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US 2005.0054688A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0054688A1 May et al. (43) Pub. Date: Mar. 10, 2005

(54) SELECTIVE SEROTONN REUPTAKE Related U.S. Application Data INHIBITORS IN THE TREATMENT OF DISEASE (60) Provisional application No. 60/528,136, filed on Dec. 9, 2003. (75) Inventors: Kathryn Elizabeth May, County of Kent (GB); Paul Quinn, County of (30) Foreign Application Priority Data Kent (GB) Aug. 8, 2003 (GB)...... O3187O6.9 Correspondence Address: PFIZER INC. Publication Classification PATENT DEPARTMENT, MS8260-1611 EASTERN POINT ROAD (51) Int. Cl." ...... A61K 31/44; A61K 31/18; GROTON, CT 06340 (US) A61K 31/137 (52) U.S. Cl...... 514/345; 514/602; 514/649 (73) Assignee: Pfizer Inc (57) ABSTRACT (21) Appl. No.: 10/911,806 The present invention provides the use of Selective reuptake inhibitors (SSRIs) to treat premature female (22) Filed: Aug. 5, 2004 Orgasm. US 2005/0054688A1 Mar. 10, 2005

SELECTIVE SEROTONIN REUPTAKE 0009 b) Interpersonal difficulties arise from female INHIBITORS IN THE TREATMENT OF DISEASE lack of motivation for/discomfort with continued Sexual Stimulation. 0001. This application claims priority from United King dom Application Number 0318706.9, filed on Aug. 8, 2003 0010 c) The disturbance gives rise to negative psy and the benefit of U.S. Provisional Application No. 60/528, chosocial consequences where arousal occurs in 136, filed on Dec. 9, 2003. inappropriate situations 0002 This invention relates to the use of compounds 0011 d) The disturbance itself causes marked dis which exhibit activity as Selective Serotonin re-uptake treSS or interpersonal difficulty inhibitors (SSRIs) to treat premature female orgasm, and to 0012. According to a first aspect, the invention provides pharmaceutical formulations containing Such compounds. for a Selective Serotonin reuptake inhibitor in the preparation 0003) Whilst anorgasmia and difficulties with orgasm are of a medicament for the treatment or prevention of prema well-represented in the female Sexual dysfunction literature, ture female orgasm. rapid orgasm-a female problem, Sharing components with 0013 By SSRI it is meant a compound with a serotonin premature ejaculation (PE) in men—is notable by its re-uptake inhibition (SRI) ICso value of less than or equal to absence. DSMIVR (2000) includes no mention of it, 100 nM. Preferred compounds have a serotonin re-uptake although it has an otherwise comprehensive Section on inhibition (SRI) ICso value of less than or equal to 50 nM. orgasmic disorders. Particularly preferred compounds have a Serotonin re-uptake inhibition (SRI) ICso value of less than or equal to 10 nM. 0004. It has been suggested that the distribution curve for female orgasm is likely to be very similar to that used to 0014. In a preferred embodiment the compounds are describe male experience (Cole and Dryden, 1988). How more than 10-fold as potent in the inhibition of serotonin ever, both clinically and in the research and its literature, the re-uptake than in the inhibition of re-uptake, retarded as opposed to the premature end of this is very preferred compounds are more than 100-fold as potent, much the focus of interest. This weighting is also Strongly particularly preferred compounds are more than a 1000-fold reflected in cases Seen, with cases of rapid orgasm in women as potent. presenting rarely and representing a far Smaller percentage 0015. In a preferred embodiment the compounds are of the female caseload than the 30% or more of male more than 10-fold as potent in the inhibition of serotonin caseload taken by PE. This is partly because male partners re-uptake than in the inhibition of noradrenaline re-uptake, often choose to take rapid orgasm as positive feedback on preferred compounds are more than 100-fold as potent, their skill as a lover and partly because, generally Speaking, particularly preferred compounds are more than a 1000-fold it presents fewer problems in terms of continuing with as potent. intercourse than PE. This is particularly So where the female partner is multi-orgasmic and therefore potentially well 0016 Particularly suitable SSRIs for use in treating pre motivated to continue. mature female orgasm may be characterised by having a rapid onset and a short duration of action. 0005. Unfortunately, a proportion of women with rapid orgasm find continued post-orgasmic Stimulation uncom 0017 Suitable SSRIs for use in the present invention include: , , , , cit fortable, if not painful. This group has no wish to continue allopram, , 3-(dimethylamino)methyl-4-4-(me with intercourse, having reached orgasm, and indeed may thylsulfanyl)phenoxybenzenesulfonamide (Example 28, feel unable to do so. This tends to give rise to interpersonal WO 0172687), 3-(dimethylamino)methyl-4-3-methyl-4- distress, which is difficult to resolve and these tend to be the (methylsulfanyl)phenoxybenzenesulfonamide (Example couples referred to Sex Therapy Clinics and gynaecology. 12, WO 0218333), N-methyl-N-({3-3-methyl-4-(methyl The problem of disengagement of the female partner is also Sulfanyl)phenoxy-4-pyridinyl)methyl)amine (Example 38, reported, with males feeling incidental or rejected, in the PCT Application no PCT/IB02/01032), methyl-3-(4-meth same way as female partners of men with PE. ylsulfanyl-phenoxy)-pyridin-4-ylmethylamine (Example 0006 Cognitive/behavioural treatments are more difficult 35 WO02/083643), , , 403U76, to describe and implement than in PE, the arousal element VN-2222, Roxindle, , RS-1439, R-fluoxetine, of the Human Sexual Response curve being So attenuated WF-32, DOV-216303, LY-393558, LY-433221, Cer that women find it immensely difficult to assert any kind of iclamine, UP-23761, , YM-992/, control. Whilst men with PE are educated to recognise the A-80426, , DuP-631, Biciifadine, , point of ejaculatory inevitability, a corresponding point of LY-214821, LY-393558, LU-10134-C, , SPD orgasmic inevitability is not identified and intervention to 473, , CI-275838, McN-5652, L792239, Vilaz disrupt it would anyway presumably prove to be problem odone, NS-2359, NS-2381, ORG-6582, , atic. The adoption of other treatment Strategies used in PE RS-1259, R-DDMS, S-Sibutramine, S-fluoxetine, Dexen (SS cream, local anaesthetics, SSRIs) is not reported in the furamine, S-34324, Du-125530, SLV-210, SLV-313, SLV Small available literature on rapid orgasm in Women. 314 and . 0018 Preferred SSRIs are sertraline, fluoxetine, fluvox 0007 Premature female orgasm may be defined as: amine, paroxetine, , dapoxetine, 3-(dimethy 0008 a) Persistent or recurrent orgasm with mini lamino)methyl-4-4-(methylsulfanyl)phenoxybenzene mal Sexual Stimulation, occurring before, upon or Sulfonamide (Example 28, WO 0172687), Shortly after penetration and generally before the 3-(dimethylamino)methyl-4-3-methyl-4-(methylsulfa perSon/couple wishes it. nyl)phenoxybenzenesulfonamide (Example 12, WO US 2005/0054688A1 Mar. 10, 2005

0218333), methyl-3-(4-methylsulfanyl-phenoxy)-pyridin H-Dopamine substrates. All reactions were carried out at 4-ylmethylamine (Example 35 WO02/083643), N-methyl room temperature in a shaking incubator. Incubation times N-(3-3-methyl-4-(methylsulfanyl)phenoxy-4- were 5 minutes for the hSERT and hDAT assays and 15 pyridinyl)methyl)amine (Example 38, PCT Application no minutes for the hNET assay. Reactions were terminated by PCT/IB02/01032). removal of the reaction mixture using a vacuum manifold 0019 More preferred SSRIs are 3-(dimethylamino)m- followed by rapid washing with ice cold assay buffer. The ethyl-4-4-(methylsulfanyl)phenoxybenzenesulfonamide quantity of H-substrate incorporated into the cells was then (Example 28, WO 0172687), 3-(dimethylamino)methyl-4- quantified. 3-methyl-4-(methylsulfanyl)phenoxybenzenesulfonamide 0030 Assay plates were dried in a microwave oven, (Example 12, WO 0218333), methyl-3-(4-methylsulfanyl Scintillation fluid added, and radioactivity measured. phenoxy)-pyridin-4-ylmethylamine (Example 35 WO02/ Potency of test compounds was quantified as ICso values 083643), N-methyl-N-(3-3-methyl-4-(methylsulfa (concentration of test compound required to inhibit the nyl)phenoxy-4-pyridinyl)methyl)amine (Example 38, PCT specific uptake of radiolabelled substrate into the cells by Application no PCT/IB02/01032), paroxetine and dapoxet 50%). C. 0031 (iii) Standard Assay Buffer Composition: 0020 Yet more preferred are 3-(dimethylamino)m- ethyl-4-4-(methylsulfanyl)phenoxybenzenesulfonamide 0.032 Trizma hydrochloride (26 mM) (Example 28, WO 0172687), 3-(dimethylamino)methyl-4- 0033 NaCl (124 mM) 3-methyl-4-(methylsulfanyl)phenoxybenzenesulfonamide (Example 12, WO 0218333), methyl-3-(4-methylsulfanyl 0034). KCl (4.5 mM) phenoxy)-pyridin-4-ylmethylamine (Example 35 WO02/ 0035). KHPO (1.2 mM) 083643), N-methyl-N-(3-3-methyl-4-(methylsulfa nyl)phenoxy-4-pyridinyl)methyl)amine (Example 38, PCT 0036) MgCl,.6HO (1.3 mM) Application no PCT/IB02/01032). 0037 Ascorbic acid (1.136 mM) 0021. The text of the aforementioned patents and all other 0038 Glucose (5.55 mM) references cited in this Specification are hereby incorporated by reference in their entirety. 0039 pH 7.40 0022. It should be understood that compounds suitable 0040 CaCl (2.8 mM) for use in the present invention, as exemplified above or as 0041 Pargyline (100 uM) identified by the assays described herein, may encompass pharmaceutically acceptable Salts, Solvates and prodrugs 0042. Note: The pH of the buffer was adjusted to 7.40 thereof. with 1M NaOH before addition of CaCl and pargyline. 0023 Compounds suitable for use as an SSRI may be 0043 (iv) Summary of Assay Parameters identified by the use of the following assay: 0024 Biological Activity hSERT hDAT hNET 0.025 Compounds may be tested for their ability to Assay Assay Assay inhibit the uptake of Serotonin by human Serotonin trans Cell concentration per 75,000 75,000 75,000 porters, dopamine by human dopamine transporters or assay well. nopradrenaline by human noradrenaline transporters as fol Substrate Concentration. H-5HT H-Dopamine H-Noradrenaline lows. (50 nM) (200 nM) (200 nM) Incubation time (minutes) 5 5 15 0026 (i) Cell Culture 0027) Human embryonic kidney cells (HEK-293) stably transfected with either the human 0044) The compounds of the invention have the advan (hSERT), noradrenaline transporter (hNET) or dopamine tage that they are Selective inhibitors of the re-uptake of transporter (hDAT) were cultured understandard cell culture serotonin (SRIs) (and so are likely to have reduced side techniques (cells were grown at 37° C. and 5% CO in effects), they have a rapid onset of action (making them DMEM-culture media (supplemented with 10% dialysed suitable for administration shortly before an effect is foetal calf serum (FCS), 2 mM 1-glutamine and 250 ug/ml required), they have desirable potency and associated prop geneticin)). Cells were harvested for the assay to yield a cell erties. Compounds that Selectively inhibit the re-uptake of suspension of 750,000 cells/ml. Serotonin, but not noradrenaline or dopamine, are preferred. 0045. It will be appreciated by those skilled in the art that 0028 (i) Determination of Inhibitor Potency certain protected derivatives of compounds of the invention, 0029 All test compounds were dissolved in 100% dim which may be made prior to a final deprotection Stage, may ethylsulfoxide (DMSO) and diluted down in assay buffer to not possess pharmacological activity as Such, but may, in give appropriate test concentrations. ASSays were carried out certain instances, be administered orally or parenterally and in 96-well filter bottom plates. Cells (7500 cells/assay well) thereafter metabolised in the body to form compounds of the were pre-incubated in Standard assay buffer containing invention which are pharmacologically active. Such deriva either test compound, Standard inhibitor or compound tives may therefore be described as “prodrugs”. Further, vehicle (1% DMSO) for 5 minutes. Reactions were started certain compounds of the invention may act as prodrugs of by addition of either H-Serotonin, H-Noradrenaline or other compounds of the invention. US 2005/0054688A1 Mar. 10, 2005

0.046 All protected derivatives and prodrugs of com dihydro-5-methyl-4-oxo-7-propylimidazo5,1-f-as pounds of the invention are included within the Scope of the trazin-2-yl)-4-ethoxyphenylsulfonyl)-4-ethylpipera invention. Examples of Suitable pro- for the com zine i.e. vardenafil/Bayer BA 38-9456 or IC351 (see pounds of the present invention are described in Drugs of structure below, Icos Lilly)). Today, Volume 19, Number 9, 1983, pp. 499-538 and in Topics in Chemistry, Chapter 31, pp. 306–316 and in “Design IC351 of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). 0047. It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when Such functionalities are present within the compounds of the invention. 0.048 Thus, according to further aspects, the invention provides: 0049) i) the use of an SSRI in the manufacture of a (Icos Lilly) medicament for the treatment or prevention of prema ture female orgasm. 0050 ii) a method of treatment or prevention of pre 0061 ix) Potassium channel openers. mature female orgasm, which comprises administering X) P2X purinergic receptor antagonists. a therapeutically effective amount of an SSRI to a 0062) patient in need of Such treatment or prevention; 0063) xi) Endothelin receptor antagonists 0051. It is to be appreciated that all references herein to 0064 xii) One or more of an androgen such as andros treatment include curative, palliative and prophylactic treat terone, dehydro-androsterone, testosterone, andros ment. tanedione and a Synthetic androgen; 0.052 The compounds of the invention may be adminis 0065 xiii) Oxytocin antagonists tered alone or as part of a combination therapy. If a com bination of active agents are administered, then they may be 0066 For human use the compounds of the invention can administered simultaneously, Separately or Sequentially. In be administered alone but in human therapy will generally particular, the compounds of the invention may be combined be administered in admixture with a Suitable pharmaceutical with the following preferably for the treatment of premature excipient, diluent or carrier Selected with regard to the female orgasm: intended route of administration and Standard pharmaceuti 0053 i) Alpha-blockers (e.g. phentolamine, doxaza cal practice. Sim, tamsulosin, teraZaSin, praZasin and Example 19 of 0067 For example, the compounds of the invention, can WO983O560. be administered orally, buccally or Sublingually in the form of tablets, capsules (including Soft gel capsules), ovules, 0054) ii) -teachings on the use of apo elixirs, Solutions or Suspensions, which may contain flavour morphine as a pharmaceutical may be found in U.S. ing or colouring agents, for immediate-, delayed-, modified-, Pat. No. 5,945,117. Sustained-, dual-, controlled-release or pulsatile delivery 0055) iii) Dopamine D2 agonists (e.g. Premiprixal, applications. The compounds of the invention may also be Pharmacia Upjohn compound number PNU95666). administered via fast dispersing or fast dissolving dosage forms. 0056 iv) Melanocortin receptor agonists (e.g. Melano tan II). 0068 Such tablets may contain excipients such as micro crystalline cellulose, lactose, Sodium citrate, calcium car 0057 v) PGE1 receptor agonists (e.g. alprostadil). bonate, dibasic calcium phosphate, glycine, and Starch (pref 0.058 i) Mono amine transport inhibitors, particularly erably corn, potato or tapioca Starch), disintegrants Such as Noradrenaline Re-uptake Inhibitors (NRIs) (e.g. Sodium Starch glycollate, croScarmelloSe Sodium and certain ), other Serotonin Re-uptake Inhibitors complex Silicates, and granulation binderS Such as polyvi (SRIs) (e.g. paroxetine) or Dopamine Re-uptake Inhibi nylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), Sucrose, gelatin and acacia. tors (DRIs). Additionally, lubricating agents Such as magnesium Stearate, 0059 vii) 5-HT3 antagonists (e.g. and Stearic acid, glyceryl behenate and talc may be included. ). 0069 Solid compositions of a similar type may also be 0060 viii) PDE inhibitors such as PDE2 (e.g. erythro employed as fillers in gelatin capsules. Preferred excipients 9-(2-hydroxyl-3-nonyl)-adenine) and Example 100 of in this regard include lactose, Starch, a cellulose, milk Sugar EP 0771799-incorporated herein by reference) and in or high molecular weight polyethylene glycols. For aqueous particular a PDE5 inhibitor (e.g. sildenafil, 1-3-(3,4- Suspensions and/or elixirs, the compounds of the invention, US 2005/0054688A1 Mar. 10, 2005

and their pharmaceutically acceptable Salts, may be com of active compound for administration Singly or two or more bined with various Sweetening or flavouring agents, colour at a time, as appropriate. The physician in any event will ing matter or dyes, with emulsifying and/or Suspending determine the actual dosage which will be most suitable for agents and with diluents Such as water, ethanol, propylene any individual patient and it will vary with the age, weight glycol and glycerin, and combinations thereof. and response of the particular patient. The above dosages are 0070 Modified release and pulsatile release dosage exemplary of the average case. There can, of course, be forms may contain excipients Such as those detailed for individual instances where higher or lower dosage ranges immediate release dosage forms together with additional are merited and Such are within the Scope of this invention. excipients that act as release rate modifiers, these being The skilled person will also appreciate that, in the treatment coated on and/or included in the body of the device. Release of certain conditions (including PE), compounds of the rate modifiers include, but are not exclusively limited to, invention may be taken as a single dose on an “as required” hydroxypropylmethyl cellulose, methyl cellulose, Sodium basis (i.e. as needed or desired). carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio EXAMPLE methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypro Tablet Formulation pylmethyl cellulose phthalate, methacrylic acid copolymer 0076. In general a tablet formulation could typically and mixtures thereof. Modified release and pulsatile release contain between about 0.01 mg and 500 mg of a compound dosage forms may contain one or a combination of release of the invention whilst tablet fill weights may range from 50 rate modifying excipients. Release rate modifying excipients mg to 1000 mg. An example formulation for a 10 mg tablet may be present both within the dosage form i.e. within the is illustrated: matrix, and/or on the dosage form, i.e. upon the Surface or coating. 0071 Fast dispersing or dissolving dosage formulations (FDDFs) may contain the following ingredients: aspartame, Ingredient % w/w aceSulfame potassium, citric acid, croScarmelloSe Sodium, Compound of the invention 1O.OOO* croSpoVidone, diascorbic acid, ethyl acrylate, ethyl cellu Lactose 64.125 Starch 21.375 lose, gelatin, hydroxypropylmethyl cellulose, magnesium Croscarmellose Sodium 3.OOO stearate, mannitol, methyl methacrylate, mint flavouring, Magnesium Stearate 1.5OO polyethylene glycol, fumed Silica, Silicon dioxide, Sodium Starch glycolate, Sodium Stearyl fumarate, Sorbitol, Xylitol. *This quantity is typically adjusted in accordance with activity. The terms dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug Sub 0077. The compounds of the invention can also be stance used i.e. where the drug Substance is insoluble a fast administered intranasally or by inhalation and are conve dispersing dosage form can be prepared and where the drug niently delivered in the form of a dry powder inhaler or an Substance is Soluble a fast dissolving dosage form can be aeroSol Spray presentation from a preSSurised container, prepared. pump, Spray or nebulizer with the use of a Suitable propel 0.072 The compounds of the invention can also be lant, e.g. dichlorodifluoromethane, trichlorofluoromethane, administered parenterally, for example, intravenously, intra dichlorotetrafluoro-ethane, a hydrofluoroalkane Such as 1,1, arterially, intraperitoneally, intrathecally, intraventricularly, 1,2-tetrafluoroethane (HFA 134A trade mark) or 1,1,1,2,3, intraurethrally, intrasternally, intracranially, intramuscularly 3.3-heptafluoropropane (HFA227EA trade mark), carbon or Subcutaneously, or they may be administered by infusion dioxide or other Suitable gas. In the case of a pressurised techniques. For Such parenteral administration they are best aeroSol, the dosage unit may be determined by providing a used in the form of a sterile aqueous Solution which may Valve to deliver a metered amount. The preSSurised con contain other Substances, for example, enough Salts or tainer, pump, Spray or nebulizer may contain a Solution or glucose to make the Solution isotonic with blood. The Suspension of the active compound, e.g. using a mixture of aqueous solutions should be suitably buffered (preferably to ethanol and the propellant as the Solvent, which may addi a pH of from 3 to 9), if necessary. The preparation of suitable tionally contain a lubricant, e.g. Sorbitan trioleate. Capsules parenteral formulations under Sterile conditions is readily and cartridges (made, for example, from gelatin) for use in accomplished by Standard pharmaceutical techniques well an inhaler or insufflator may be formulated to contain a known to those skilled in the art. powder mix of a compound of the invention and a Suitable 0073. The following dosage levels and other dosage powder base Such as lactose or Starch. levels herein are for the average human Subject having a 0078 Aerosol or dry powder formulations are preferably weight range of about 65 to 70 kg. The skilled person will arranged So that each metered dose or "puff contains from readily be able to determine the dosage levels required for a 1 to 50 mg of a compound of the invention for delivery to Subject whose weight falls outside this range, Such as the patient. The overall daily dose with an aerosol will be in children and the elderly. the range of from 1 to 50 mg which may be administered in 0.074 For oral and parenteral administration to human a single dose or, more usually, in divided doses throughout patients, the daily dosage level of the compounds of the the day. invention or salts or solvates thereof will usually be from 10 0079 The compounds of the invention may also be to 500 mg (in single or divided doses). formulated for delivery via an atomiser. Formulations for 0075 Thus, for example, tablets or capsules of the com atomiser devices may contain the following ingredients as pounds of the invention may contain from 5 mg to 250 mg Solubilisers, emulsifiers or Suspending agents: water, etha US 2005/0054688A1 Mar. 10, 2005 nol, glycerol, propylene glycol, low molecular weight poly 0084 Oral administration is preferred. Preferably, admin ethylene glycols, Sodium chloride, fluorocarbons, polyeth istration takes place shortly before an effect is required. ylene glycol ethers, Sorbitan trioleate, oleic acid. 0085 Thus according to a further aspect, the invention 0080 Alternatively, the compounds of the invention can provides a pharmaceutical formulation containing a com be administered in the form of a Suppository or pessary, or pound of the invention and a pharmaceutically acceptable they may be applied topically in the form of a gel, hydrogel, adjuvant, diluent or carrier. lotion, Solution, cream, ointment or dusting powder. The compounds of the invention may also be dermally or trans dermally administered, for example, by the use of a skin patch. They may also be administered by the ocular, pull 1.) A method of treating or preventing premature female monary or rectal routes. orgasm comprising administering a therapeutically effective amount of a Selective Serotonin reuptake inhibitor to a 0.081 For application topically to the skin, the com patient in need of Such treatment or prevention. pounds of the invention can be formulated as a Suitable ointment containing the active compound Suspended or 2) The method of claim 1 wherein the compound has a dissolved in, for example, a mixture with one or more of the serotonin re-uptake inhibition (SRI) ICs value of less than following: mineral oil, liquid petrolatum, white petrolatum, or equal to 50 Nm. propylene glycol, polyoxyethylene polyoxypropylene com 3) The method of claim 1 or 2 wherein the compounds are pound, emulsifying wax and water. Alternatively, they can more than 100-fold as potent in the inhibition of serotonin be formulated as a Suitable lotion or cream, Suspended or re-uptake than in the inhibition of dopamine re-uptake. dissolved in, for example, a mixture of one or more of the 4) The method of claims 1 and 2 wherein the compounds following: mineral oil, Sorbitan monoStearate, a polyethyl are more than 10-fold as potent in the inhibition of serotonin ene glycol, liquid paraffin, polySorbate 60, cetyl esters, wax, re-uptake than in the inhibition of noradrenaline re-uptake. cetearyl , 2-octyldodecanol, benzyl alcohol and 5) The method of claim 1 wherein the selective serotonin Water. reuptake inhibitor is Selected from: 0082 The compounds of the invention may also be used Sertraline, fluoxetine, fluvoxamine, paroxetine, citalo in combination with a cyclodextrin. Cyclodextrins are pram, dapoxetine, 3-(dimethylamino)methyl-4-4- known to form inclusion and non-inclusion complexes with (methylsulfanyl)phenoxybenzenesulfonamide, drug molecules. Formation of a drug-cyclodextrin complex 3-(dimethylamino)methyl-4-3-methyl-4-(methylsul may modify the solubility, dissolution rate, bioavailability fanyl)phenoxybenzenesulfonamide, N-methyl-N-({3- and/or Stability property of a drug molecule. Drug-cyclo 3-methyl-4-(methylsulfanyl)phenoxy-4- dextrin complexes are generally useful for most dosage pyridinyl)methyl)amine, Escitalopram, Litoxetine, forms and administration routes. AS an alternative to direct ROXindle, Milnacipran, R-fluoxetine, , complexation with the drug the cyclodextrin may be used as Indalpine, methyl-3-(4-methylsulfanyl-phenoxy)-py an auxiliary additive, e.g. as a carrier, diluent or Solubiliser. ridin-4-ylmethylamine, Lubazodone, Nefazodone, Alpha-, beta- and gamma-cyclodextrins are most commonly Biciifadine, Duloxetine, Sibutramine, Tramadol, Vilaz used and suitable examples are described in WO-A-91/ Odone, Femoxetine, S-Sibutramine, S-fluoxetine, Dex 11172, WO-A-94/02518 and WO-A-98/55148. enfuramine, and Venlafaxine. 0.083 For oral or parenteral administration to human 6) The method of claim 5 wherein the selective serotonin patients the daily dosage levels of compounds of the inven reuptake inhibitor is Selected from tion will be from 0.01 to 30 mg/kg (in single or divided 3-(dimethylamino)methyl-4-4-(methylsulfanyl)phe doses) and preferably will be in the range 0.01 to 5 mg/kg. noxybenzenesulfonamide, Thus tablets will contain 1 mg to 0.4 g of compound for administration Singly or two or more at a time, as appropri 3-(dimethylamino)methyl-4-3-methyl-4-(methylsulfa ate. The physician will in any event determine the actual nyl)phenoxybenzenesulfonamide, dosage which will be most Suitable for any particular patient and it will vary with the age, weight and response of the N-methyl-N-(3-3-methyl-4-(methylsulfanyl)phenoxy particular patient. The above dosages are, of course only 4-pyridinyl)methyl)amine, and methyl-3-(4-methyl exemplary of the average case and there may be instances Sulfanyl-phenoxy)-pyridin-4-ylmethylamine. where higher or lower doses are merited, and Such are within the Scope of the invention.