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US006037360A United States Patent (19) 11 Patent Number: 6,037,360 Smith et al. (45) Date of Patent: *Mar. 14, 2000

54 ADMINISTRATION OF 5-HT, RECEPTOR Cavallini (1995.) “Alpha-1 Blockade Pharmacotherapy in ANTAGONSTS TO TREAT PREMATURE Primitive Psychogenic Premature Ejaculation Resistant to EJACULATION Psychotherapy,” Eur: Urology 28:126-130. Di Silverio et al. (1996), “Effects Comparés de l'Incision 75 Inventors: William L. Smith, Oakland; Paul C. Cervico-Prostaticue (ICP) et de l'Association ICP et Ago Doherty, Jr., Cupertino, both of Calif.; nistes de la LHRH dans le Traitement de l’Hypertrophie Virgil A. Place, Kawaihae, Hi. Bénigne de la Prostate,” Journal D'Urologie 73 Assignee: Vivus, Incorporated, Mountain View, 102(3):111-116. Calif. Falaschi et al. (1981), “Brain and Premature Ejaculation: Results of Treatment with Dopamine Antago * Notice: This patent is Subject to a terminal dis nists.” and Other Dopaminomimetics claimer. 1:117-121. Feinberg (1991), “ for Obsessive-Compul 21 Appl. No.: 08/959,061 sive Disorder, AFP Clinical Pharmacology 22 Filed: Oct. 28, 1997 43(5):1735-1738. Ferrarietal (1994), “The Selective D. 51) Int. Cl." ...... A61K 31/415; A61K 31/405 Antagonist Counteracts the Ejaculatio Praecox 52 U.S. Cl...... 514/397; 514/415 Induced by the Selective D. Dopamine SND 919 in 58 Field of Search ...... 514/415, 397 the Rat,” Life Sciences 55(14): 1155–1162. 56) References Cited Hull et al. (1994), “The Roles of Nitric Oxide in Sexual Function of Male Rats,” Neuropharmacology U.S. PATENT DOCUMENTS 33(11):1499–1504. 3,717,634 2/1973 Wu et al.. Metz et al. (1997), “Premature Ejaculation: A Psychophysi 4,507.323 3/1985 Stern. 4,521,421 6/1985 Foreman. ological Review,” Journal of Sex & Marital Therapy 4,766,119 8/1988 Davis. 23(1):3–23. 4,828,544 5/1989 Lane et al...... 604/9 Napoli-Farris et al. (1984), “Stimulation of Dopamine 4,940,731 7/1990 Bick. Autoreceptors Elicits Premature Ejaculation in Rats.” Phar 5,063.915 11/1991 Wyckoff. macology Biochemistry & Behavior 20:69–72. 5,151,448 9/1992 Crenshaw et al.. 5,242,391 9/1993 Place et al.. Waldinger et al. (1997), “Ejaculation-Retarding Properties 5.248,699 9/1993 Sysko et al.. of Paroxetine in Patients with Primary Premature Ejacula 5,276,042 1/1994 Crenshaw et al.. tion: A Double-Blind, Randomized, Dose-Response 5,327.910 7/1994 Flynn. Study,” British Journal of Urology 79:592–595. 5,468,212 11/1995 Shooter. 5,474,535 12/1995 Place et al.. WPIDS Abstract, AN 96–18821819), Nomura, K. et al., 5,476,121 12/1995 Place et al.. WO 9609069 A1, Mar. 28, 1996. 5,482,039 1/1996 Place et al.. 5.535,758 7/1996 Hagihara. CA Abstract, AN 119:21000, Pomerantz, S. M. et al., 1993. 5,552,429 9/1996 Wong et al...... 514/415 Pomerantz et al., Psychopharmacology, Vol. 111, pp. 47-54, 5,587,167 12/1996 Choi et al.. 1993. 5,597,826 1/1997 Howard et al.. 5,672,612 9/1997 Ronsen et al.. 5,707,999 1/1998 Cavallini. Primary Examiner Minna Moezie 5,922,341 7/1999 Smith et al...... 424/430 Attorney, Agent, or Firm-Dianne E. Reed; J. Elin Hartrum FOREIGN PATENT DOCUMENTS 57 ABSTRACT 781561 A1 7/1997 European Pat. Off.. WO 91/16021 10/1991 WIPO. A method is provided for delaying the onset of ejaculation WO95/13072 5/1995 WIPO. in an individual. The method involves administration of a WO95/33048 10/1995 WIPO. 5-HT, within the context of an effective WO 96/28142 9/1996 WIPO. dosing regimen. The preferred mode of administration is transurethral; however, the selected inhibitor may also be OTHER PUBLICATIONS delivered via intracavernoSal injection or using alternative Balon (1996) “ in the Treatment of Prema rOuteS. ture Ejaculation,” Journal of Sex & Marital Therapy 22(2):85–96. 23 Claims, 1 Drawing Sheet U.S. Patent Mar. 14, 2000 6,037,360

6,037,360 1 2 ADMINISTRATION OF 5-HT, RECEPTOR the same problems as ; see Martindale, The Extra ANTAGONSTS TO TREAT PREMATURE Pharmacopoeia, 31st edition, at p. 333 (London: The Royal EJACULATION Pharmaceutical Society, 1996). Sertraline is metabolized in the liver, and is excreted in the urine and feces. Thus, TECHNICAL FIELD patients with cirrhosis must take lower doses, and caution must be exercised when administering Sertraline to patients This invention relates generally to methods and pharma with renal impairment. Individuals taking monoamine oxi ceutical compositions for treating Sexual dysfunction; more dase inhibitors cannot take Sertraline due to the risk of particularly, the invention relates to treatment of premature toxicity, leading to memory changes, confusion, irritability, ejaculation by administration of compounds that are 5-HT chills, pyrexia and muscle rigidity. Side effects resulting () receptor and antagonists. from oral Sertraline administration include nausea, diarrhea, BACKGROUND dyspepsia, insomnia, Somnolence, Sweating, dry mouth, tremor and mania. Rare instances of coma, convulsions, Premature ejaculation is a debilitating Sexual dysfunction. fecal incontinence and gynecomastia have occurred in This dysfunction can lead to an inability to enter or Sustain 15 patients undergoing Sertraline therapy. relationships and can cause psychological damage to Suf U.S. Pat. No. 5,276,042 describes the administration of ferers. Premature ejaculation can also impair reproductive paroxetine for the treatment of premature ejaculation. Par SCCCSS. oxetine is predominantly excreted in the urine, and Previous methods of treating premature ejaculation decreased doses are recommended in patients with hepatic include psychological therapies, topical anesthetics and the and renal impairments. Like Sertraline, paroxetine cannot be use of devices (U.S. Pat. Nos. 5.535,758, 5,063,915, 5,327, given to patients undergoing treatment with a monoamine 910, and 5,468,212). All of these methods have significant oxidase inhibitor. Side effects from oral administration of drawbacks. Psychological therapies benefit only a Subset of paroxetine include hyponatremia, asthenia, Sweating, patients and require Specialized therapists who may not be nausea, decreased appetite, oropharynx disorder, available to all patients, particularly in remote areas. Somnolence, dizziness, insomnia, tremor, anxiety, impaired Furthermore, psychological therapies cannot alleviate pre 25 micturition, weakneSS and paresthesia. mature ejaculation resulting from non-psychological causes. Thus there is a need for a method of treating premature Anesthetic agents decrease Sensitivity of tissues, thereby ejaculation that requires no specialized psychological diminishing Sexual pleasure. Also, topical anesthetics can be therapy, can be used conveniently and without transferred to Sexual partners and thereby decrease their embarrassment, and does not involve the problems associ Sensitivity and pleasure as well. With regard to devices, ated with prior therapeutic methods. these can be awkward, inconvenient and embarrassing to Serotonin, or 3-(B-aminoethyl)-5-hydroxyindole use. Devices are highly conspicuous, and reveal the very (5-hydroxytryptophan, or “5-HT”) is a neurotransmitter in condition which the Suffering partner may prefer to conceal. the central nervous System which is known to play an Additionally, devices can cause irritation to one or both 35 important role in the pathogenesis of affective illness. Sev partners. eral different 5-HT receptor types have been identified, Methods for treating premature ejaculation by Systemic including 5-HT, 5-HT, and 5-HT, which are further administration of Several different com divided into a number of different Subtypes, e.g., -HT1A, pounds have been described (U.S. Pat. Nos. 4,507.323, 5-HT, 5-HT, 5-HT, and 5-HT. It has now been 4,940,731, 5,151,448, and 5,276,042; PCT Publication No. 40 discovered that administration of various Serotonin agonists WO95/13072). However, these may not be effective and antagonists is quite effective in the treatment of prema for all patients, and the Side effects of these drugs can halt ture ejaculation, and addresses a number of the above-noted treatment or impair patient compliance. Disease States or deficiencies in the art. Accordingly, the present invention is adverse interactions with other drugs may contraindicate the directed to the administration of Serotonin agonists and use of these compounds or require lower dosages that may 45 antagonists, preferably 5-HT, receptor antagonists (also not be effective to delay the onset of ejaculation. referred to herein as “5-HT, antagonists”) and 5-HT, recep Additionally, the Stigma of mental illness associated with tor agonists (also referred to herein as “5-HT agonists'), in antidepressant therapy can discourage patients from begin the treatment of premature ejaculation. ning or continuing Such treatments. SUMMARY OF THE INVENTION Administration of the antidepressant fluoxetine has been 50 claimed to treat premature ejaculation (U.S. Pat. No. 5,151, Accordingly, it is a primary object of the invention to 448). However, the administration of fluoxetine has many address the above-described need in the art by providing a undesired aspects. Patients with hepatic or renal impair novel method for treating premature ejaculation by admin ments may not be able to use fluoxetine due to its metabo istering an effective amount of a Serotonin antagonist or lism in the liver and excretion via the kidney. Systemic 55 agonist to an individual in need of Such therapy. events during fluoxetine treatment involving the lungs, It is another object of the invention to provide such a kidneys or liver have occurred, and death has occurred from method wherein the pharmacologically active agent is Overdoses. In addition, Side effects of oral fluoxetine admin administered orally. istration include hair loSS, nausea, vomiting, dyspepsia, It is a further object of the invention to provide such a diarrhea, anorexia, anxiety, nervousness, insomnia, 60 method wherein the pharmacologically active agent is drow SineSS, fatigue, headache, tremor, dizziness, administered parenterally. convulsions, Sweating, pruritis, and Skin rashes. Fluoxetine It is another object of the invention to provide such a interacts with a range of drugs, often by impairing their method wherein the pharmacologically active agent is metabolism by the liver. administered buccally. U.S. Pat. No. 4,940,731 describes the oral or parenteral 65 It is also an object of the invention to provide Such a administration of Sertraline for treating premature ejacula method wherein the pharmacologically active agent is tion. It has been recognized that Sertraline shares many of administered nasally. 6,037,360 3 4 It is another object of the invention to provide such a It must be noted that, as used in this specification and the method wherein the pharmacologically active agent is appended claims, the singular forms “a,” “an” and “the” administered transurethrally. include plural referents unless the context clearly dictates It is an additional object of the invention to provide such otherwise. Thus, for example, reference to “a pharmacologi a method wherein the pharmacologically active agent is cally active agent' includes a combination of two or more administered via intracavernoSal injection. pharmacologically active agents, reference to “a transure It is yet a further object of the invention to provide thral permeation enhancer includes combinations of two or pharmaceutical formulations for carrying out the aforemen more enhancers, and the like. tioned method. In describing and claiming the present invention, the It is another object of the invention to provide a kit 1O following terminology will be used in accordance with the capable of use by an individual in carrying out the afore definitions set out below. mentioned method. The terms “active agent,” “” and “pharmacologically Additional objects, advantages and novel features of the active agent” are used interchangeably herein to refer to a invention will be set forth in part in the description which chemical material or compound which, when administered 15 to an organism (human or animal) induces a desired phar follows, and in part will become apparent to those skilled in macologic effect. Included are derivatives and analogs of the art upon examination of the following, or may be learned those compounds or classes of compounds Specifically men by practice of the invention. tioned which also induce the desired pharmacologic effect. In a first aspect of the invention, a method is provided for The terms “transurethral,” “intraurethral” and “urethral” treating premature ejaculation, the method comprising to specify the preferred mode of administration herein are administering to an individual in need of Such treatment a used interchangeably to refer to delivery of the drug into the pharmaceutical formulation containing a Serotonin antago urethra Such that the drug contacts and passes through the nist or agonist. Administration of the pharmaceutical for wall of the urethra. AS noted elsewhere herein, the transure mulation is carried out within the context of a predetermined thral administration preferably involves delivery of the drug dosing regimen Such that the agent is effective in the 25 at least about 3 cm and more preferably at least about 7 cm treatment of premature ejaculation. Drug delivery may be into the urethra. accomplished through any route effective to provide relief The term “intracavernosal” as used herein refers to an from premature ejaculation, including oral, parenteral, alternative mode of drug administration and involves injec buccal, rectal, topical, transdermal, transurethral, and intra tion into one or both corpora of the corpora cavernoSal cavernoSal injection. tissueS of the penis. In another aspect of the invention, a pharmaceutical By the term “transdermal” delivery, applicants intend to formulation is provided for carrying out the method of the include both transdermal (or "percutaneous') and transmu invention. The pharmaceutical formulation comprises an cosal administration, i.e., delivery by passage of a drug effective amount of a Selected Serotonin antagonist or ago through the skin or mucosal tissue and into the bloodstream. nist or a combination thereof, a pharmacologically accept 35 The term “body surface” will sometimes be used herein to able carrier or vehicle, and, optionally (i.e., in topical, refer to either the skin or the mucosal tissue. transdermal or transurethral formulations), an enhancer. The term “topical administration” is used in its conven Other types of components may be incorporated into the tional Sense to mean delivery of a topical drug or pharma formulation as well, e.g., excipients, Surfactants, preserva cologically active agent to the skin or mucosa. tives (e.g., antioxidants), Stabilizers, enzyme inhibitors, 40 “Penetration enhancement' or “permeation enhance chelating agents, and the like, as will be appreciated by those ment” as used herein relates to an increase in the perme skilled in the art of pharmaceutical formulation preparation ability of the urethral wall to the Selected pharmacologically and drug delivery. active agent, i.e., So that the rate at which the drug permeates In another aspect of the invention, a kit is provided to through the urethral wall is increased. assist an individual in administering a drug to treat prema 45 “Carriers' or “vehicles” as used herein refer to carrier ture ejaculation. Generally, the kit will include the following materials Suitable for drug administration. Carriers and components: a pharmaceutical formulation comprising an vehicles useful herein include any Such materials known in active agent as provided herein; a device for effecting the art, e.g., any liquid, gel, Solvent, liquid diluent, delivery of the pharmaceutical formulation; a container Solubilizer, or the like, which is nontoxic and which does not housing the pharmaceutical formulation during Storage and 50 interact with other components of the composition in a prior to use; and instructions for carrying out drug admin deleterious manner. istration in a manner effective to delay the onset of ejacu The term “premature ejaculation' as used herein intends lation. a Sexual dysfunction wherein a male is unable to control the BRIEF DESCRIPTION OF THE DRAWING ejaculatory process to a degree Sufficient to Satisfy a partner. 55 Generally, "premature ejaculation” refers to persistent or FIG. 1 illustrates an embodiment of a transurethral thera recurring ejaculation with minimal Stimulation before or peutic device which may be used in conjunction with the during Sexual intercourse. The term includes both “congeni present method. tal' or “lifelong premature ejaculation and “primary” or DETAILED DESCRIPTION OF THE “acquired” premature ejaculation as Set forth, for example, INVENTION 60 in U.S. Pat. No. 5,151,448, and in Male Infertility and Overview and Definitions: Sexual Dysfunction at p. 356 (New York: Springer-Verlag, Before describing the present invention in detail, it is to 1997). See also Diagnostic and Statistical Manual of Mental be understood that this invention is not limited to particular Disorders (Washington, D.C.: American Psychiatric drugs or drug delivery Systems, as Such may vary. It is also Association, 1994). to be understood that the terminology used herein is for the 65 By an “effective” amount of a drug or pharmacologically purpose of describing particular embodiments only, and is active agent is meant a nontoxic but Sufficient amount of the not intended to be limiting. drug or agent to provide the desired effect. 6,037,360 S 6 Active Agents for Treating Premature Ejaculation: Suitable acid. Generally, the base form of the drug is In order to carry out the method of the invention, a dissolved in a polar organic Solvent Such as methanol or Selected pharmacologically active agent is administered to ethanol and the acid is added thereto. The resulting Salt an individual with a history of premature ejaculation. The either precipitates or may be brought out of Solution by active agent may be administered orally, parenterally, addition of a less polar Solvent. Suitable acids for preparing buccally, rectally, or locally by intracavernoSal injection or acid addition Salts include both organic acids, e.g., acetic by delivery to the urethra. Suitable pharmacologically active acid, propionic acid, glycolic acid, pyruvic acid, Oxalic acid, agents include, but are not limited to: malic acid, malonic acid, Succinic acid, maleic acid, fumaric Serotonin agonists including 2-methyl Serotonin, acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, , ipsaperone, tiaspirone, , D-lySergic mandelic acid, methaneSulfonic acid, ethaneSulfonic acid, acid diethylamide ("LSD"), , 8-hydroxy ptoluenesulfonic acid, Salicylic acid, and the like, as well as (2-N,N-dipropylamino)-tetraline, 1-(4-bromo-2,5- inorganic acids, e.g., hydrochloric acid, hydrobromic acid, dimethoxyphenyl)-2-aminopropane, , Sulfuric acid, nitric acid, phosphoric acid, and the like. An , m-chlorophenylpiperazine, , acid addition salt may be reconverted to the free base by and meZacopride; and 15 treatment with a Suitable base. Conversely, preparation of Serotonin antagonists including , , basic Salts of acid moieties which may be present on a drug , , , , are prepared in a similar manner using a pharmaceutically trimethoben Zamide, , , acceptable base Such as Sodium hydroxide, potassium , , , , MDL hydroxide, ammonium hydroxide, calcium hydroxide, 100,507 (Marion Merrell Dow), azatadine, trimethylamine, or the like. Preparation of esters involves cy proheptadine, fenclonine, and functionalization of hydroxyl and/or carboxyl groups which . may be present within the molecular Structure of the drug. Serotonin, or 5-HT, plays a variety of roles throughout the The esters are typically acyl-substituted derivatives of free body, regulating Smooth muscle and platelet function, and groups, i.e., moieties which are derived from car acting as a neurotransmitter in the central nervous System. 25 boxylic acids of the formula RCOOH where R is alkyl, and Serotonin acts through specific cellular receptors which preferably is lower alkyl. Esters can be reconverted to the comprise at least 15 individual Subtypes. These receptors free acids, if desired, by using conventional hydrogenolysis can be grouped into at least four families based on Structural or hydrolysis procedures. Preparation of amides and pro and functional characteristics. The 5-HT, 5-HT, and 5-HT drugs can be carried out in an analogous manner. families are G-protein coupled receptors linked to enzymatic Other derivatives and analogs of the active agents may be and electrical effector systems, while the 5-HT receptor is prepared using Standard techniques known to those skilled in a gated ion channel. Serotonin agonists are agents which the art of Synthetic organic chemistry, or may be deduced by mimic the effect of Serotonin on at least one Serotonin reference to the pertinent literature. In addition, chiral active receptor Subtype. For example, 5-HT agonists mimic the agents may be in enantiomerically pure form, or they may be effect of serotonin on at least one 5-HT, receptor. 35 administered as an enantiomeric mixture. Conversely, Serotonin antagonists are agents which block Pharmaceutical Formulations and Modes of Administration: the effect of Serotonin on at least one Serotonin receptor Depending on the intended mode of administration, the Subtype, 5-HT antagonists block the effect of Serotonin on pharmaceutical compositions may be in the form of Solid, the 5-HT receptor. Semi-Solid or liquid dosage forms, Such as, for example, Preferred active agents are 5-HT, antagonists and 5-HT 40 tablets, Suppositories, pills, capsules, powders, liquids, agonists. 5-HT, receptors can be found, for example, on Suspensions, creams, ointments, lotions or the like, prefer parasympathetic terminals in the gastrointestinal tract and in ably in unit dosage form Suitable for Single administration of the central nervous System, both of which participate in the a precise dosage. The compositions will include an effective emetic response. 5-HT, receptors are found throughout the amount of the Selected drug in combination with a pharma body, including on nerve terminals in the CNS, the gas 45 ceutically acceptable carrier and, in addition, may include trointestinal tract, and on Smooth muscle and Secretory cells. other pharmaceutical agents, adjuvants, diluents, buffers, 5-HT, receptors activate adenylyl cyclase, and are involved etc. The compounds may thus be administered orally, in the regulation of Secretion and peristalsis. Examples of parenterally, transdermally, rectally, nasally, buccally, topi 5-HT antagonists include ondansetron, ergot alkaloids, cally or via an implanted reservoir in dosage formulations granisetron, metoclopramide, trimethoben Zamide, 50 containing conventional non-toxic pharmaceutically accept tropisetron, dolasetron, and Zacopride. able carriers, adjuvants and vehicles. The term "parenteral' Examples of 5-HT agonists include cisapride and as used herein is intended to include Subcutaneous, D-ly Sergic acid diethylamide. intravenous, and intramuscular injection. The amount of The active agents may be administered in the form of active compound administered will, of course, be dependent pharmaceutically acceptable Salts, esters, amides or pro 55 on the Subject being treated, the Subjects weight, the drugs or combinations thereof. However, conversion of manner of administration and the judgment of the prescrib inactive ester, amide or prodrug forms to an active form ing physician. must occur prior to or upon reaching the target tissue or cell. For Solid compositions, conventional nontoxic Solid car Salts, esters, amides and prodrugs of the active agents may riers include, for example, pharmaceutical grades of be prepared using Standard procedures known to those 60 mannitol, lactose, Starch, magnesium Stearate, Sodium skilled in the art of Synthetic organic chemistry and Saccharin, talc, cellulose, glucose, Sucrose, magnesium described, for example, by J. March, Advanced Organic carbonate, and the like. Liquid pharmaceutically adminis Chemistry. Reactions, Mechanisms and Structure, 4th Ed. trable compositions can, for example, be prepared by (New York: Wiley-Interscience, 1992). For example, acid dissolving, dispersing, etc., an active compound as described addition salts are prepared from the free base (typically 65 herein and optional pharmaceutical adjuvants in an wherein the neutral form of the drug has a neutral -NH excipient, Such as, for example, Water, Saline, aqueous group) using conventional means, involving reaction with a dextrose, glycerol, ethanol, and the like, to thereby form a 6,037,360 7 8 Solution or Suspension. If desired, the pharmaceutical com trademark AZone(R) from Nelson Research & Development position to be administered may also contain minor amounts Co., Irvine, Calif.), SEPAGR) (available from Macrochem Co., of nontoxic auxiliary Substances Such as wetting or emulsi Lexington, Mass.), (e.g., ethanol), detergents (Such fying agents, pH buffering agents and the like, for example, as Tergitol(R), Nonoxynol-9(E) and TWEEN-80(R) and the Sodium acetate, Sorbitan mono-laurate, triethanolamine like. Sodium acetate, triethanolamine oleate, etc. Actual methods TranSurethral formulations may additionally include one of preparing Such dosage forms are known, or will be or more enzyme inhibitors effective to inhibit drug apparent, to those skilled in this art; for example, See degrading enzymes which may be present in the urethra. Remington's Pharmaceutical Sciences, referenced above. Such enzyme inhibiting compounds may be determined by For oral administration, the composition will generally those skilled in the art by reference to the pertinent literature take the form of a tablet or capsule, or may be an aqueous and/or using routine experimental methods. Additional or nonaqueous Solution, Suspension or Syrup. Tablets and optional components include excipients, preservatives (e.g., capsules are preferred oral administration forms. Tablets and antioxidants), chelating agents, Solubilizing agents (e.g., capsules for oral use will generally include one or more Surfactants), and the like, as will be appreciated by those commonly used carrierS Such as lactose and corn Starch. 15 skilled in the art of drug formulation preparation and deliv Lubricating agents, Such as magnesium Stearate, are also ery. typically added. When liquid Suspensions are used, the Transurethral drug administration, as explained in PCT active agent may be combined with emulsifying and Sus Publication WO91/16021, entitled “Treatment of Erectile pending agents. If desired, flavoring, coloring and/or Sweet Dysfunction,” can be carried out in a number of different ening agents may be added as well. Other optional compo ways using a variety of urethral dosage forms. For example, nents for incorporation into an oral formulation herein the drug can be introduced into the urethra from a flexible include, but are not limited to, preservatives, Suspending tube, Squeeze bottle, pump or aeroSol Spray. The drug may agents, thickening agents, and the like. also be contained in coatings, pellets or Suppositories which Parenteral administration, if used, is generally character are absorbed, melted or bioeroded in the urethra. In certain ized by injection. Injectable formulations can be prepared in 25 embodiments, the drug is included in a coating on the conventional forms, either as liquid Solutions or exterior Surface of a penile insert. A preferred drug delivery Suspensions, Solid forms Suitable for Solubilization or SuS device for administering a drug transurethrally is shown in pension in liquid prior to injection, or as emulsions. FIG. 1. It is preferred, although not essential, that the drug Preferably, Sterile injectable Suspensions are formulated be delivered at least about 3 cm into the urethra, and according to techniques known in the art using Suitable preferably at least about 7 cm into the urethra. Generally, carriers, dispersing or Wetting agents and Suspending agents. delivery at about 3 cm to about 8 cm into the urethra will The sterile injectable formulation may also be a sterile provide effective results in conjunction with the present injectable Solution or a Suspension in a nontoxic parenterally method. acceptable diluent or Solvent. Among the acceptable Urethral Suppository formulations containing PEG or a vehicles and Solvents that may be employed are water, 35 PEG derivative are particularly preferred urethral dosage Ringer's Solution and isotonic Sodium chloride Solution. In forms herein, and may be conveniently formulated using addition, Sterile, fixed oils, fatty esters or polyols are con conventional techniques, e.g., compression molding, heat ventionally employed as Solvents or Suspending media. A molding or the like, as will be appreciated by those skilled more recently revised approach for parenteral administration in the art and as described in the pertinent literature and involves use of a slow release or Sustained release System, 40 pharmaceutical texts. See, for example, Remington. The Such that a constant level of dosage is maintained. See, e.g., Science and Practice of Pharmacy, 19th Ed. (Easton, PA: U.S. Pat. No. 3,710,795. Mack Publishing Co., 1995), which discloses typical meth IntracavernoSal injection can be carried out by use of a ods of preparing pharmaceutical compositions in the form of Syringe any other Suitable device. An example of a hypo urethral Suppositories. The PEG or PEG derivative prefer dermic Syringe useful herein, that can be used for Simulta 45 ably has a molecular weight M in the range of about 200 neous injection into both corpora, is described in U.S. Pat. to 2500, more preferably in the range of about 1000 to 2000. No. 4,127,118 to Latorre. The injection is made on the Suitable polyethylene glycol derivatives include polyethyl dorsum of the penis by placement of the needle to the side ene glycol fatty acid esters, for example, polyethylene glycol of each dorsal vein and inserting it deep into the corpora. monoStearate, polyethylene glycol Sorbitan esters, e.g., The active agent can be administered in a pharmaceutical 50 polySorbates, and the like. It is also preferred that urethral formulation suitable for transurethral drug delivery. The Suppositories contain one or more Solubilizing agents effec formulation contains one or more Selected carriers or tive to increase the solubility of the active agent in the PEG excipients, Such as water, Silicone, waxes, petroleum jelly, or other transurethral vehicle. polyethylene glycol (“PEG”), propylene glycol (“PG”), The Solubilizing agent may be a nonionic, anionic, cat liposomes, SugarS Such as mannitol and lactose, and/or a 55 ionic or amphoteric Surfactant. Nonionic Surfactants include: variety of other materials, with polyethylene glycol and long-chain fatty acids, i.e., acids having the Structural for derivatives thereof particularly preferred. mula CH3(CH2)COOH where m is an integer in the range Depending on the drug administered, it may be desirable of 8 to 16; fatty alcohols, that is, alcohols having the to incorporate a transurethral permeation enhancer in the structural formula CH-(CH2)C(H)OH, such as lauryl, cetyl urethral dosage form. Examples of Suitable transurethral 60 and Stearyl alcohols, glyceryl esterS Such as the naturally permeation enhancers include dimethylsulfoxide occurring mono-, di- and triglycerides, and esters of fatty (“DMSO”), dimethyl formamide (“DMF"), N,N- alcohols or other alcohols Such as propylene glycol, poly dimethylacetamide ("DMA"), decylmethylsulfoxide ethylene glycol, Sorbitan, Sucrose, and cholesterol. (“CoMSO”), polyethylene glycol monolaurate Examples of water-Soluble nonionic Surfactant derivatives (“PEGML'), glycerol monolaurate, lecithin, the 65 include Sorbitan fatty acid esters (Such as those sold under 1-Substituted azacycloheptan-2-ones, particularly 1-n- the tradename Span(R), polyoxyethylene Sorbitan fatty acid dodecylcyclazacycloheptan-2-one (available under the esters (such as those sold under the tradename TWEENCR), 6,037,360 9 10 polyoxyethylene fatty acid esters (such as those sold under elongate cap 17 which fits snugly over flange 18 at the the tradename Myrie), polyoxyethylene Steroidal esters, proximal end of shaft 15. The cap 17 is provided with a polyoxypropylene Sorbitan fatty acid esters, polyoxypropy Series of parallel ridges 19 to facilitate gripping of the cap lene fatty acid esters, polyoxypropylene Steroidal esters, and removal from inserter 11. polyoxyethylene ethers (such as those Sold under the trade Although the transurethral drug delivery device shown in name Brij(E)), polyglycol ethers (Such as those sold under the FIG. 1 represents a preferred device for use herein, again, it tradename Tergitol(R), and the like. Preferred nonionic Sur should be emphasized that a wide variety of device con factants for use as the Solubilizing agent herein are polyg figurations and urethral dosage forms can be used. lycol ether, polyoxyethylene Sorbitan trioleate, Sorbitan Examples of other devices Suited to deliver a drug tran monopalmitate, polySorbate 80, polyoxyethylene 4-lauryl Surethrally are those described and illustrated in PCT Pub ether, propylene glycol, and mixtures thereof. Anionic Sur lication No. WO91/16021. factants which may be used as the Solubilizing agent herein The devices can either be manufactured under Sterile include long-chain alkyl Sulfonates, carboxylates, and conditions, thereby eliminating the need for post Sulfates, as well as alkyl aryl Sulfonates, and the like. manufacturing Sterilization, or they can be manufactured Preferred anionic Surfactants are Sodium dodecyl Sulfate, 15 under non-Sterile conditions and then Subsequently Sterilized dialkyl Sodium SulfoSuccinate (e.g., Sodium bis(2- by any Suitable technique, e.g., radiation Sterilization. The ethylhexyl)-sulfosuccinate), sodium 7-ethyl-2-methyl-4- devices can be manufactured by typical plastic forming and dodecyl Sulfate and Sodium dodecylbenzene Sulfonate. Cat coating processes known in the art, including molding ionic Surfactants which may be used to Solubilize the active extrusion, heat forming, dip coating, and the like. agent are generally long-chain amine Salts or quaternary The method of drug delivery herein may involve an ammonium Salts, e.g., decyltrimethylammonium bromide, “active' delivery mechanism Such as iontophoresis, elec dodecyltrimethylammonium bromide, tetradecyltrimethy troporation or phonophoresis. Devices and methods for lammonium bromide, tetradecyltrimethylammonium delivering drugs in this way are well known in the art. chloride, and the like. Amphoteric Surfactants are generally, Iontophoretically assisted drug delivery is, for example, although not necessarily, compounds which include a car 25 described in PCT Publication No. WO96/40054, cited boxylate or phosphate group as the anion and an amino or above. Briefly, the active agent is driven through the urethral quaternary ammonium moiety as the cation. These include, wall by means of an electric current passed from an external for example, various polypeptides, proteins, alkyl betaines, electrode to a Second electrode contained within or affixed to and natural phospholipids Such as lecithins and cephalins. a urethral probe. Other Suitable Solubilizing agents include glycerin, propy The compounds of the invention may also be delivered lene glycol, fatty acids and fatty alcohols. The Solubilizing through the skin using conventional transdermal drug deliv agent will be present in the range of approximately 0.01 wt. ery Systems, i.e., transdermal "patches' wherein the agent is % to 40 wt.%, more preferably in the range of approxi typically contained within a laminated Structure that Serves mately 5.0 wt.% to 40 wt.%, and most preferably in the as a drug delivery device to be affixed to the skin. In Such a range of approximately 10.0 wt.% to 40 wt.%. 35 Structure, the drug composition is typically contained in a It may be desirable to deliver the active agent in a urethral layer, or “reservoir, underlying an upper backing layer. The dosage form which provides for controlled or Sustained laminated device may contain a single reservoir, or it may release of the agent. In Such a case, the dosage form typically contain multiple reservoirs. In one embodiment, the reser comprises a biocompatible, biodegradable material, typi voir comprises a polymeric matrix of a pharmaceutically cally a biodegradable polymer. Examples of Such polymers 40 acceptable contact adhesive material that Serves to affix the include polyester, polyalkylcyanoacrylate, polyorthoester, System to the skin during drug delivery. Examples of Suit polyanhydride, albumin, gelatin and Starch. AS explained, able skin contact adhesive materials include, but are not for example, in PCT Publication No. WO96/40054, these limited to, polyethylenes, polysiloxanes, polyisobutylenes, and other polymers can be used to provide biodegradable polyacrylates, polyurethanes, and the like. Alternatively, the microparticles which enable controlled and Sustained drug 45 drug-containing reservoir and skin contact adhesive are release, in turn minimizing the required dosing frequency. present as Separate and distinct layers, with the adhesive The urethral Suppository will preferably, although not underlying the reservoir which, in this case, may be either a necessarily, be on the order of 2 to 20 mm, preferably 5 to polymeric matrix as described above, or it may be a liquid 10 mm in length and less than about 5 mm, preferably less or hydrogel reservoir, or may take Some other form. than about 2 mm in width. The weight of the Suppository 50 The backing layer in these laminates, which Serves as the form will typically be in the range of approximately 1 mg to upper Surface of the device, functions as the primary Struc 50 mg. However, it will be appreciated by those skilled in tural element of the laminated Structure and provides the the art that the Size of the Suppository can and will vary, device with much of its flexibility. The material selected for depending on the potency of the drug, the nature of the the backing material should be Selected So that it is Substan formulation, and other factors. 55 tially impermeable to the active agent and any other mate In FIG. 1, a suitable transurethral drug delivery device is rials that are present. The backing layer may be either shown generally at 10. The device comprises a transurethral occlusive or nonocclusive, depending on whether it is inserter 11 having an easily graspable Segment 12 that has desired that the skin become hydrated during drug delivery. opposing Symmetrically concave Surfaces 13 and 14 adapted The backing is preferably made of a sheet or film of a to be held by two fingers. Drug is contained within a urethral 60 preferably flexible elastomeric material. Examples of poly suppository (not shown) within shaft 15, which is sized to fit mers that are Suitable for the backing layer include within the urethra. A longitudinal plunger, the tip of which polyethylene, polypropylene, polyesters, and the like. is seen at 16, is slidably insertable into the longitudinal bore During Storage and prior to use, the laminated Structure contained within shaft 15. To extrude drug into the urethra, includes a release liner. Immediately prior to use, this layer shaft 15 is inserted into the urethra, and plunger tip 16 is 65 is removed from the device to expose the basal Surface pushed into segment 12. The inserter 11 is then removed. thereof, either the drug reservoir or a separate contact Prior to use, and during Storage, the device is capped with adhesive layer, So that the System may be affixed to the skin. 6,037,360 11 12 The release liner should be made from a drug/vehicle N-cysteine and S-nitroso-N-glutathione (“SNO-GLU”); impermeable material. long and Short acting C.-blockerS Such as Transdermal drug delivery devices may be fabricated , dibenamine, , , using conventional techniques, known in the art, for , , , , , example by casting a fluid admixture of adhesive, drug and and ; ergot alkaloids Such as ergota vehicle onto the backing layer, followed by lamination of the mine and analogs, e.g., acetergamine, release liner. Similarly, the adhesive mixture may be cast braZergoline, , cianergoline, delorgotrile, onto the release liner, followed by lamination of the backing disulergine, ergonoVine maleate, ergotamine tartrate, layer. Alternatively, the drug reservoir may be prepared in etisulergine, , lysergide, , , the absence of drug or excipient, and then loaded by metergotamine, , , propisergide, proter “Soaking in a drug/vehicle mixture. guride and ; antihypertensive agents Such as The laminated transdermal drug delivery Systems may in diaZOxide, hydralazine and minoxidil; vasodilatorS Such as addition contain a skin permeation enhancer. That is, nimodepine, pinacidil, cyclandelate, dipyridamole and isox because the inherent permeability of the Skin to Some drugs Suprine; chlorpromazine, , , Rec15/ may be too low to allow therapeutic levels of the drug to pass 15 2739; traZodone; naturally occurring Such as through a reasonably sized area of unbroken skin, it is PGE, PGE, PGA, PGB, PGF, 19-hydroxy-PGA, necessary to coadminister a skin permeation enhancer with 19-hydroxy-PGB, PGE, PGA, PGB, 19-hydroxy-PGA, Such drugs. Suitable enhancers are well known in the art. 19-hydroxy-PGB, PGE, PGF; semisynthetic or syn Alternatively, the pharmaceutical compositions of the thetic derivatives of natural prostaglandins, including car invention may be administered in the form of Suppositories boprost tromethamine, dinoprost tromethamine, for rectal administration. These can be prepared by mixing dinoprostone, lipoprost, , metenoprost, Sulpros the agent with a Suitable non-irritating excipient which is tone and tiaprost, and vasoactive intestinal peptides. Solid at room temperature but liquid at the rectal temperature Prazosin, E, prostaglandin E and prostag and therefore will melt in the rectum to release the drug. landin E are particularly preferred vasoactive agents to be Such materials include cocoa butter, beeswax and polyeth 25 co-administered with the active agent. ylene glycols. The amount of active agent administered, and the dosing The pharmaceutical compositions of the invention may regimen used, will, of course, be dependent on the particular also be administered by nasal aerosol or inhalation. Such drug Selected, the age and general condition of the Subject compositions are prepared according to techniques well being treated, the Severity of the Subject's condition, and the known in the art of pharmaceutical formulation and may be judgment of the prescribing physician. Generally, the daily prepared as Solutions in Saline, employing benzyl alcohol or dosage when administered locally will be less than the other Suitable preservatives, absorption promoters to dosage normally given in conjunction with Systemic modes enhance bioavailability, propellants Such as fluorocarbons or of administration, and typically, the drug will be adminis nitrogen, and/or other conventional Solubilizing or disperS tered one to four times daily or, with Some active agents, just ing agents. 35 prior to intercourse. Alternatively, a large initial loading Preferred formulations for topical drug delivery are oint dose can be used to achieve effective levels of the agent and ments and creams. Ointments are Semisolid preparations can be followed by smaller doses to maintain those levels. which are typically based on petrolatum or other petroleum A typical daily dose of an active agent as administered derivatives. Creams containing the Selected active agent, locally is generally in the range of approximately 0.1 to 500 are, as known in the art, Viscous liquid or Semisolid 40 mg. Depending on the half-life of the drug and the avail emulsions, either oil-in-water or water-in-oil. Cream bases ability via the chosen route of administration, the dosing are water-washable, and contain an oil phase, an emulsifier regimen can be modulated in order to achieve Satisfactory and an aqueous phase. The oil phase, also Sometimes called control of the onset of ejaculation. the “internal' phase, is generally comprised of petrolatum Kits: and a fatty alcohol Such as cetyl or Stearyl alcohol; the 45 The invention also encompasses a kit for patients to carry aqueous phase usually, although not necessarily, exceeds the out the present method of treating premature ejaculation. oil phase in Volume, and generally contains a humectant. The kit contains the pharmaceutical formulation to be The emulsifier in a cream formulation is generally a administered, a device for administering the formulation nonionic, anionic, cationic or amphoteric Surfactant. The (e.g., a transurethral drug delivery device Such as shown in Specific ointment or cream base to be used, as will be 50 FIG. 1, or a Syringe), a container, preferably Sealed, for appreciated by those skilled in the art, is one that will housing the drug and device during Storage and prior to use, provide for optimum drug delivery. AS with other carriers or and instructions for carrying out drug administration in an vehicles, an ointment base should be inert, stable, nonirri effective manner. The formulation may consist of the drug in tating and nonsensitizing. unit dosage form. The kit may contain multiple formulations Formulations for buccal administration include tablets, 55 of different dosages of the same agent. The kit may also lozenges, gels and the like. Alternatively, buccal adminis contain multiple formulations of different active agents. The tration can be effected using a transmucosal delivery System instructions may be in written or pictograph form, or can be as known to those skilled in the art. on recorded media including audio tape, video tape, or the The pharmaceutical formulation may contain one or more like. pharmacologically active agents in addition to the Serotonin 60 Use in Conjunction with Venous Flow Control (“VFC”) agonist or antagonist. Vasoactive agents, particularly Device: vasodilators, are preferred additional agents. In an alternative embodiment of the invention, the phar Suitable vasoactive agents include, but are not limited to: macologically active agent is administered in combination nitrates Such as nitroglycerin, isosorbide dinitrate, erythrityl with a venous flow control device Such as that described in tetranitrate, amyl nitrate, Sodium nitroprus Side, 65 commonly assigned U.S. patent application Ser. No. 08/782, molsidomine, linsidomine chlorhydrate (“SIN-1”), 867, filed Jan. 10, 1997, entitled “Venous Flow Control S-nitroso-N-acetyl-d,1-penicillamine (“SNAP), S-nitroso Element for Maintaining Penile Erection” now U.S. Pat. No. 6,037,360 13 14 5,855,548. Preferred devices are formed from a length of EXAMPLE 6 flexible tubing having an integral fastening means, So as to provide for readily adjustable venous flow control when A penile insert coated with a Serotonin agonist or antago applied to the penis. The device is applied to the base of the nist is prepared as follows. An ethylene vinyl acetate (28% penis prior to and during Sexual intercourse, Such that it VA) rod is formed into an insert having a shaft approxi effectively enhances retention of blood within the penis mately 10 cm long with a spherical, blunted tip. A dipping without Substantially obstructing arterial inflow or becoming bath comprising a 50-50 weight blend of PEG 1450 and too constrictive during the erectile process. Use of the VFC PEG 4000 and sufficient agent to attain the desired concen device also enables enhanced effectiveness of local drug tration in the coating is prepared and heated to 70° C. The therapy, in that the active agent is retained within the penis, insert is Suspended by its head, dipped into the dipping bath allowing movement into the corpus cavernosa. This pro and removed. A penile insert Suitable for transurethral duces Smooth muscle response and a consistent erectile administration of agent is thus provided. response. In this embodiment, a kit will include the venous EXAMPLE 7 flow control device in addition to the components noted above, along with instructions for using the device. 15 A pharmaceutical formulation Suitable for injection can be It is to be understood that while the invention has been made by dissolving 4 mg of the 5-HT antagonist described in conjunction with the preferred specific embodi ondansetron hydrochloride dihydrate, 9.0 mg of sodium ments thereof, that the foregoing description as well as the chloride, 0.5 mg of citric acid monohydrate and 0.25 mg of examples which follow are intended to illustrate and not Sodium citrate dihydrate in water to give a 2 mL Solution. limit the Scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be EXAMPLE 8 apparent to those skilled in the art to which the invention A pharmaceutical formulation Suitable for oral adminis pertains. tration can be prepared by admixing either 4 or 8 mg of the All patents, patent applications, and publications men 5-HT antagonist ondansetron hydrochloride dihydrate with tioned herein are hereby incorporated by reference in their 25 appropriate amounts of lactose, microcrystalline cellulose, entirety. pregelatinized Starch, hydroxypropyl methylcellulose, mag nesium Stearate and titanium dioxide and forming the mix EXAMPLE 1. ture into tablets. A pharmaceutical formulation for transurethral adminis tration is prepared by mixing 0.1-25 mg of the Serotonin EXAMPLE 9 agonist Sumatriptan with polyethylene glycol, molecular A pharmaceutical formulation Suitable for oral adminis weight (M) approximately 4000, and heating the mixture to tration can be made Suspending the 5-HT agonist cisapride a temperature just high enough to produce a Sumatriptan monohydrate at 1 mg/mL in an aqueous Solution containing polymer melt. The Sumatriptan-glycol mixture can then be appropriate amounts of Sodium chloride, hydroxypropyl poured into a mold Suitable to provide a Sumatriptan Sup 35 methylcellulose, methylparaben, microcrystalline cellulose pository approximately 5 mm in length and 1.5 mm in width, and carboxymethylcellulose Sodium, polySorbate 20, and allowed to cool. The Suppository So provided is a unit propylparaben, and Sorbitol. dosage form Suitable for transurethral administration. If desired, the Sumatriptan-glycol mixture may be allowed to EXAMPLE 10 cool on the tip of a rod adapted to be inserted into the 40 A pharmaceutical formulation Suitable for oral adminis urethra. tration can be prepared by admixing either 10 or 20 mg of the 5-HT agonist cisapride monohydrate with appropriate EXAMPLE 2 amounts of lactose monohydrate, microcrystalline cellulose, The procedure of Example 1 is repeated, except that 1-50 polySorbate 20, povidone, corn Starch, magnesium Stearate mg of the Serotonin agonist cisapride is Substituted for 45 and colloidal Silicon dioxide and forming the mixture into Sumatriptan. A Suppository Suitable for transurethral admin tablets. istration of a unit dosage of cisapride is thus provided. EXAMPLE 11 EXAMPLE 3 Individuals are assessed and pre-Screened to assemble an The procedure of Example 1 is repeated, except that 50 experimental group of Subjects prone to premature ejacula 0.1-25 mg of the Serotonin antagonist risperidone is Substi tion. The formulations prepared in the preceding Examples tuted for Sumatriptan. A Suppository Suitable for transure are administered to the individuals and evaluated with thral administration of a unit dosage of risperidone is thus respect to the capability of delaying the onset of ejaculation. provided. 55 The dosage regimen can be altered for Subjects not experi encing improvement in their ability to delay the onset of EXAMPLE 4 ejaculation. Alternatively, different active agents can be The procedure of Example 1 is repeated, except that administered to Subjects not experiencing improvement. 1-100 mg of the Serotonin antagonist clozapine is Substi Each of the formulations prepared and administered is tuted for Sumatriptan. A Suppository Suitable for transure 60 expected to be effective in treating premature ejaculation. thral administration of a unit dosage of clozapine is thus provided. EXAMPLE 12 The procedure of Example 11 is repeated, except that a EXAMPLE 5 flexible, adjustable venous flow control device is used prior The procedures of the foregoing Examples are repeated, 65 to and during Sexual intercourse, in combination with the except that cocoa butter is Substituted for polyethylene drug therapy described. Substantially the same results are glycol. expected. 6,037,360 15 16 We claim: 13. The method of claim 12, wherein the urethral Sup 1. A method for treating an individual with a history of pository contains a pharmacologically acceptable carrier premature ejaculation, comprising administering to the indi comprised of polyethylene glycol. vidual an effective amount of a pharmaceutical formulation 14. The method of claim 13, wherein the urethral Sup comprising a 5-HT, receptor antagonist as the active agent pository further includes a Solubilizing compound for wherein the active agent of the formulation is effective to delay the onset of ejaculation by the individual during Sexual increasing the Solubility of the agent in the carrier. intercourse. 15. The method of claim 1, wherein the 5-HT, receptor 2. The method of claim 1, wherein the formulation is antagonist is Selected from the group consisting of administered transurethrally. on danse tron, ergot alkaloids, granise tron, 3. The method of claim 1, wherein the formulation is , tropisetron, dolasetron, batanopride and administered by intracaVernoSal injection. Zacopride. 4. The method of claim 1, wherein the formulation is 16. The method of claim 15, wherein the 5-HT receptor administered transdermally. antagonist is ondansetron. 5. The method of claim 1, wherein the formulation is 15 17. The method of claim 15, wherein the 5-HT receptor administered topically. antagonist is an ergot . 6. The method of claim 1, wherein the formulation is 18. The method of claim 15, wherein the 5-HT receptor administered orally. antagonist is granisetron. 7. The method of claim 1, wherein the formulation is 19. The method of claim 15, wherein the 5-HT, receptor administered parenterally. antagonist is trimethobenzamide. 8. The method of claim 1, wherein the formulation is 20. The method of claim 15, wherein the 5-HT receptor administered buccally. antagonist is tropisetron. 9. The method of claim 1, wherein the formulation is 21. The method of claim 15, wherein the 5-HT receptor administered nasally. antagonist is dolasetron. 10. The method of claim 1, wherein a predetermined dose 25 of the agent is administered to the individual one to four 22. The method of claim 15, wherein the 5-HT, receptor times in a twenty-four hour period. antagonist is batanopride. 11. The method of claim 1, wherein the pharmaceutical 23. The method of claim 15, wherein the 5-HT receptor formulation further comprises a vasoactive agent. antagonist is Zacopride. 12. The method of claim 2, wherein the pharmaceutical formulation comprises a urethral Suppository.