AU2003239038A1

AU2003239038A1 - New sexual-dysfunction-compound-containing rapid-onset pharmaceutical formulations comprising cocoa powder and use thereof

Info

Publication number: AU2003239038A1
Application number: AU2003239038A
Authority: AU
Inventors: Nils-Olof Lindberg; Katarina Lindell; Alice C. Martino; Kristina Thyresson
Original assignee: Pharmacia AB
Current assignee: McNeil AB
Priority date: 2002-08-05
Filing date: 2003-06-18
Publication date: 2004-02-23
Anticipated expiration: 2023-06-18
Also published as: SE0202365D0; CN1674866A; RU2005102835A; IL166031A0; NZ537520A; RU2312665C2; EP1539096A1; AR040797A1; JP2005539008A; AU2003239038B2; MXPA05000978A; CA2495527C; ZA200500051B; BR0313224A; WO2004012702A1; CN1674866B; CA2495527A1; TW200418470A

Description

WO 2004/012702 PCT/SE2003/001022 New sexual-dysfunction-compound-containing rapid-onset pharmaceutical formulations comprising cocoa powder and use thereof Field of the Invention This invention relates to novel rapid-onset orally administered pharmaceutical compositions of sexual dysfunction (SD) compounds and use thereof. More particularly, 5 the present invention relates to compositions comprising SD compounds and cocoa powder, methods to prepare said compositions, and to methods for using said compo sitions in sexual dysfunction therapy, including enhancement of sexual desire, and interest or performance. Background and Prior Art 10 Orally administered therapies for sexual dysfunction, in particular for male erectile disorder, are well known. See for example Gingell & Lockyer (1999), "Emerging pharmacological therapies for erectile dysfunction", Expert Opinion on Therapeutic Patents 9, 1689-1696. Drugs in use or in development include phospho diesterase type 5 (PDE5) inhibitors, e.g., sildenafil citrate, available under the trademark 15 Viagra@ of Pfizer, cyclic AMP activators, x-adrenergic antagonists, e.g., yohimbine, and dopaminergic agonists, e.g., apomorphine. International Patent Publication No. WO 00/40226 discloses compounds useful in treating sexual dysfunction in men and women, these compounds being of formula (I) R X

R

3 N 20 (B)n (I) or pharmaceutically acceptable salts thereof, wherein R1, R2 and R are the same or different and are H, C 1

-

6 alkyl (optionally phenyl substituted), C 3 - alkenyl or alkynyl or C 3

-

10 cycloalkyl, or where R 3 is as above and R' and R 2 are cyclized with the attached N atom to form 25 pyrrolidinyl, piperidinyl, morpholinyl, 4-methylpiperazinyl or imidazolyl groups; X is H, F, Cl, Br, I, OH, C 1

.

6 alkyl or alkoxy, CN, carboxamide, carboxyl or

(C

1

-

6 alkyl)carbonyl; WO 2004/012702 PCT/SE2003/001022 2 A is CH, CH 2 , CHF, CHCI, CHBr, CII, CHCH 3 , C=O, C=S, CSCH 3 , C=NH,

CNH

2 , CNHCH 3 , CNHCOOCH 3 , CNHCN, S02 or N; B is CH, CH 2 , CHF, CHCI, CHBr, CHI, C=O, N, NH or NCH 3 , and n is 0 or 1; and 5 D is CH, CH2, CIF, CHCI, CHBr, CHI, C=O, 0, N, NH or NCH 3 ; with various provisos indicated therein. WO 00/40226 further contemplates prescription of the drug (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5-ij]-quinolin-2(1H)-one (Z)-2-butenedioate (1:1) to male and female subjects at a dose of 1-3 mg, to be taken 0.5-1 h before engaging in sexual activity, and indicates that at such a dose and timing 10 of administration the drug is therapeutically effective. No information is provided as to the route of administration or nature of dosage form. The class of compounds proposed for treatment of sexual dysfunction in WO 00/40226 was earlier disclosed in U.S. Patent No. 5,273,975 to Moon et al. to have therapeutically useful central nervous system activity. Certain compounds of the above 15 class are the subject of a paper by Heier et al. (1997), "Synthesis and biological activi ties of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites", J. Med. Chem. 40, 639-646. In spite of the availability of sildenafil citrate, apomorphine and other drugs in orally deliverable form, there remains a need for dosage forms of a therapeutic agent for 20 treating sexual dysfunction in men and women, having one or more of the following benefits: (a) rapid absorption leading to rapid onset of therapeutic effect; (b) reduced unpleasantness of taste; (c) no requirement to be taken with water; 25 (d) high bioavailability for substances with high first pass metabolism; (e) provision for an association of pleasure; and (f) no immediate patient-perceived association with medicines. In one aspect, sexual dysfunction as addressed herein comprises sexual disorders including, without limitation, hypoactive sexual desire disorder, female sexual arousal 30 disorder, male erectile disorder, female orgasmic disorder and male orgasmic disorder, all as defined in Diagnostic and Statistical Manual of Mental Disorders. 4th edition (DSM-IV) (1994), and DSM-IV Guidebook (1995), both published by American Psychiatric Press, Inc., Washington, DC. In another aspect, sexual dysfunction as addressed herein comprises diminish- WO 2004/012702 PCT/SE2003/001022 3 ment of sexual desire, interest and/or function arising from primary diseases or condi tions that are not sexual disorders in a strict sense. Such diseases and conditions include, without limitation, epilepsy, craniopharyngioma, hypogonadism and general psychiatric disorders such as depression. Sexual dysfunction as addressed herein additionally com 5 prises sexual deficiencies following hysterectomy and/or oophorectomy as well as those arising as side effects of medication. European Patent Application No. 0 960 621 discloses that sildenafil citrate has an unpleasant taste that cannot be completely masked by flavoring agents, and proposes rapidly disintegrating oral dosage forms of sildenafil in the form of its free base, which 10 has extremely low solubility in water and is virtually tasteless. International Patent Publication No. WO 99/66933 proposes intranasal admini stration of sildenafil, illustratively in the form of salts such as the hydrochloride salt, for treatment of erectile dysfunction. Dosage forms proposed include a nasal spray and an aqueous nasal gel. Aqueous solutions are said to be preferred. Rapid onset of therapeu 15 tic effect is contemplated; however, no solution is suggested to the problem of unplea sant taste arising from drainage of the drug into the mouth. Further, intranasal admini stration is not a sufficiently discreet way of administering SD compounds. Dosage rates are contemplated in WO 99/66933 to be lower than are required when the drug is orally administered; a 30 mg dose of sildenafil hydrochloride in the form of a nasal spray is 20 exemplified. Also exemplified is a nasal spray formulation delivering 30 mg of sildena fil hydrochloride and 1 mg of apomorphine hydrochloride. European Patent Application No. 0 992 240 discloses cGMP-PDE inhibitory compounds said to be useful in treatment of male erectile dysfunction and proposes transmucomembranous administration, for example in the form of sublingual prepa 25 rations, of such compounds. International Patent Publication No. WO 00/76509 also proposes nasal admini stration of apomorphine, illustratively as its hydrochloride salt. Heaton (1996), "Buccal apomorphine", J. Urol. 155, 49, reports efficacy of a sublingual formulation of apomorphine in treatment of male non-organic erectile dys 30 function. U.S. Patent No. 5,985,889 to El-Rashidy et al proposes sublingual administra tion of apomorphine for treatment of male psychogenic erectile dysfunction. Various sublingual tablet formulations of apomorphine hydrochloride are disclosed therein. International Patent Publication No. WO 00/35457 proposes use of apomorphine WO 2004/012702 PCT/SE2003/001022 4 for treatment of male organic, e.g., vasculogenic, erectile dysfunction, and exemplifies use of a sublingual tablet formulation of apomorphine hydrochloride. WO 00/35457 further suggests that nausea, a common side effect of apomorphine, can be controlled by inclusion of an anti-emetic agent such as nicotine in the formulation. 5 U.S. Patent No. 6,121,276 to El-Rashidy & Ronsen discloses flavored sublingual tablets containing apomorphine hydrochloride and nicotine. International Patent Publication No. WO 01/49292 discloses sublingual tablets of apomorphine providing prolonged release of the drug, said to be useful in treatment of Parkinson's disease. 10 International Patent Publication No. WO 00/42992 discloses a dosage unit com prising a water-soluble hydrocolloid and sildenafil citrate in a mucoadhesive film said to be suitable for application to the oral mucosa. Pharmacokinetic data presented in WO 00/42992 indicate no faster absorption into the bloodstream with sublingual application of such a film than with a commercial tablet formulation of sildenafil citrate (Viagra@) 15 at the same dosage. International Patent Publication No. WO 01/10406 discloses compositions said to be suitable for a wide range of routes of administration of sildenafil citrate, including buccal and sublingual routes. Preferred compositions disclosed are said to comprise a solution, gel, semisolid, suspension, metered dose device, transdermal patch or film. 20 International Patent Publication No. WO 02/05820 discloses film dosage forms comprising sildenafil citrate. These dosage forms are prepared by mixing a solid dis persion of sildenafil citrate and a water soluble sugar with a hydrocolloid and optionally other ingredients, and are said, upon placement on a mucosal surface, to form a coating that subsequently disintegrates and dissolves to release sildenafil. 25 International Patent Publication No. WO 02/041840 discloses the use of cocoa powder as a flavorant, though not a taste-masker, in chewing gums for sildenafil citrate. International Patent Publication No. WO 00/30641 discloses the use of cocoa powder as a flavorant in oral compositions containing nicotine. International Patent Publication No. WO 99/66916 discloses the use of chocolate 30 flavor in oral compositions containing apomorphine. Chocolate, which is very different from cocoa powder as such, has very rarely been used as an ingredient in pharmaceutical products on the market, hitherto only in laxatives. One example is Ex-Lax* being chocolated laxative pieces marketed by WO 2004/012702 PCT/SE2003/001022 5 Novartis comprising sennosides. Purex, a laxative wherein phenolphthalein was formulated with chocolate, was marketed in the 1950s. It has now surprisingly been found that a rapid onset of orally administered pharmaceutical compositions of SD compounds is achieved concomitantly with suffi 5 cient taste masking of badly tasting ingredients, such as buffering agents, through the use of SD-compound-containing formulations comprising cocoa powder as filler/diluent and taste masking or flavoring agent and agent for providing a smooth texture. No similar formulations have been disclosed hitherto. Summary of the invention 10 The present invention provides an orally administered rapid-onset pharmaceu tical composition useful for treatment of sexual dysfunction, stimulation of sexual activity and enhancement of sexual desire, interest and performance in men and women. The composition is a dosage form comprising a therapeutically or sexual-stimulatorily effective amount of one or more SD compounds. A "therapeutically effective amount" 15 herein is an amount sufficient to improve sexual desire, interest or performance in a subject having a sexual dysfunction condition. A "sexual-stimulatorily effective amount" herein is an amount sufficient to improve sexual desire, and interest or per formance in a subject whether or not the subject has a sexual dysfunction condition. Suitable such SD compounds are chosen from the below agents, but are not 20 limited thereto: A compound of formula (I) Ri N R2 X R N -A (B)' (I) or a pharmaceutically acceptable salt thereof, wherein R', R 2 and R 3 are the same or different and are H, C 1

.

6 alkyl (optionally phenyl 25 substituted), C 3 - alkenyl or alkynyl or C3-10 cycloalkyl, or where R 3 is as above and R1 and R 2 are cyclized with the attached N atom to form pyrrolidinyl, piperidinyl, morpholinyl, 4-methylpiperazinyl or imidazolyl groups; X is H, F, Cl, Br, I, OH, C 1

-

6 alkyl or alkoxy, CN, carboxamide, carboxyl or (C1.

WO 2004/012702 PCT/SE2003/001022 6 6 alkyl)carbonyl; A is CH, CH 2 , CHF, CHCl, CHBr, CHI, CHCH 3 , C=O, C=S, CSCH 3 , C=NH,

CNH

2 , CNHCH 3 , CNHCOOCH 3 , CNHCN, SO 2 or N; B is CH, CH 2 , CHF, CHCl, CHBr, CHI, C=O, N, NH or NCH 3 , and n is 0 or 1; 5 and D is CH, CH 2 , CIF, CHCI, CHBr, CHI, C=O, 0, N, NH or NCH 3 ; said compound of formula (I) or salt thereof being water-soluble. A suitable dosing is from around 0.1 mg to around 10 mg per dose. A compound of formula (II) H CH3 N HN 10 X (II) wherein X is 0 or S, and pharmaceutically acceptable salts thereof. A suitable dosing is from around 0.05 mg to around 10 mg per dose. A compound chosen from phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil in base form and pharmaceutically'acceptable salts thereof, including sildena 15 fil citrate marketed under the trademark Viagra@, vardenafil marketed as Nuviva and tadalafil marketed as Cialis*. Suitable dosing is from around 5 mg to around 100 mg per dose. A compound chosen from dopaminergic agonists, such as apomorphine, with or without addition of anti-emetic agents. Suitable dosing is from 0.5 mg to around 10 mg 20 per dose. A compound chosen from noradrenergic alpha antagonists or o-adrenergic anta gonists, such as phentolamine mesylate marketed as Vasomax, yohimbine and prazosin. A compound chosen from cyclic AMP activators. Pharmaceutically acceptable salts, complexes and mixtures of the above com 25 pounds are also useful. It is preferred that the amount of the SD compound, salt, complex or mixture thereof be lower than an amount causing significant side effects. A particularly useful dosage form of the present invention is a formulation that disintegrates or melts in the mouth without need for drinking water or other fluid.

WO 2004/012702 PCT/SE2003/001022 7 Preferred dosage forms are tablets, sublingual tablets and lozenges. Chewing gums are not preferred dosage forms. The invention is adapted for discreet self-administration. By "discreet self administration" herein is meant self-administration shortly prior to sexual activity in a 5 way that does not draw attention of a sexual partner to, or emphasize, the existence of a sexual dysfunction, a need for therapy or a need or desire for enhancement of sexual performance. The combination of discreetness and rapid onset that is permitted by the present invention provides a benefit in spontaneity; by contrast, prior art compositions for treating sexual dysfunction can be seriously compromised in their effectiveness if 10 their self-administration requires premeditation and/or cannot be done discreetly, such self-administration being thereby not conducive to spontaneity. Also provided by the present invention are methods of use of compositions of the present invention for treatment of sexual dysfunction and for enhancement of sexual desire, and interest or performance, and a method of use of a composition of the inven 15 tion for preparing a medicament. Other features of this invention will be in part apparent and in part pointed out hereinafter. Compositions for the therapeutic delivery of SD compounds are provided. Said compositions comprising SD compounds provide rapid transmucosal absorption in the oral cavity. 20 The SD compounds of the present invention include the parent forms as well as salts and complexes of the parent forms. An object of the invention is to provide new pharmaceutical compositions of SD compounds for uptake buccaly or by other mucosa in the oral cavity, especially such compositions comprising a large percentage of cocoa powder. 25 A second object of the invention is to provide methods for preparing said com positions. A third object of the invention is methods for using said formulations in sexual dysfunction therapy, including enhancement of sexual desire, and interest or perfor mance. 30 Further objects of the invention will become apparent to one skilled in the art and still other objects will become apparent hereinafter from the specification and claims. The main advantages provided by a composition according to the present inven tion are: WO 2004/012702 PCT/SE2003/001022 8 1) It allows for rapid onset of the pharmacological effect; 2) It provides for good taste masking properties due to the presence of cocoa powder; 3) It does not require any water for swallowing; 4) It provides for possible high bioavailability for substances with high first pass meta 5 bolism; 5) It provides for an association of pleasure; 6) It does not give an immediate patient-perceived association with medicines (traditional tablets). Detailed Description of the Invention 10 It is the primary object of the present invention to provide rapid-onset pharma ceutical compositions useful for treatment of sexual dysfunction, stimulation of sexual activity and enhancement of sexual desire, interest or performance in men and women. The term "rapid-onset" means that a therapeutic effect is achieved within a short period of time, for example less than about 1 hour, preferably less than 30 minutes, following 15 administration. More specifically it is the object of the invention to provide such a SD compound-containing composition, for transmucosal, preferably buccal, delivery, that disintegrates and/or melts at body temperature with or without the aid of salivary fluid or mechanical erosion, or a combination thereof after which the formulation preferably 20 shows adhesiveness towards the tissues in the oral cavity. The addition of buffering agents provides for a transient change in local pH of the saliva. Thereby a higher fraction of the active agent is transformed into its less ionized form. Thereupon the transmucousal permeation is facilitated, which enhances the absorption of the active agent. For those skilled in the art it is evident that the choice 25 of the buffering system is dependent on the one or more pKas of the active agent. It has surprisingly been found that a rapid buccal absorption of SD compounds concomitantly with sufficient taste masking of badly tasting ingredients, such as the active compound and/or buffering agents, is achieved through the use of cocoa powder. The cocoa powder acts as filler/diluent as well as taste masking or flavoring agent and 30 agent for providing a smooth texture. No similar formulations have been disclosed hitherto. A preferred formulation is a composition, weighing around 400 mg - 500 mg, having the following ingredients: A therapeutically efficient amount of a SD compound, WO 2004/012702 PCT/SE2003/001022 9 cocoa powder around 200 mg, fatty components around 180 mg, aspartame around 2.5 mg, sodium carbonate around 15 mg, 5 lecithin around 4 mg. Preferably the composition should comprise at least 15 % by weight of cocoa powder. Cocoa powder is defined as cocoa nib with some fat removed and ground into a powder. Cocoa nib is defined as cocoa beans with the shell removed. Cocoa butter is 10 defined as fat expelled from the center (kernels or nib) of cocoa beans. Cocoa powder is prepared from roasted cocoa beans. It is a complex compound, which consists of starch, cocoa butter, amino acids, proteins, xanthines, amines, mono and polysaccharides, phospholipids, flavonoids, pyrazines, etc. Preferred fatty components are fats/lipids chosen from tempering fats, including 15 cocoa butter equivalents (CBE) and cocoa butter improvers (CBI), and non-tempering fats, including cocoa butter replacers (CBR) and cocoa butter substitutes (CBS). According to Industrial Chocolate Manufacture and Use, S. T. Beckett, ed., 2 "d edition, Blackier Academic & Professional, London, 1994, p 382, chocolate is defined as a product obtained from cocoa nib, cocoa mass powder and sucrose with or without 20 added cocoa butter, having a minimum dry cocoa solids content of 35%, at least 14% of dry non-fat cocoa solids and 18% cocoa butter. Chocolate has two major distinguishing characteristics: its flavor and its texture. A primary feature of the texture is that the chocolate must be solid at a temperature of 20 - 25 0 C and yet melt rapidly in the mouth at 37'C thereby being transferred to a liquid, which appears smooth to the tongue. The 25 processing of chocolate is related to obtaining these two criteria (ibid. p 2). Neither milk chocolate nor light cooking chocolate or dark cooking chocolate may mask the disagreeable taste of most buffering agents. The cocoa content of milk chocolate is comparatively low (a cocoa mass content of 10 - 16%, corresponding to approximately 5 - 8% cocoa powder). The beans'/cocoa mass'content of dark, bitter 30 sweet chocolate is 55 - 70% (Beckett, pp. 276 - 277), corresponding to approximately 28 - 35% cocoa powder. By making a vehicle with a high proportion of cocoa powder (30 - 70%) and fatty components (30 -50%), as per the present invention, an effective masking is though obtained. The higher the cocoa powder concentration the better the taste masking.

WO 2004/012702 PCT/SE2003/001022 10 Examples Below-follows non-limiting examples on preparation of certain embodiments of the present invention. Example 1: Preparation of a preferred embodiment 5 A composition, weighing around 400 mg, having the following preferred composition (w/w): Active: A SD compound according to above formula (I) in an amount from around 0.25 mg to around 10 mg. Diluent/filler and 10 flavoring/taste masking agent and agent for pro viding a smooth texture: cocoa powder around 50% 15 Lipid ingredient: cocoa butter equivalents (CBE) around 44% Buffering agent: sodium carbonate around 4% Sweetener: aspartame around 0,6% Emulsifier/solubilizer: lecithin around 1% Flavoring agent: mint or vanilla flavor 0,5% 20 is prepared in the following way: A part of the CBE is melted. The solid components, i e the SD compound, cocoa powder, aspartame, sodium carbonate and the flavoring agent if solid, are added and mixed. A reduction of particle size of the solid components is performed by milling in a roll-refiner. If the solid components have already got the required particle size, e g by 25 milling before the mixing with the fatty components, roll refining is dispensed with. After treatment in the roll-refiner the mixture is mixed with the rest of the melted fatty components or remelted (if solidified) and mixed with the rest of the melted CBE. A mixing of the melt is performed in a suitable mixer. The liquid components, i e lecithin and the flavoring agent if liquid, are added. Tablets or other solid dosage forms are 30 subsequently made using suitable techniques, such as molding, extrusion or congealing, including pastillation, when necessary after suitable preconditioning. Also other suitable manufacturing methods may be used. Example 2: Preparation of a further embodiment WO 2004/012702 PCT/SE2003/001022 11 In essentially the same way as in Example 1 is manufactured a composition with a weight from around 400 mg to around 500 mg having the below ingredients: from 0.25 mg to around 10 mg thereof of a compound of above formula (II), around 50% (w/w) cocoa powder, 5 around 44% (w/w) cocoa butter equivalents (CBE), around 4% (w/w) sodium carbonate, around 0,6% (w/w) aspartame and/or acesulfame potassium, and around 1% (w/w) lecithin. Example 3: Preparation of a still further embodiment 10 In essentially the same way as in Example 1 is manufactured a composition with the below contents: Active: A SD-compound in a therapeutically sufficient amount. Diluent/filler and Cocoa powder and optionally a small amount of a flavoring/taste- substance/substances chosen from one or more of the 15 masking agent and compounds fructose, glucose, galactose, invert sugar, agent for providing a a pharmaceutically acceptable polyol such as xylitol, smooth texture: sorbitol, maltitol, mannitol, isomalt and glycerol, or polydextrose, or any mixture thereof, from around 30% to around 70% (w/w), 20 Lipid ingredient: from around 30% to around 50% (w/w), Buffering agent: from 0 % to around 10% (w/w), Sweetener: from around 0.3% to around 3% (w/w), Emulsifier/solubilizer: from around 0.3% to around 5% (w/w), Flavoring agent: from 0 % to around 4% (w w). 25 Example 4: Preparation of alternative embodiments Useful embodiments are obtained by exchanging some of the excipients in the embodiments of the above examples for equivalently functioning alternative com pounds. A small part of the cocoa powder may be exchanged for one or more of the 30 compounds fructose, glucose, galactose, lactose, maltose, invert sugar, a pharmaceu tically acceptable polyol such as xylitol, sorbitol, maltitol, mannitol, isomalt and glycerol, or polydextrose, or any mixture thereof, but only to such an extent that the taste-masking effect of the cocoa-powder remains sufficient.

WO 2004/012702 PCT/SE2003/001022 12 The lipid ingredient, being fatty components, may be chosen from one or more of the following compounds: cocoa butter and cocoa butter alternatives, including cocoa butter equivalents (CBE), cocoa butter substitutes (CBS), cocoa butter replacers (CBR) and cocoa butter 5 improvers (CBI), - coconut, palmkernel oil and other similar oils characterized by being predomi nantly based on lauric and myristic acids, - palm oil, shea butter, karite butter, illipe butter, mango kernel oil, sal fat and other similar fats characterized by being predominantly based on palmitic, oleic and 10 stearic acids, - corn oil, sunflower oil, hybrid sunflower oil, soybean oil, rapeseed oil, canola oil, olive oil, ricebran oil, cottonseed oil, arachis (peanut, groundnut) oil and other oils characterized by being predominantly based on oleic, linoleic and linolenic acids and hydrogenated to a suitable melting point, 15 - fish oil, tallow, lard, butterfat and other animal derived fats, and - synthetic fats, reesterified fats, hard fats obtained by a chemical reaction of fatty acids with glycerol using no, acidic, alkaline or enzymatic catalysis, whereby said compound(s) is/are used as a single component or mixed with each other, being either crude or refined using physical or alkaline refining, or being subject 20 ted to further processing including catalytic hydrogenation, interesterification, trans esterification and fractionation. The buffer sodium carbonate may be exchanged for carbonates, bicarbonates, acetates, gluconates, glycerophosphates, phosphates or glycinates of sodium, potassium or ammonium, or mixtures thereof. Most phosphates are though less suitable because 25 their taste usually is disagreeable and difficult to mask. The sweetener aspartame may entirely or in part be exchanged for one or more other artificial sweeteners, such as acesulfame potassium, saccharine, sodium saccha rine, cyclamate and glycyrrhizine and/or salts thereof. The emulsifier lecithin is preferably soy lecithin and/or egg lecithin, but may be 30 exchanged for - a nonionic surfactant, such as poloxamer, polyoxyethylene alkyl ether, poly oxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, monoglyce ride, diglyceride and esther thereof, polyoxyethylene stearate, polyglycerolester of fatty acids (including polyglycerolpolyricinoleic acid (PGPR)), sorbitan fatty acid ester, WO 2004/012702 PCT/SE2003/001022 13 - an anionic surfactant, such as fatty acid, soap of fatty acid, lactylate, especially sodium and/or calcium stearoyllactylate, sodium lauryl sulfate and latanol, - a zwitterionic surfactant, such as zwitterionic phospholipid, such as phosphati dylcholine and phosphatidylethanolamine, 5 or mixtures, fractions or derivatives thereof or with lecithin. In principally the same way as in the above examples compositions comprising other SD compounds may be manufactured. The dose range and the percentages of the excipients should in such cases be accordingly adjusted.

Claims

1. A sexual-dysfunction-compound-containing orally administered rapid-onset pharmaceutical composition, c h a r a c t e r i z e d in that it comprises cocoa powder.

2. A composition according to claim 1, c h a r a c t e r i z e d in that it comprises 5 at least 15% cocoa powder.

3. A composition according to claim 1 or 2, c h a r a c t e r i z e d in that it further comprises one or more lipid ingredients.

4. A composition according to any preceding claim, c h a r a c t e r i z e d in that the sexual-dysfunction-compound/s is/are chosen among the following compounds 10 a compound of formula (I) R N R2 X R 3 N (B) A or a pharmaceutically acceptable salt thereof, wherein R', R 2 and R 3 are the same or different and are H, C1- 6 alkyl (optionally phenyl substituted), C 3 - 5 alkenyl or alkynyl or C 3 - 1 0 cycloalkyl, or where R 3 is as 15 above and R' and R 2 are cyclized with the attached N atom to form pyrrolidinyl, piperidinyl, morpholinyl, 4-methylpiperazinyl or imidazolyl groups; X is H, F, Cl, Br, I, OH, C 1 - 6 alkyl or alkoxy, CN, carboxamide, carboxyl or (C 1 . 6 alkyl)carbonyl; 20 A is CH, CH 2 , CHF, CHC, CHBr, CHI, CHCH 3 , C=O, C=S, CSCH 3 , C=NH, CNH 2 , CNHCH 3 , CNHCOOCH 3 , CNHCN, SO 2 or N; B is CH, CH 2 , CHF, CHCl, CHBr, CHI, C=O, N, NH or NCH 3 , and n is 0 or 1; and D is CH, CH 2 , CHF, CHCl, CHBr, CHI, C=O, 0, N, NH or NCH 3 ; 25 said compound of formula (I) or salt thereof being water-soluble; a compound of formula (II) WO 2004/012702 PCT/SE2003/001022 15 H N CH 3 N HN x (II) wherein X is 0 or S, and pharmaceutically acceptable salts thereof; a compound chosen from phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil in base form and pharmaceutically acceptable salts thereof, including 5 sildenafil citrate, vardenafil and tadalafil; a compound chosen from dopaminergic agonists, such as apomorphine optionally with the addition of anti-emetic agents; a compound chosen from noradrenergic alpha antagonists or a-adrenergic antagonists, such as phentolamine mesylate, yohimbine and prazosin; 10 a compound chosen from cyclic AMP activators; and pharmaceutically acceptable salts, complexes and mixtures thereof.

5. A composition according to any of claims 1-4, c h a r a c t e r i z e d in that it further comprises one or more buffering agents.

6. A composition according to claim 5, c h a r a c t e r i z e d in that the one or 15 more buffering agents is/are chosen from carbonates, bicarbonates, acetates, gluconates, glycerophosphates, phosphates or glycinates of sodium, potassium or ammonium, or mixtures thereof.

7. A composition according to any preceding claim, c h a r a c t e r i z e d in that it further comprises one or more sweeteners and optionally one or more flavoring 20 agents.

8. A composition according to claim 7, c h a r a c t e r i z e d in that the one or more sweeteners is/are aspartame, acesulfame potassium, saccharine, sodium saccha rine, cyclamate and/or glycyrrhizine and/or salts thereof.

9. A composition according to any of claims 3-8, c h a r a c t e r i z e d in that 25 the one or more lipid ingredients is/are chosen from - cocoa butter and cocoa butter alternatives, including cocoa butter equivalents (CBE), cocoa butter substitutes (CBS), cocoa butter replacers (CBR) and cocoa butter improvers (CBI), WO 2004/012702 PCT/SE2003/001022 16 - coconut, palmkemel oil and other similar oils characterized by being predomi nantly based on.lauric and myristic acids, - palm oil, shea butter, karite butter, illipe butter, mango kernel oil, sal fat and other similar fats characterized by being predominantly based on palmitic, oleic and 5 stearic acids, - corn oil, sunflower oil, hybrid sunflower oil, soybean oil, rapeseed oil, canola oil, olive oil, ricebran oil, cottonseed oil, arachis (peanut, groundnut) oil and other oils characterized by being predominantly based on oleic, linoleic and linolenic acids and hydrogenated to a suitable melting point, 10 - fish oil, tallow, lard, butterfat and other animal derived fats, and - synthetic fats, reesterified fats, hard fats obtained by a chemical reaction of fatty acids with glycerol using no, acidic, alkaline or enzymatic catalysis, whereby said compound(s) is/are used as a single component or mixed with each other, being either crude or refined using physical or alkaline refining, or being subject 15 ted to further processing including catalytic hydrogenation, interesterification, trans esterification and fractionation.

10. A composition according to claim 9, c h a r a c t e r i z e d in that the one or more lipid ingredients is/are chosen from cocoa butter equivalents (CBE), cocoa butter substitutes (CBS) and cocoa butter replacers (CBR). 20

11. A composition according to any preceding claim, c h a r a c t e r i z e d in that it further comprises one or more emulsifiers/solubilisers.

12. A composition according to claim 11, c h a r a c t e r i z e d in that the one or more emulsifiers/solubilisers is/are chosen from - lecithin, preferably soy lecithin and/or egg lecithin, 25 - a nonionic surfactant, such as poloxamer, polyoxyethylene alkyl ether, poly oxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, monoglyce ride, diglyceride and esther thereof, polyoxyethylene stearate, polyglycerolester of fatty acids (including polyglycerolpolyricinoleic acid (PGPR)), sorbitan fatty acid ester, - an anionic surfactant, such as fatty acid, soap of fatty acid, lactylate, especially 30 sodium and/or calcium stearoyllactylate, sodium lauryl sulfate and latanol, - a zwitterionic surfactant, such as zwitterionic phospholipid, such as phosphati dylcholine and phosphatidylethanolamine, or mixtures, fractions or derivatives thereof or with lecithin. WO 2004/012702 PCT/SE2003/001022 17

13. A composition according to claim 12, c h a r a c t e r i z e d in that the one or more emulsifiers/solubilisers is/are chosen from lecithin, preferably soy lecithin and/or egg lecithin.

14. A composition according to any preceding claim, c h a r a c t e r i z e d in 5 that it further comprises a small amount of a substance/substances chosen from one or more of the compounds fructose, glucose, galactose, lactose, maltose, invert sugar, a pharmaceutically acceptable polyol such as xylitol, sorbitol, maltitol, mannitol, isomalt and glycerol, or polydextrose, or any mixture thereof.

15. A sexual-dysfunction-compound-containing orally administered rapid-onset 10 pharmaceutical composition, c h a r a c t e r i z e d in that a unit dose thereof comprises Active: A sexual-dysfunction-compound in a therapeutically sufficient amount, Diluent/filler and Cocoa powder and optionally a small amount of a flavoring/taste- substance/substances chosen from one or more of the 15 masking agent and compounds fructose, glucose, galactose, invert sugar, agent for providing a a pharmaceutically acceptable polyol such as xylitol, smooth texture: sorbitol, maltitol, mannitol, isomalt and glycerol, or polydextrose, or any mixture thereof, from around 30% to around 70% (w/w), 20 Lipid ingredient: from around 30% to around 50% (w/w), Buffering agent: from 0% to around 10% (w/w), Sweetener: from around 0.3% to around 3% (w/w), Emulsifier/solubilizer: from around 0.3% to around 5% (w/w), Flavoring agent: from 0% to around 4% (w/w). 25

16. A sexual-dysfunctioncompound-co retaining orally administered rapid-onset pharmaceutical composition, c h a r a c t e r i z e d in that a unit dose thereof comprises from 0.25 mg to around 10 mg thereof of a compound of formula ((/) H ~ N HN__ wherein X is 0 or S, and pharmaceutically acceptable salts thereof, WO 2004/012702 PCT/SE2003/001022 18 around 50% (w/w) cocoa powder, around 44% (w/w) cocoa butter equivalents (CBE), around 4% (w/w) sodium carbonate, around 0,6% (w/w) aspartame and/or acesulfame potassium, 5 and around 1% (w/w) lecithin.

17. A sexual-dysfunction-compound-containing orally administered rapid-onset pharmaceutical composition, c h a r a c t e r i z e d in that a unit dose thereof comprises Active: A sexual-dysfunction compound according to formula (I) Ri N R2 XR N 10 (B) A or a pharmaceutically acceptable salt thereof, wherein R', R2 and R3 are the same or different and are H, C 1 6 alkyl (optionally phenyl substituted), C 3 - 5 alkenyl or alkynyl or C 3 - 10 cycloalkyl, or where R 3 is as above and R' and R2 are cyclized with the attached N atom to form 15 pyrrolidinyl, piperidinyl, morpholinyl, 4-methylpiperazinyl or imidazolyl groups; X is H, F, Cl, Br, I, OH, C 1 - 6 alkyl or alkoxy, CN, carboxamide, carboxyl or (C 1 6 alkyl)carbonyl; A is CH, CH 2 , CHF, CHCl, CHBr, CHI, CHCH 3 , C=O, C=S, CSCH 3 , C=NH, 20 CNH 2 , CNHCH 3 , CNHCOOCH 3 , CNHCN, SO 2 or N; B is CH, CH 2 , CHF, CHCl, CHBr, CHI, C=O, N, NH or NCH 3 , and n is 0 or 1; and D is CH, CH 2 , CHF, CHCL, CHBr, CHI, C=O, 0, N, NH or NCH 3 ; in an amount from around 0.25 mg to around 10 mg. 25 Diluent/filler and flavoring/taste masking agent and agent for pro viding a smooth WO 2004/012702 PCT/SE2003/001022 19 texture: cocoa powder around 50% Lipid ingredient: cocoa butter equivalents (CBE) around 44% Buffering agent: sodium carbonate around 4% Sweetener: aspartame around 0,6% 5 Emulsifier/solubilizer: lecithin around 1% Flavoring agent: mint or vanilla flavor 0,5%

18. A composition according to any preceding claim, which is formulated as an oral dosage form and which provides for delivery of sexual-dysfunction-compounds through the buccal mucosa and/or other mucosa of the oral cavity. 10

19. A composition according to any preceding claim, which is formulated as a tablet, as a sublingual tablet or as a lozenge.

20. A composition according to any of claims 1-18, which is formulated as an oral dosage form not being a chewing gum.

21. Use of a composition according to any preceding claim for the manufacture 15 of a medicament useful for treatment of sexual dysfunction, stimulation of sexual activity and enhancement of sexual desire and interest or performance.

22. Method for treating sexual dysfunction in a subject comprising admini stration of a sexual-dysfunction-compound-containing rapid-onset orally administered pharmaceutical composition according to anyone of claims 1-18 to the subject. 20

23. Method according to claim 22 comprising administration of a sexual dysfunction-compound-containing rapid-onset orally administered pharmaceutical com position according to anyone of claims 1-20 to the subject less than 1 hour, preferably less than 30 minutes prior to sexual activity.