MXPA99006585A - Dosage forms and method for ameliorating male erectile dysfunction - Google Patents

Abstract

The use of a pharmaceutical composition for oral administration comprising a carrier and active ingredient selected from a dopamine agonist, testosterone and mixtures thereof, the composition being in the form of a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity for the manufacture of a medicament for treatment of male erectile dysfunction.

Description

DOSAGE FORMS AND METHOD FOR IMPROVING MEN'S MALE DYSFUNCTION Field of the Invention The present invention relates to the dosage forms and methods for improving erectile dysfunction in male patients. More particularly, this invention relates to the use of dosage forms of rapid drug dispersion, for the improvement of erectile dysfunction in male patients.

Background of the Invention A normal erection occurs as a result of a coordinated vascular event in the penis. This is activated or neurally triggered and involves the vasodilation and relaxation of the smooth muscles in the penis and arterial supply vessels. The arterial inflow causes the aggravation of the substance of the corporeal cavernous tissue. The venous outflow is trapped by this enlargement, allowing sustained high blood pressures in the penis enough Ref.30714 to cause rigidity. The muscles in the perineum also help to create and maintain the rigidity of the penis. The _erection can be induced centrally in the nervous system by sexual thoughts or fantasies, and is usually reinforced locally by mechanisms of _reflection. Male erectile dysfunction (MED) is defined as the inability to achieve and sustain an erection sufficient for intercourse. In any case this may result from. physiological alterations (psychogenic), of physiological abnormalities in general ; (organic), neurological alterations (neurogenic), "hormonal (endocrine) deficiencies or a combination of the above. The effect of apomorphine has been studied 'on penile tumescence in male patients. These studies show that although the * apomorphine can actually induce an erection in a psychogenic male patient, the dose of apomorphine required to achieve a significant erectile response -usually accompanied by nausea or other serious undesirable side effects such as hypertension, -appearance of flushing and diaphoresis. However, the specific mechanisms by which apomorphine * acts to produce an erectile response in a human patient are still not fully understood. In addition, apomorphine has been shown to have very poor bioavailability. See, for example, Baldessarini et al., In Gessa et al., Eds. , Apomorphine and Other Dopa inomimetics, Basic Pharmacology, Vol. 1, Raven Press, N.Y. (1981), pp. 219-228. WO95 / 28930 discloses sublingual apomorphine dosage forms, usually containing from about 2.5 to about 10 milligrams of apomorphine, and dissolving them in water within a period of time of at least about 2 minutes but less than about 10 minutes, preferably about 3 minutes to about 5 minutes, it has been found to be effective in patients "Men suffering from psychogenic erectile dysfunction for the induction and maintenance of a sufficient erection for intercourse (ie vaginal penetration) without nausea or other effects "Undesirable laterals. Apomorphine is administered blingually, preferably about 15 to 20 minutes prior to sexual activity, and thus maintain a level in the circulating serum and a predetermined intermediate brain tissue level of apomorphine during the period of sexual activity. The previous sublingual apomorphine dosage forms are also suitable for selecting patients who complain of dysfunction erectile, to identify patients of psychogenic etiology. The patent ~ PCT / GB96 / 02020 describes one - > pharmaceutical composition for oral administration comprising a carrier and, as an active ingredient, a dopamine agonist, in which the composition is in the form of a rapidly dispersing dosage form, designed to release the active ingredient Rapidly in the oral cavity. It has been found that such rapid dispersion dosage forms promote pre-gastric absorption of the active ingredient, i.e.

Absorption of the active ingredient from this part of the ^ alimentary canal previous to the stomach. The term "pre-gastric absorption" thus includes buccal, sublingual, oropharyngeal and oesophageal absorption. The dopamine agonists absorbed by such pregastric absorption pass directly into the systemic circulatory system whereby the first step of metabolism in the liver is avoided. Consequently, the bioavailability of dopamine agonists absorbed in this way can also be increased.

This means that the dosage of such dopamine agonists can be reduced while the desired beneficial effects are still produced and this increase -in the dosage will lead to a reduction -corresponding side effects unwanted. The pharmaceutical compositions described in PCT / GB96 / 02020 were developed for the treatment and / or evaluation of Parkinson's disease. US-A-5135752 discloses a matrix for a buccal dosage form that melts in the oral cavity at body temperature, but will not deform spontaneously at the higher temperatures found in shipping and storage, which comprise 75 to 90% polyethylene glycol of low MW, 0 to 4% polyethylene glycol of medium to high MW, 0 to 4% of the long chain saturated carboxylic acid, 0.1 to 4% polyethylene oxide (MW 100,000 to 5,000,000) and to 20% colloidal silica Examples 2 and 3 describe oral tablets containing methyltestosterone which dissolves in the oral space of volunteers for a period from 3 to 12 minutes US-A =? 4877774 discloses tablets which can be administered by contact with the mucosa comprising crystalline complexes of spheroidal hormones with gamma-cyclodextrin.When administered sublingually, the complete dissolution of the tablets occurred during a period of for 10 to 15 minutes. It has now been found that dosage forms for rapid dispersion containing the dopamine agonist, such as apomorphine, can be used to treat male erectile dysfunction. In accordance with the present invention there is provided the use of a pharmaceutical composition for oral administration comprising a carrier and an active ingredient selected from a dopamine agonist, testosterone and mixtures thereof, the composition being in the form of a rapid, solid dispersion dosage, which disintegrates within 1 to 60 seconds of being placed in the oral cavity, for the manufacture of a medicament for the treatment of male erectile dysfunction. - The use of a solid rapid dispersion form has several advantages over the use of conventional sublingual tablets. The efficiency of the rapid dispersion dosage form allows low doses to be employed whereby undesirable side effects, particularly nausea and vomiting, are reduced. Dosage forms act more "Quickly than sublingual tablets which allows the dosage to be" "taken when required rather than a considerable period of time before sexual activity." This is both psychological and -socially preferable to sucking a tablet during -several minutes prior to sexual activity. There is a faster displacement of action since the active ingredient is absorbed quickly instead of being absorbed for a period of time -dragged on. The fastest displacement avoids "painful persistent erection.The rapid onset and the -action is less likely to induce tolerance to the dopamine agonist. An example of a rapid dispersion dosage form is described in U.S. Pat. No. 4855326 in which a melt-spun carrier agent, such as sugar, is combined with an active ingredient and the resulting mixture spun into a "syrup yarn candy" -like preparation. The spun yarn candy product is then compressed into a highly porous solid dosage form, which disperses rapidly. The U.S. patent No. 5120549 describes a system "Fast dispersion matrix which is prepared by first solidifying a matrix formation system dispersed in a first solvent and subsequently • contacting the solidified matrix with a "second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the elements of ^ formation of the matrix and the active ingredient that is "substantially insoluble in the second solvent, so .which the first solvent is substantially removed "Driving to a fast dispersion matrix" U.S. Patent No. 5079018 describes a form "of rapid dispersion dosing which comprises Tina porous skeleton structure of a gel or foam "Hydratable, soluble in water, which forms the material that has - is hydrated with water, stiffened in the hydrated state with a stiffening agent and dehydrated with a liquid organic solvent at a temperature of about 0 ° C or lower to leave spaces in place of the hydration liquid.; International Published Application No. WO 93/12769 (PCT / JP93 / 01631) describes very low density rapid dispersion dosage forms formed : gelling, with agar, aqueous systems containing the ^ 'elements of formation of the matrix and the active ingredient, and then removing the water by means of pressurized air or vacuum drying. The U.S. Patent No. 5298261 discloses rapid dispersion dosage forms which comprise "a matrix network collapsed or partially contracted that has been dried to vacuum "above the shrinkage temperature of the matrix, however, the matrix is preferably dried at least partially below the : equilibrium freezing point of the matrix. The International Application Published No. WO -91 / 04757 (PCT / US90 / 05206) discloses fast dispersing dosage forms containing an effervescent disintegrating agent designed to effervesce "during contact with saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity." U.S. Patent No. 5,595,761 discloses a particulate support matrix for use in the oral cavity. ^ manufacture of a rapidly dissolving tablet, comprising: a first polypeptide component having a net charge when in solution, for example unhydrolyzed gelatin; a second polypeptide component having a net charge of the same sign as the net charge of the first polypeptide component when in solution _ for example hydrolyzed gelatin; and a volumetric agent, and wherein the first component of the polypeptide and the second component of the polypeptide together, comprise approximately 2% to 20% by weight of the particulate support matrix and wherein the volumetric agent comprises approximately 60% - at 96% by weight of the particulate support matrix; and wherein the second component of the polypeptide has a solubility in the aqueous solution larger than that of the first component of the polypeptide and wherein the ratio of the first component of the - polypeptide with respect to the second component of The polypeptide is from about 1: 1/2 to about 1:14; and wherein when the support matrix is introduced in an aqueous environment, the support matrix is disintegrable in the range of less than about 20 seconds.

The term "rapid dispersion dosage form" therefore encompasses all types of dosage forms described in the preceding paragraphs. However, it is particularly preferable that the fast dispersion dosage form be of the type described - in the U.K Patent No. 1548022, that is, a rapid, solid dispersion dosage form, comprising • "a network of the active ingredient and a dispersible carrier "in water or water soluble which is inert towards the active ingredient, the network that has been obtained" sublimated the solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent ~ The composition of the invention disintegrates in the range of 1 to 60 seconds, more preferably 1 to seconds, especially 1 to 10 seconds and -particularly 2 to 8 seconds, of being placed in the oral cavity. In the case of the preferred type of the rapid dispersion dosage form described above, the composition will preferably contain, in addition to the - Active ingredient, the formation agents of the matrix and the secondary components. Matrix-forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as gelatins, dextrins "-and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers - such as polyvinyl pyrrolidone; and complexes "polypeptide / protein or polysaccharide such as complexes ^ of acacia-jelly. * _ 'Other suitable matrix forming agents for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids that have 'from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine. One or more matrix forming agents can be incorporated into the solution or suspension prior to solidification. The agent forming the matrix may be present in addition to a surfactant or for the exclusion of a surfactant. In addition to the formation of the matrix, the agent forming the matrix can help maintain the dispersion of any active ingredient within the solution or suspension. This is especially useful in the case of active agents that are not sufficiently soluble in the Jagua and, therefore, should be suspended instead of being dissolved. Secondary components such as preservatives, antioxidants, surfactants, viscosity improvers, coloring agents, flavoring agents, pH modifiers, sweeteners or masking agents - flavor can also be incorporated into the composition. Suitable coloring agents include red, black and yellow iron oxides and FD & C such as FD & C blue No. 2 and FD & Red C No. 40 available from Ellis & Everard. Suitable seasoning agents include flavors of mint, raspberry, sweet stick, orange, lemon, grapefruit, caramel, vanilla, cherry and grape and combinations of debris. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated active substances It is preferred that the dopamine agonist be selected from 5, 6, 6a , 7-tetrahydro-6-methyl-4H-dibenzo [de, g] quinoline-10, 11-diol (apomorphine), 5, 6, 6a, 7-tetrahydro-6-propyl-4H-dibenzo [de, g] quinoline-10, 11-diol (N-propylnoraporphin), (5 'a) -2-bromo-12' -hydroxy-2 '- (1-methylethyl) -5' - (2-methylpropyl) ergotaman-3 ', 6 ', 18-trione (bromocriptine), 1- [(β-allylergolin-8β-yl) carbonyl] -1- [3- (dimethylamino) propyl] -3-ethylurea (cabergoline), N' - [(8a) -9, 10-didehydro-6-methylergolin-8-yl] -N, N-diethylurea (lisuride), [[(8β) -1,6-dimethylergolin-8-yl] methyl] -carbamic acid phenylmethyl ester (metergoline), (4aR) -trans-3, 4, 4a, 5, 6, 10b-hexahydro-4-propyl-2H-naft [1, 2-b] -1,4-oxazin-9-lo (naxagolide), - [(methylthio) methyl] -6-propylergoline (pergolide), 2- [4- (1,3-benzodioxol-5-ylmethyl) -1-piperazinyl] pyrimidine (pyribedyl), 4- [2- (dipropylamino) ethyl] ] indolin-2-one (ropinirole), N, N-diethyl-N '- [(8a) -6-methylergolin-8-yl] urea (terguride) and (+) -N, N-diethyl-N' - [(3R, 4aR * , 10aS *) -1,2,3,4, 4a, 5, 10, 10a-octahydro-6-hydroxy-l-propylbenzo [g] quinolin-3-yl] sulfamide (quinagolide), salts thereof and mixtures from the same. More preferably, the dopamine agonist is apomorphine or a salt, preferably an acid addition salt thereof, especially the hydrochloride salt. It is also preferred that the dopamine agonist be present in the composition in an amount from 0.05 to 10 mg, preferably 0.05 to 5 mg. The ability of dopamine receptor agonists to cause penile erections in rodents has been reported in a review by Lal (Prog. Neuro-Psychopharmacol. &Biol. Psychiat., 1988, vol.12, pp. 117-164) . It has been said that the dose, and presumably the plasma concentration, is critical with the lower doses of apomorphine or bromocriptine more effective than the higher doses. It has been postulated that the biological response is mediated by the activation of the central D2 Preceptors, since it has been shown that domperidone, a peripheral dopamine antagonist, does not interfere with this response. Therefore, it is believed that plasma levels of apomorphine which induce stimulation of the dopamine receptor in Parkinsonian patients should also be effective in the treatment of male erectile dysfunction. However, the adverse side effects, observed with apomorphine, of nausea, hypotension and sedation should be minimized by the use of as low a dose as possible.

Heaton et al, (1995), Urology, 45: 200-206 reports patients with MED who were given liquid apomorphine ^ sublingually (10 mg and 20 mg dose), a sublingual tablet (5 mg) or a sublingual tablet of ^ Slow dissolution (3 mg and 4 mg). Plasma levels were not recorded, but all doses and dosage forms were active, although side effects were a problem in some groups. Van Laar et al, 1996, Movement Disorders, 11: 634-638 reported peak plasma levels after administration of sublingual apomorphine tablets (10 mg). Maximum plasma levels (ng / ml) were 7.0 + 0.8 in one experiment and 7.4 + 1.0 in another. In a third experiment, the sublingual tablets were acidified with ascorbic acid, - the plasma level was slightly reduced to 4.3 + 1.5. Since the efficacy in the Heaton et al document was observed at doses as low as 3 mg, the maximum plasma level to achieve this (based on the dose corrected data from the van Laar document) could be about from 1.3 to 2.2 ng / ml. A study on the therapeutic window of apomorphine in 3 groups of Insonian Par patients, by the use of a gradual administration of apomorphine by intravenous infusion, demonstrated that it is possible to separate the onset of pharmacological activity and side effects. Clinical efficacy, in the treatment of symptoms of Parkinson's disease, was observed at median serum apomorphine levels, above 3.8-5.0 ng / ml while adverse effects were observed at serum apomorphine levels medium, above 12.2-18.5 ng / ml. These reports may suggest that the treatment of MED with apomorphine should generally be directed to plasma levels of at least 1 to 5 ng / ml and should not be allowed to exceed 10 ng / ml. The precise amount of the active ingredient will depend on the chosen dopamine agonist. Typical dosage ranges for the aforementioned dopamine agonists are as follows: Apomorphine 1-20 mg, preferably 1-10 mg N-propylnoraporphin 1-20 mg, preferably 1-10 mg Bromocriptine 0.5-10 mg, preferably 0.5-5 mg = Cabergoline 0.05-2 mg, preferably 0.05-0.5 mg L Liissuurriiddee 0.05-2 mg, preferably 0.05-0.4 mg Metergoline 4-20 mg, preferably 4-8 mg Naxagolide 0.1-10 mg, preferably 0.1-5 mg Pergolide 0.05-1 mg, preferably 0.05-0.5 mg Piribedil 1-20 mg, preferably 1-10 mg R Rooppiinniirroollee 0.25-20 mg, preferably 0.25-5 mg Terguride 1-10 mg, preferably 1-5 mg Quinagolide 0.1-5 mg, preferably 0.1-1 mg Dopamine agonists can produce side effects such as nausea and vomiting. The composition used in the invention can be administered in conjunction with an antiemetic. The antiemetic can conveniently be administered in the same composition as the dopamine agonist. Alternatively, the anti-emetic can be administered separately from the dopamine agonist by any of the oral or parenteral routes of administration, for example, by means of tablets, capsules, suspensions, suppositories, infusions, injections, etc., in a range of adequate time on "which may be before, after or simultaneously with the administration of the dopamine agonist, It is particularly preferred that the antiemetic be formulated in a fast dispersing dosage form of the type described above as contemplated, such that a form of rapid dispersion dosage of the antiemetic could have many of the advantages associated with such formulations, such as increased bioavailability, dose reduction, ease of administration, etc., as described above, although the precise advantages observed will depend on the nature of the It is preferred that the antiemetic be present in the composition in an amount of from 1 to 60 mg, however, the precise amount of the antiemetic to be administered to the patient will depend on the antiemetic that is selected. anti-histamines, such as trimethobenzamide; Peripheral dopamine ntagonists, such as 5-chloro-1- [1- [3- (2,3-dihydro-2-oxo-lH-benzimidazol-1-yl) propyl] -4-piperidinyl] -1, 3- dihydro-2H-benzimidazol-2-one (domperidone) and salts thereof, and serotonin (5-HT3) receptor antagonists, such as endo-1-methyl-N- (9-methyl-9-azabicyclo) [3.3.1] non-3-yl) -lH-indazole-3-carboxamide (granisetron), 1, 2, 3, 9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazole-1) -yl) methyl] -4H-carbazol-4-one (ondansetron) and indole-3-carboxylate of lOaH, 5aH-tropan-3a-yl (tropisetron) and the salts thereof. Of these, domperidone is especially preferred. Typical dosage ranges for the antiemetics mentioned above are as follows: Domperidone 20-120 mg, preferably 30-60 mg Granisetron 1-10 mg, preferably 1-3 mg Ondansetron 4-32 mg, preferably 4-8 mg Tropisetron 1- 10 mg, preferably 1-5 mg -N- [p [dimethylamino-. 750-1000 mg ethoxy] benzyl] -3,4,5, trimethoxybenzamide Apomorphine is an alkaloid of opium. Therefore, as mentioned above, when apomorphine or another opioid alkaloid or synthetic derivative is selected as the dopamine agonist, additional side effects may occur, such as sedation, respiratory depression, hypotension, bradycardia, perspiration and yawning. However, it has been found that all side effects can be treated by the administration of an opioid antagonist. : in conjunction with the opioid dopamine agonist. The opioid antagonist can be administered conveniently in the same composition as the agonist 'of dopamine. Therefore, such a composition also - "may include an antiemetic in addition to the agonist of the 3-phopamine and the opioid antagonist although this is not essential since the opioid antagonist also counteracts some of the emetic effects of the dopamine agonist. Alternatively, the opioid antagonist can be administered separately from the dopamine agonist by any of the usual oral or parenteral routes of administration in a suitable time interval which can be before, after or simultaneously with the administration of the dopamine agonist. It is particularly preferred that the opioid antagonist be formulated in a "rapid dispersion" dosage form of the type described above because it is contemplated that such a rapidly dispersing dosage form of the opioid antagonist could exhibit many of the advantages associated with such formulations, ease of administration, etc., as described above, although the precise advantages observed will depend on the nature of the opioid antagonist chosen. It is preferred that the opioid antagonist be present in the composition in an amount of 0.5 to 100 mg, more preferably 0.5 to 50 mg. However, the precise amount of the opioid antagonist to be administered to the patient will depend on the opioid antagonist that is chosen. Suitable opioid antagonists include 4,5-epoxy-3,14-dihydroxy-17- (2-propenyl) morphinan-6-one "(naloxone) and 17- (cyclopropylmethyl) -4,5-epoxy- 3, 14-dihydroxymorfinan-6-one (naltrexone) and the salts, particularly the acid addition salts and, especially, the hydrochloride, thereof. A typical dose range for naxolone is 0.25-10 mg, and for naltrexone it is 10-100 mg.

Alteration in endocrine function -represents approximately a third of the total organic causes of male erectile dysfunction as reported in Aversa et al, 1995, Mol Androl 7, 3-4 The administration of testosterone in the dosage form rapid dispersion aids in the improvement of this condition.A typical dosage range for oral administration of testosterone is from 10 to 100 mg, preferably 10 to 50 mg.The composition may contain testosterone alone or in combination with a dopamine agonist. The invention is further illustrated by the following Examples.

Example 1 Preparation of a fast dispersing dosage form of apomorphine (a) Preparation of a 2.0% dispersion of apomorphine hydrochloride Gelatin (792 g) and mannitol (594 g) are dispersed in a portion of purified water (16 kg) by mixing thoroughly in a vacuum mixer vessel.

The mixture was then heated to 40 ° C + 2 ° C and homogenized for 10 minutes. The mixture is gradually cooled to room temperature (20-24 ° C). When it is cooled, apomorphine hydrochloride _ (360 g) is added. The mixture is homogenized to ensure dissolution of the drug. Citric acid (166.32 g) is gradually added with stirring, to adjust the pH of the solution to 3.0. The remaining water (87.68 g) is added to the mixer and the volumetric mixture is homogenized to ensure that the dissolution is complete. (b) Preparation of units of 10 mg of apomorphine hydrochloride 500 g of the 2.0% dispersion of apomorphine hydrochloride formed in (a) above are dosed into each of a series of preformed ampoule cavities having a cavity diameter of 16 mm. The laminate of the ampoule comprised 200 μm of PVC coated with 40 g per square meter of PVdC. The product was immediately frozen in a liquid nitrogen freezing tunnel. The frozen product was then stored below -20 ° C for a minimum of 12 hours prior to freeze drying in a freeze dryer using a drying temperature of + 10 ° C and a chamber pressure of 0.5 bar. The freeze dried units were then inspected for the presence of critical defects and the rest of the batch is sealed with a cover aluminum foil consisting of a sheet / paper laminate (20-μm aluminum). Each blister was then coded with a batch number and overwrapped in a preformed pouch by placing the ampoule in the pouch and sealing the open end of the pouch completely. Each pouch was then labeled with the name of the product, the batch number, the date of manufacture and the name of the supplier. Each dosage unit had the following composition.

* Means removed during the lyophilization process, Example 2 The following formulation was prepared using the process described in Example 1. * means removed during the lyophilization process.

Example 3 Comparative pharmacokinetic study The objective of this study was to compare the bioavailability of the different rapid dispersion formulations of apomorphine hydrochloride, prepared by the method of Example 1, following administration to six healthy volunteers. Due to the emetic properties of apomorphine, the subjects were pretreated with the anti-emetic domperidone. Following the two days of pretreatment with domperidone, the subjects were randomly divided to receive the following apomorphine treatments: 10 mg of Apomorphine HCl (one unit of Example 1) mg of Apomorphine HCl (one unit of Example 2) Blood samples for pharmacokinetic analysis were taken prior to dosing and at six hour intervals after each dose of apomorphine. The results are reported in Figure 1 of the attached drawings. It will be noted that the apomorphine is rapidly absorbed from both formulations of the fast dispersing dosage form, reaching a maximum concentration in the plasma after approximately 30 minutes. The following examples further exemplify the formulations which can be prepared using the described example. in Example 1: Example 4 ignifies removed during the lyophilization process.

Example 5 ignifies removed during the lyophilization process.

Example 6 means removed during the lyophilization process, Example 7 Example 8 means removed during the lyophilization process, Example 9 means removed during the lyophilization process Example 10 means removed during the lyophilization process.

Example 11 ignifies removed during the lyophilization process.

Example 12 means removed during the lyophilization process.

Example 13 ignifies removed during the lyophilization process.

Example 14 ignifies removed during the lyophilization process.

Example 15 ignifies removed during the lyophilization process Example 16 * means removed during the lyophilization process It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. - Having described the invention as above, property is claimed as contained in the following

Claims (2)

1. CLAIMS 1. The use of a pharmaceutical composition for oral administration, comprising a carrier and the active ingredient selected from a dopamine agonist, testosterone and mixtures thereof, the composition is in the form of a dosage form of rapid, solid dispersion, which disintegrates in the course of 1 to 60 seconds of being placed in the oral cavity, for the manufacture of a medicament for and the treatment of male erectile dysfunction.
2. 2. The use according to claim 1, wherein the composition is in the form of a fast dispersing dosage form comprising a network of the active ingredient and a water-soluble or water-dispersible carrier, which is inert towards the active ingredient, the network that has been obtained by sublimating the solvent from a composition in the solid state, this composition comprises the active ingredient and a solution of the carrier in a solvent. a 3. The use according to claim 1, wherein the composition comprises a 9. The use according to claim 8, wherein the opioid antagonist is present in an amount from 0.5 to 100 mg. 10. The use according to claim 1, wherein the active ingredient comprises testosterone. 11. The use according to claim 10, wherein the testosterone is present in an amount of 10 to 100 mg. 12. A method of treating male erectile dysfunction, characterized in that it comprises administering to the oral cavity of a patient a dopamine and / or testosterone agonist in a form of "Rapid dispersion, which disintegrates within the time interval of 1 to 60 seconds of being placed in the oral cavity. 13. A method according to claim 12, characterized in that it comprises the "administration of a pharmaceutical composition as defined in any of claims 2 to 10.