethral carrier.

It is desirable to transport the active ingredient into a urethral dosage form that provides controlled or sustained release of the active agent. In such cases, the dosage form typically comprises a biocompatible, biodegradable material, typically a biodegradable polymer. Examples of such polymers include polyesters, polyalkyl cyanoacrylates, polyorthoesters, polyanhydrides, albumin, gelatin, and starch. These and other polymers may be used to form biodegradable microparticles capable of controlled and delayed drug release, for example, as explained in PCT application WO96/40054, thereby minimizing the required frequency of administration.

The method of administration within the urethra may involve a "active ingredient" transport mechanism such as iontophoresis, electroporation or phonophoresis. Devices and methods for delivering drugs in this manner are well known in the art. Iontophoresis-assisted drug delivery is described, for example, in PCT application WO 96/40054. Briefly, the active agent is driven through the urethral wall by means of an electrical current from an external electrode to a second electrode contained within or affixed to the urethral sound.

Pharmaceutical formulations of the tramadol material may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind described above.

Pharmaceutical compositions containing tramadol material and methods of making the pharmaceutical compositions have been described. See, for example, U.S. Pat. Nos. 3,652,589, 3,830,934, 5,223,541, 5,591,452, 5,601,842, 5,728,885, 6,017,963, 6,090,856, and 6,156,342, the entire disclosures of which are incorporated herein by reference. In addition, pharmaceutical compositions containing tramadol and its pharmaceutically acceptable salts are manufactured and widely sold. In the united states, (±) cis-2- [ (dimethylamino) methyl ] -1- (3-methoxyphenyl) -cyclohexanol hydrochloride for oral administration is commercially available as ULTRAM tablets from Ortho-McNeil Pharmaceutical, inc., Raritan, New Jersey 08869. Each ULTRAM contained 50mg (. + -.) cis-2- [ (dimethylamino) methyl ] -1- (3-methoxyphenyl) -cyclohexanol hydrochloride and a number of inactive ingredients (corn starch, hydroxypropylmethyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax). It will be appreciated that the commercial preparation of tramadol sold under the trade name ULTRAM consists of a mixture of the R, R and S, S isomers of tramadol hydrochloride.

Examples

Example 1: tramadol hydrochloride delaying ejaculation

The administration of 10mg and more than 10mg tramadol material by a male partner about 30-60 minutes prior to sexual intercourse significantly delayed ejaculation. For example, it was observed that a typical male subject delayed ejaculation by oral dose of 25mg tramadol hydrochloride (half of a 50mg ULTRAM tablet, Ortho-McNeil pharmaceutical, Inc., Raritan, N.J.) 30-60 minutes prior to intercourse by at least 10-15 minutes. Similar effects were observed at doses of 50-100 mg. However, drowsiness, dizziness, dry mouth and mild excitement (opioids) occur, whereas at 100mg dose ejaculation/hypersensitiveness is sometimes not observed. From these observations it can be concluded that a dose of 10-50mg tramadol material, preferably 15-35mg, most preferably 25mg, can significantly delay ejaculation and can be used to treat (prevent or alleviate) premature ejaculation.

Claims (12)

1. Use of a tramadol material in the manufacture of a medicament for delaying ejaculation in a male.

2. The use of claim 1 wherein the tramadol material is tramadol or a pharmaceutically-acceptable salt thereof.

3. The use of claim 2 wherein the tramadol material is (±) cis-tramadol or a pharmaceutically acceptable salt thereof.

4. The use of claim 3 wherein the tramadol material is the (+) -enantiomer of cis-tramadol or a pharmaceutically acceptable salt thereof.

5. The use of claim 3 wherein the tramadol material is the (-) -enantiomer of cis-tramadol or a pharmaceutically acceptable salt thereof.

6. The use of claim 3, wherein the tramadol material is (±) cis-tramadol hydrochloride.

7. The use of any one of claims 1-5, wherein the medicament is suitable for oral administration.

8. The use of claim 6, wherein the medicament is suitable for oral administration.

9. The use of any one of claims 1-5, wherein the male suffers from premature ejaculation.

10. The use of claim 6, wherein the male suffers from premature ejaculation.

11. The use of claim 7, wherein the male suffers from premature ejaculation.

12. The use of claim 8, wherein the male suffers from premature ejaculation.