sign in sign up
<<
Home , Batanopride, Morphiceptin

USOO6974839B2 (12) United States Patent (10) Patent No.: US 6,974,839 B2 Bar-Or (45) Date of Patent: Dec. 13, 2005

(54) METHOD OF DELAYING EJACULATION 5,728,885 A 3/1998 Buschmann et al...... 564/304 5,801.201 A 9/1998 Graudums et al...... 514/646 (75) Inventor: David Bar-Or, Englewood, CO (US) 5,811,582 A 9/1998 Buschmann et al...... 564/355 5,874,620 A 2/1999 Lerman et al...... 564/443 (73) Assignee: DMI BioSciences, Inc., Englewood, 5,919,826 A 7/1999 Caruso ------... 514/629 CO (US) 5,922,341 A 7/1999 Smith et al. ... 424/430 5,929,122 A 7/1999 Reimann ...... 514/646 - - - 6,017,963 A 1/2000 Alfonso et al...... 514/646 (*) Notice: Subject to any disclaimer, the term of this 6,037,360 A 3/2000 Smith et al...... 514/397 patent is extended or adjusted under 35 6,090,856. A 7/2000 Sasaki ...... 514/646 U.S.C. 154(b) by 0 days. 6,156,342 A 12/2000 Sriwongjanya et al...... 424/473 6.228.864 B1 5/2001 Smith et al...... 514/288 (21) Appl. No.: 10/098,826 6,297.286 B1 10/2001 Huckle ...... 514/646 6,339,105 B1 1/2002 Kamin et al...... 514/646 (22) Filed: Mar 15, 2002 6,369,051 B1 4/2002 Jenkins ...... 514/217.08 6,376,554 B1 4/2002 Cheetham et al...... 514/646 (65) Prior Publication Data 6,399,618 B1 6/2002 Zolotoy et al...... 514/255.01 6,403,597 B1 6/2002 Wilson et al...... 514/256 US 2002/0132857 A1 Sep. 19, 2002 2001/0049391 A1 12/2001 Alfonso et al...... 514/564 O O 2002/0052341 A1 5/2002 Fang et al...... 514/58 Related U.S. Application Data 2002/005.5544 A1 5/2002 Kamin et al...... 514/650 (60) Provisional application No. 60/276,806, filed on Mar. FOREIGN PATENT DOCUMENTS 16, 2001. GB 2 340 O37 2/2000 (51) Int. Cl."7 ...... A61K 31/135 (Continued) (52) U.S. Cl...... 514/647 (58) Field of Search ...... 514/647 OTHER PUBLICATIONS (56) References Cited Wilder-Smith et al., Br. J. Clin. Pharmacol., 1997:43:71-75.* U.S. PATENT DOCUMENTS (Continued)Continued 3,652,589 A 3/1972 Flick et al...... poss Primary Examiner–San-Ming Hui 3,830,934. A 8/1974 Flick et al...... 2/3 (74) Attorney, Agent, or Firm-Sheridan Ross P.C. 4,507,323 A 3/1985 Stern ...... 514/649 4,940,731. A 7/1990 Bick ...... 514/657 (57) ABSTRACT 5,151,448 A 9/1992 Crenshaw et al...... 514/651 5,223,541 A 6/1993 Maryanoff et al...... 514/644 The invention provides a method of delaying ejaculation. 5,276,042 A 1/1994 Crenshaw et al...... 514/321 The method comprises administering an effective amount of 5,336,691 A 8/1994 Raffa et al...... 514/629 a material to a human male prior to Sexual inter 5,468,744. A 11/1995 Raffa et al...... 514/282 course. The method is particularly useful for treating pre 5,516,803 A 5/1996 Raffa ...... 514/570 mature eiaculation 5,591,452. A 1/1997 Miller et al...... 424/468 5,601,842 A 2/1997 Bartholomaeus ...... 424/464 5,723,668 A 3/1998 Buschmann et al...... 564/304 17 Claims, 1 Drawing Sheet C OMe OMe OH

Hé HC () (R,R) cis (-) (S,S) cis

US 6,974,839 B2 Page 2

FOREIGN PATENT DOCUMENTS (abstract) Retrieved May 1, 2003) Retrieved from PubMed, PMID: 10553695. WO WO95/13072 11/1994 WO WO 99/215.08 5/1999 Rodriguez-Manzo et al., “ antagonists and the Sexual WO WOOO/67729 11/2000 Satiation phenomenon. Psychopharmacology (Berl), Nov. WO WO 01/17521 3/2001 1995, 122(2): 131-6. (abstract) Retrieved May 1, 2003) WO WO O1/59084 8/2001 Retrieved from PubMed, PMID: 8848528. WO WO O2/41883 5/2002 Sanchez et al., “Comparison of the Effects of Antidepres sants and Their Metabolites on Reuptake of Biogenic OTHER PUBLICATIONS Amines and on Receptor Binding, Cellular and Molecular Jeffrey et al., British Journal of Anaesthesia, 1999; 83: Neurobiology, vol. 19, No. 4, 1999, pp. 467-489. 245-249. Stahl, “Not So Selective Reuptake Inhibitors”, Gobbi et al., European Journal of Pharmacology, 1999; Jul. 1998, Retrieved Apr. 2, 2003 from http://www. 370:23-26.* psychiatrist.com/pcc/brainstorm/brS907.htm. Agmo et al., “ and Sexual behavior in the male Trynke et al., “Citalopram alone does not, but combined rabbit: the role of central and peripheral opioid receptors'. with a Silent 5-HT1A does inhibit male J Neural Transm Gen Sect 1994; 97(e):211-23. (abstract) sexual behavior” Retrieved Apr. 7, 2003 from http://www Retrieved Apr. 15, 2003). Retrieved from PubMed, PMID: nin.sci.kun.nl/NIN%20abstracts.htm). 7873.130. Waldinger et al., “SSRIs and ejaculation: a double-blind, Balfour et al., “Activation of Ventral Tegmental Neurons randomized, fixed-dose Study with paroxetine and Following Sexual Behavior in Male Rats', Horm. Behav., citalopram”. J. Clin Psychopharmacol, Dec. 2001, 21(6): 39(4): 324 (2001). 556-60. (absract) Retrieved Mar. 31, 2003 Retrieved from Dunbar et al., “Concurrent Spinal Infusion of MK801 PubMed, PMID: 11763001. Blocks Spinal Tolerance and Dependence Induced by Waldinger et al., “ and ejaculation: a double Chronic Intrathecal in the Rat', Anesthesiology, blind, randomized, placebo-controlled, fixed-dose Study V. 84, No. 5, 1996, pp 1177-1188. with paroxetine, Sertraline, and '. J. Clin Frink et al., “Influence of Tramadol on Neurotransmitter Systems of the Rat Brain”, Arzneim.-Forsch/ Res. 46 Psychopharmacol, Jun. 2001, 21(3): 293-7. (abstract) (II), Nr. 11 (1996), pp 1029-1036. Retrieved Mar. 31, 2003 Retrieved from PubMed, PMID: Gomez-Marrero et al., “Stimulation of opioid receptors 11386492. suppresses penile erectile reflexes and seminal emission in Waldinger et al., “Effect of SSRI antidepressants on ejacula rats”. In: Pharmacol Biochem Behav, Oct. 1988:31(2): 393 tion: a double-blind, randomized, placebo-controlled Study 6 (abstract) Retrieved Apr. 15, 2003). Retrieved from with , fluvoxamine, paroxetine, and Sertraline'. J PubMed, PMID 2854263. Clin Psychopharmacol, Aug. 1998, 18(4): 274-81. (abstract) Jaw et al., “Involvement of kappa-opioid receptors in opioid Retrieved Mar. 31, 2003 Retrieved from PubMed, PMID: dependence/withdrawal: Studies using '. Eur J. 9690692. Pharmacol, May 12, 1994, 247 (1-2): 153-60 (abstract) Olivier et al., "Serotonin, receptors, Selective Retrieved Apr. 15, 2003). Retrieved from PubMed, PMID: serotonin reuptake inhibitors and sexual behaviour'. Int Clin 8082697. Psychopharmacol, Jul. 1998, 13 Suppl 6:S9-14, (abstract) Jaw et al., “Involvement of delta-opioid receptors in physi Retrieved Mar. 31, 2003 Retrieved from PubMed, PMID: cal dependence on butorphanol'. Eur J Pharmacol, Aug. 10, 97.28669. 1993, 240 (1): 67-72 (abstract) Retrieved Apr. 15, 2003). Waldinger, “Selective serotonin reuptake inhibitor-induced Retrieved from PubMed, PMID: 8405123. Sexual dysfunction clinical and research considerations”. Int Jaw et al., “Opioid antagonists and butorphanol Clin Psychopharmacol, Jul. 1998, 13 Suppl 6:S27-33. dependence". Pharmacol Biochem Behav, Mar. 1993: 44(3) (abstract) Retrieved Mar. 31, 2003 Retrieved from 497-500 (abstract) Retrieved Jun. 16, 2002 Retrieved from PubMed, PMID: 9728672. PubMed, PMID: 8383850. Waldinger et al., “The selective serotonic re-uptake inhibi Leyton et al., “The Stimulation of central kappa opioid tors fluvoxamine and paroxetine differ in Sexual inhibitory receptorS decreases male Sexual behavior and locomotor effects after chronic treatment'. Psychopharmacology activity”. Brain Res Oct. 23, 1992, 594(1): 56-74. (abstract) (Berl), Mar. 2002, 160(3):283-9. (abstract) Retrieved Apr. Retrieved Apr. 15, 2003 Retrieved from PubMed, PMID: 7, 2003 Retrieved from PubMed, PMID: 11889497. 1334765. Balfour et al., “MU Activation in Ventral Matuszewich, “Bilateral injections of a Selective mu-recep Tegmental Neurons Following Sexual Behavior”, tor (morphiceptin) into the medial preoptic nucleus International Research Conference, Monterey, produces a marked delay in the initiation of Sexual behavior CA, 2002. in the male rat'. Psychopharmacology (Berl), 1992; 106(3): Zarrindast et al., “Morphine inhibits dopaminergic and 391-6. (abstract) Retrieved Apr. 15, 2003 Retrieved from cholinergic induced ejaculation in rats'. In: Gen Pharmacol, PubMed, PMID: 1315063. Jul. 1994, 25(4):803-8. (abstract) Retrieved May 1, 2003) Melis et al. “Morphine injected into the paraventricular Retrieved from PubMed, PMID: 7958745. nucleus of the hypothalamus prevents noncontact penile “Link Found Between Pain, Immune, and Reproductive erections and impairs copulation: involvement of nitric Systems”, Indiana University School of Medicine, Apr. 21, oxide.” Eur J Neurosci, Jun. 1999, 11(6): 1857-64. (abstract) 1997. Retrieved Apr. 15, 2003 from http://medicine/ Retrieved Apr. 15, 2003 Retrieved from PubMed, PMID: indiana.edu/news releases/archieve 97/pain2.htm. 10336653. “ & Sexual Function”, IDMU Ltd. 1994-2002. Paredes et al., “What do female rats like about Sex Paced Retrieved Apr. 15, 2003 from http://www.idmu.co.uk/ mating.” Behav Brain Res, Nov. 1, 1999; 105(1): 117-27. opiateSex.htm. US 6,974,839 B2 Page 3

Pybus et al., “Opiates and Sexual Function'; Nature; 310 Venlafaxine drug monograph. Internet Mental Health (21); p. 636. online retrieved on Jul. 11, 2002 Retrieved from the Eledam et al., “Effects Non Analgésiques des Internet:

OMe

Cr-c,f HC (+) (R,R) cis (-) (S,S) cis

OMe

OH

(S,R) trans

Figure 1 US 6,974,839 B2 1 2 METHOD OF DELAYING EJACULATION Thus, a need clearly exists for other methods of treating premature ejaculation. In particular, there is a need for a CROSS REFERENCE TO RELATED method of treating premature ejaculation that requires no APPLICATIONS Specialized psychological therapy, can be used conveniently and without embarrassment, and does not involve the prob This application claims benefit of provisional application lems associated with prior therapeutic methods. 60/276,806, filed Mar. 16, 2001, the entire disclosure of Tramadol is a centrally acting Synthetic com which is considered to be part of the disclosure of this pound. Its mode of action is not completely understood. application and is hereby incorporated by reference. From animal tests, at least two complementary mechanisms appear applicable: (1) the binding of the parent compound FIELD OF THE INVENTION (tramadol) and the O-demethylated M1 metabolite to pu-opioid receptors; and (2) a weak inhibition of reuptake of The invention relates to a method of delaying ejaculation. norepinephrine and Serotonin. Opioid activity is due to both In particular, the invention relates to a method of delaying low affinity binding of the parent compound and higher ejaculation by the administration of a tramadol material. 15 affinity binding of the M1 metabolite to u-opioid receptors. In animal models, M1 is up to 6 times more potent than BACKGROUND OF THE INVENTION tramadol in producing analgesia and 200 times more potent in u-opioid binding. Tramadol has been shown to inhibit reuptake of norepinephrine and Serotonin in vitro, as have Premature ejaculation is a debilitating Sexual dysfunction. Some other opioid . These mechanisms may con This dysfunction can lead to an inability to enter into, or tribute independently to the overall analgesic profile of Sustain, relationshipS and can cause psychological damage tramadol. to Sufferers. Premature ejaculation can also impair repro Apart from analgesia, the use of tramadol to treat frequent ductive Success. urination and urinary incontinence (see U.S. Pat. No. 6,090, Treatments for premature ejaculation include psychologi 25 856) and to treat coughs, bronchitis and the common cold cal therapies, topical anesthetics, and the use of devices. All (see U.S. Pat. Nos. 3,652,589 and 3,830,934) have been of these treatments have significant drawbacks. Psychologi described. There is no teaching or Suggestion in the prior art cal therapies benefit only a Subset of patients and require that tramadol could be used to delay ejaculation. Specialized therapists who may not be available to all patients. Furthermore, psychological therapies cannot alle SUMMARY OF THE INVENTION Viate premature ejaculation resulting from non-psychologi cal causes. Anesthetic agents decrease Sensitivity of tissues, The invention provides a method of delaying ejaculation. thereby diminishing Sexual pleasure. Also, topical anesthet The method comprises administering an effective amount of ics can be transferred to Sexual partners and thereby a tramadol material to a human male prior to Sexual inter decrease their Sensitivity and pleasure as well. With regard 35 COSC. to devices, these can be awkward, inconvenient and embar rassing to use. Devices are highly conspicuous and reveal BRIEF DESCRIPTION OF THE DRAWINGS the very condition which the Suffering partner may prefer to conceal. Additionally, devices can cause irritation to one or FIG. 1 shows stereoisomers of tramadol. both partners. 40 Methods for treating premature ejaculation by Systemic DETAILED DESCRIPTION OF THE administration of Some antidepressant compounds (includ PRESENTLY PREFERRED EMBODIMENTS OF ing fluoxetine, Sertraline, paroxetine) have been described. THE INVENTION See U.S. Pat. Nos. 4,507,323, 4,940,731, 5,151,448, and 5,276,042 and Rosen et al., J. Clin. Psychopharmacol., 19, 45 The term "premature ejaculation' as used herein means a 67-85 (1999). However, these antidepressants may not be Sexual dysfunction wherein a male is unable to control the effective for all patients, and their Side effects can halt ejaculatory process to a degree Sufficient to Satisfy a partner. treatment or impair patient compliance. Disease States or Generally, premature ejaculation refers to persistent or adverse interactions with other drugs may contraindicate the recurring ejaculation with minimal Stimulation before or use of these compounds or require lower dosages that may 50 during Sexual intercourse. The term includes both “congeni not be effective to delay the onset of ejaculation. tal' or “lifelong premature ejaculation and “primary” or U.S. Pat. No. 6,037,360 describes a method of treating “acquired” premature ejaculation. Specific definitions premature ejaculation by administration of certain Serotonin include: (i) ejaculation prior to penetration or within ten to and antagonists. A Serotonin agonist is defined in twenty strokes after intromission; (ii) ejaculation in less than this patent to be a compound which mimics the effect of 55 1-2 minutes; and (iii) ejaculation 50% of the time more Serotonin on at least one of its receptors, and a Serotonin rapidly than the female is able to have an orgasm if she has antagonist is defined to be a compound which blocks the no orgasmic dysfunction. See, e.g., U.S. Pat. No. 6,037,360 effect of serotonin on at least one of its receptors. Preferred and 5,151,448; Male Infertility and Sexual Dysfunction, are Serotonin 5HT receptor antagonists (e.g., , page 356 (Springer-Verlag 1997); Diagnostic and Statistical ergot alkaloids, , , trimethoben 60 Manual of Mental Disorders (American Psychiatric Asso Zamide, , , batanopride, and Zacro ciation 1994). Premature ejaculation, however defined, can pride) and Serotonin 5HT agonists (e.g., and be treated by the method of the invention. D-lysergic acid diethylamide). Unfortunately, these com AS used herein, “delay ejaculation” means that a male pounds have side effects which may contraindicate their use receiving a tramadol material is able to control the ejacula (e.g., ergot alkaloids and D-lysergic acid diethylamide) or 65 tory proceSS So as to prevent ejaculation for a time which is have limited effectiveness (e.g., metoclopramide and the longer than that normally experienced by the male when not like; see PCT application WO95/13072). receiving the tramadol material. It is expected that, in the US 6,974,839 B2 3 4 case of a male who Suffers from premature ejaculation, the to Sexual intercourse. However, it is understood by those male will be able to control the ejaculatory process to a skilled in the art that the dosage amount will vary with the degree Sufficient to better or completely Satisfy his partner. particular form of tramadol employed, the route(s) of admin "Delay ejaculation' does not mean to totally prevent ejacu istration, the timing of the administration, the identity of any lation. other drugs being administered, whether or not the male The term “tramadol material' is used herein to refer to Suffers from premature ejaculation and the Severity of the 2-(dimethylamino)methyl-1-( 3-methoxyphenyl)-cyclo premature ejaculation condition, the age, Size and condition hexanol ("tramadol') and all pharmaceutically-acceptable of the patient, and like factors known in the medical art. In forms and derivatives of tramadol. In particular, the term general, a Suitable dose will be that amount of the compound includes the N-oxide derivative (“tramadol N-oxide’”) and which is the lowest dose effective to delay ejaculation the O-desmethyl derivative (“O-desmethyl tramadol'). The without toxicity. However, the dosage, route of administra term also includes the Solvates, polymorphs, and pharma tion, etc., will be determined by an attending physician ceutically-acceptable acid addition Salts of tramadol and its within the Scope of Sound medical judgement. derivatives. The term further includes all of the stereoiso The tramadol material may be administered by any Suit mers of any of the foregoing, including individual Stereoi 15 able route of administration, including orally, nasally, rec Somers (including individual enantiomers) and mixtures of tally, parenterally (e.g., intravenously, Subcutaneously, or Stereoisomers (including the racemates). intramuscularly), topically (i.e., delivery to the skin or The stereoisomers of tramadol are shown in FIG.1. There mucosa), transdermally (i.e., delivery by passage of a drug appears to be Some discrepancy in the literature regarding through the skin into the bloodstream), transmucosally (i.e., the nomenclature of the individual Stereoisomers of trama delivery by passage of a drug through the mucosal tissue into dol. For the purposes of the present application, the desig the bloodstream), intracavernoSally (i.e., injection into one nations of “cis' and “trans' stereoisomers of tramadol are or both corpora of the corpora cavernosal tissues of the made in reference to the relative positions of the dimethy penis), and intarurethrally (i.e., delivery into the urethra). lamino and the hydroxy Substituents on the cyclohexane ring Highly preferred is oral administration. within the tramadol molecule. As shown in FIG. 1, the R.R 25 While it is possible for the tramadol material to be and S.S enantiomers will be referred to herein as the “cis' administered alone, it is preferable to administer it as a isomers while the R.S and S.R isomers will be referred to pharmaceutical formulation (composition). The pharmaceu herein as the “trans' isomers. As also shown in FIG. 1, the tical compositions will comprise a tramadol material as the R.R isomer of tramadol will be referred to herein as the "+” active ingredient in admixture with one or more pharma cis isomer and the S.S isomer will be referred to as the “-” ceutically-acceptable carriers and, optionally, with one or cis isomer. It is presently understood that R,S and S.R more other compounds, drugs, or other materials. Each isomers are not optically active. carrier must be "acceptable' in the sense of being compat Presently preferred is tramadol and the acid addition salts ible with the other ingredients of the formulation and not thereof, particularly the hydrochloride. Even more preferred injurious to the male who will take the composition. Phar is (t)cis-tramadol, the acid addition Salts, particularly the 35 maceutically-acceptable carriers are well known in the art. hydrochloride, and the individual enantiomers. Regardless of the route of administration Selected, the active Methods of making tramadol, tramadol N-oxide, and ingredients are formulated into pharmaceutically-acceptable O-desmethyl tramadol are well known. See, e.g. U.S. Pat. dosage forms by conventional methods known to those of Nos. 3,652,589, 3,830,934, 5,223,541, 5,336,691, 5,723, skill in the art. See, e.g., Remington's Pharmaceutical 668, 5,728,885, and 5,874,620, the complete disclosures of 40 Sciences. which are incorporated herein by reference. Tramadol is also Formulations of the invention Suitable for oral adminis commercially available from Gruenenthal GmbH, Aschen, tration may be in the form of capsules, cachets, pills, tablets, Germany. powders, granules or as a Solution or a Suspension in an The pharmaceutically-acceptable acid addition Salts are aqueous or non-aqueous liquid, or an oil-in-water or water prepared by conventional methods well known in the art 45 in-oil liquid emulsions, or as an elixir or Syrup, or as pastilles using pharmaceutically-acceptable, Substantially non-toxic, (using an inert base, Such as gelatin and glycerin, or Sucrose organic and inorganic acids. Such acids include hydrochloric and acacia), and the like, each containing a predetermined acid, nitric acid, Sulfuric acid, phosphoric acid, hydrobromic amount of the active ingredient. Preferred oral administra acid, acetic acid, propionic acid, maleic acid, malonic acid, tion forms are tablets and capsules. Succinic acid, citric acid, tartaric acid, malic acid, benzoic 50 In Solid dosage forms of the invention for oral adminis acid, Salicylic acid, phthalic acid, nicotinic acid, etc. Pre tration (capsules, tablets, pills, dragees, powders, granules ferred is hydrochloric acid, and tramadol hydrochloride is and the like), the active ingredient is mixed with one or more the most preferred compound for practicing the invention. pharmaceutically acceptable carriers, Such as Sodium citrate To delay ejaculation, an effective amount of a tramadol or dicalcium phosphate, and/or any of the following: (1) material is administered to a male prior to Sexual inter 55 fillers or extenders, Such as Starches, lactose, Sucrose, glu course. By an “effective amount' is meant a nontoxic, but cose, mannitol, and/or Silicic acid; (2) binders, Such as, for Sufficient, amount of a tramadol material to delay ejacula example, carboxymethylcellulose, alginates, gelatin, poly tion. Effective dosage forms, modes and times of adminis vinyl pyrrolidone, Sucrose and/or acacia; (3) humectants, tration, and dosage amounts maybe determined empirically, Such as glycerol; (4) disintegrating agents, Such as agar-agar, and making Such determinations is within the skill of the art. 60 calcium carbonate, potato or tapioca Starch, alginic acid, Preferred is a single dose taken orally shortly before sexual certain Silicates, and Sodium carbonate; (5) Solution retard intercourse. In particular, it has been found that an effective ing agents, Such as paraffin; (6) absorption accelerators, Such dosage of (t)cis-2-(dimethylamino)methyl-1-(3-methox as quaternary ammonium compounds; (7) wetting agents, yphenyl)-cyclohexanol hydrochloride to delay ejaculation is Such as, for example, cetyl and glycerol monoster from about 10 to about 50 milligrams (mg), preferably from 65 ate; (8) absorbents, Such as kaolin and bentonite clay; (9) about 15 to about 35 mg, most preferably about 25 mg, lubricants, Such as talc, calcium Stearate, magnesium Stear administered orally from about 30 to about 60 minutes prior ate, Solid polyethylene glycols, Sodium lauryl Sulfate, and US 6,974,839 B2 S 6 mixtures thereof, and (10) coloring agents. In the case of Dosage forms for the topical, transdermal or transmucosal capsules, tablets and pills, the pharmaceutical compositions administration of the active ingredient include powders, may also comprise buffering agents. Solid compositions of Sprays, ointments, pastes, creams, lotions, gels, Solutions, a similar type may be employed as fillers in Soft and patches, drops and inhalants. The active ingredient may be hard-filled gelatin capsules using Such excipients as lactose mixed under Sterile conditions with a pharmaceutically or milk Sugars, as well as high molecular weight polyeth acceptable carrier, and with any buffers, or propellants ylene glycols and the like. which may be required. A tablet may be made by compression or molding option The ointments, pastes, creams and gels may contain, in ally with one or more accessory ingredients. Compressed addition to the active ingredient, excipients, Such as animal tablets may be prepared using binder (for example, gelatin and vegetable fats, oils, waxes, paraffins, Starch, tragacanth, or hydroxypropylmethyl cellulose), lubricant, inert diluent, cellulose derivatives, polyethylene glycols, Silicones, ben preservative, disintegrant (for example, Sodium starch gly tonites, Silicic acid, talc and Zinc oxide, or mixtures thereof. colate or cross-linked Sodium carboxymethyl cellulose), Powders and SprayS can contain, in addition to the active Surface-active or dispersing agent. Molded tablets may be ingredient, excipients Such as lactose, talc, Silicic acid, made by molding in a Suitable machine a mixture of the 15 aluminum hydroxide, calcium Silicates and polyamide pow powdered compound moistened with an inert liquid diluent. der or mixtures of these Substances. SprayS can additionally The tablets, and other Solid dosage forms of the pharma contain customary propellants Such as chlorofluorohydro ceutical compositions of the present invention, Such as carbons and Volatile unsubstituted hydrocarbons, Such as dragees, capsules, pills and granules, may optionally be butane and propane. Scored or prepared with coatings and shells, Such as enteric The active ingredient may also be delivered through the coatings and other coatings well known in the pharmaceu skin using conventional transdermal drug delivery Systems, tical-formulating art. They may also be formulated So as to i.e., transdermal patches, wherein the agent is typically provide Slow or controlled release of the active ingredient contained within a laminated Structure that Serves as a drug therein using, for example, hydroxypropylmethyl cellulose delivery device to be affixed to the skin. In such a structure, in varying proportions to provide the desired release profile, 25 the active ingredient is typically contained in a layer, or other polymer matrices, liposomes and/or microSpheres. “reservoir, underlying an upper backing layer. The lami They may be Sterilized by, for example, filtration through a nated device may contain a Single reservoir, or it may bacteria-retaining filter. These compositions may also contain multiple reservoirs. In one embodiment, the reser optionally contain opacifying agents and may be of a voir comprises a polymeric matrix of a pharmaceutically composition that they release the active ingredient only, or acceptable contact adhesive material that Serves to affix the preferentially, in a certain portion of the gastrointestinal System to the skin during drug delivery. Examples of Suit tract, optionally, in a delayed manner. Examples of embed able skin contact adhesive materials include, but are not ding compositions which can be used include polymeric limited to, polyethylenes, polysiloxanes, polyisobutylenes, Substances and waxes. The active ingredient can also be in polyacrylates, polyurethanes, and the like. Alternatively, the microencapsulated form. 35 drug-containing reservoir and skin contact adhesive are Liquid dosage forms for oral administration of the com present as Separate and distinct layers, with the adhesive pounds of the invention include pharmaceutically-accept underlying the reservoir which, in this case, may be either a able emulsions, microemulsions, Solutions, Suspensions, polymeric matrix as described above, or it may be a liquid SyrupS and elixirs. In addition to the active ingredient, the or hydrogel reservoir, or may take Some other form. liquid dosage forms may contain inert diluents commonly 40 The backing layer in these laminates, which Serves as the used in the art, Such as, for example, water or other Solvents, upper Surface of the device, functions as the primary Struc Solubilizing agents and emulsifiers, Such as ethyl alcohol, tural element of the laminated Structure and provides the isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl device with much of its flexibility. The material selected for alcohol, benzyl benzoate, propylene glycol, 1,3-butylene the backing material should be Selected So that it is Substan glycol, oils (in particular, cottonseed, groundnut, corn, germ, 45 tially impermeable to the active ingredient and any other olive, castor and Sesame oils), glycerol, tetrahydrofuryl materials that are present. The backing layer may be either alcohol, polyethylene glycols and fatty acid esters of Sorbi occlusive or nonocclusive, depending on whether it is tan, and mixtures thereof. desired that the skin become hydrated during drug delivery. Besides inert diluents, the oral compositions can also The backing is preferably made of a sheet or film of a include adjuvants Such as wetting agents, emulsifying and 50 preferably flexible elastomeric material. Examples of poly Suspending agents, Sweetening, flavoring, coloring, perfum mers that are Suitable for the backing layer include polyeth ing, thickening, and preservative agents. ylene, polypropylene, polyesters, and the like. Suspensions, in addition to the active ingredient, may During Storage and prior to use, the laminated Structure contain Suspending agents as, for example, ethoxylated 55 includes a release liner. Immediately prior to use, this layer isoStearyl alcohols, polyoxyethylene Sorbitol and Sorbitan is removed from the device to expose the basal Surface esters, microcrystalline cellulose, aluminum metahydroxide, thereof, either the drug reservoir or a separate contact bentonite, agar-agar and tragacanth, and mixtures thereof. adhesive layer, So that the System may be affixed to the skin. Formulations of the pharmaceutical compositions of the The release liner should be made from a drug/vehicle invention for rectal administration may be presented as a 60 impermeable material. Suppository, which may be prepared by mixing one or more Transdermal drug delivery devices maybe fabricated compounds of the invention with one or more Suitable using conventional techniques, known in the art, for nonirritating excipients or carriers comprising, for example, example by casting a fluid admixture of adhesive, drug and cocoa butter, polyethylene glycol, a Suppository wax or vehicle onto the backing layer, followed by lamination of the Salicylate, and which is Solid at room temperature, but liquid 65 release liner. Similarly, the adhesive mixture may be cast at body temperature and, therefore, will melt in the rectum onto the release liner, followed by lamination of the backing and release the active ingredient. layer. Alternatively, the drug reservoir may be prepared in US 6,974,839 B2 7 8 the absence of drug or excipient, and then loaded by forms may be brought about by the inclusion of agents “Soaking in a drug/vehicle mixture. which delay absorption Such as aluminum monosterate and The laminated transdermal drug delivery Systems may in gelatin. In Some cases, in order to prolong the effect of the active addition contain a skin permeation enhancer. That is, ingredient, it is desirable to Slow the absorption of the active because the inherent permeability of the Skin to Some drugs ingredient from Subcutaneous or intramuscular injection. may be too low to allow therapeutic levels of the drug to pass This may be accomplished by the use of a liquid Suspension through a reasonably sized area of unbroken skin, it is of crystalline or amorphous material having poor water necessary to coadminister a skin permeation enhancer with solubility. The rate of absorption of the active ingredient Such drugs. Suitable enhancers are well known in the art. then depends upon its rate of dissolution which, in turn, may The pharmaceutical compositions of the invention may depend upon crystal size and crystalline form. Alternatively, also be administered by nasal aerosol or inhalation. Such delayed absorption of a parenterally-administered active compositions are prepared according to techniques well ingredient is accomplished by dissolving or Suspending the known in the art of pharmaceutical formulation and may be drug in an oil vehicle. prepared as Solutions in Saline, employing benzyl alcohol or 15 Injectable depot forms are made by forming microencap other Suitable preservatives, absorption promoters to Sule matrices of the active ingredient in biodegradable enhance bioavailability, propellants Such as fluorocarbons or polymerS Such as polylactide-polyglycolide. Depending on nitrogen, and/or other conventional Solubilizing or disperS the ratio of active ingredient to polymer, and the nature of ing agents. the particular polymer employed, the rate of release of the Preferred formulations for topical drug delivery are oint active ingredient can be controlled. Examples of other ments and creams. Ointments are Semisolid preparations biodegradable polymers include poly(orthoesters) and poly which are typically based on petrolatum or other petroleum (anhydrides). Depot injectable formulations are also pre derivatives. Creams containing the Selected active agent, pared by entrapping the active ingredient in liposomes or are, as known in the art, Viscous liquid or Semisolid emul microemulsions which are compatible with body tissue. The Sions, either oil-in-water or water-in-oil. Cream bases are 25 injectable materials can be Sterilized for example, by filtra water-washable, and contain an oil phase, an emulsifier and tion through a bacterial-retaining filter. an aqueous phase. The oil phase, also Sometimes called the IntracavernoSal injection can be carried out by use of a “internal' phase, is generally comprised of petrolatum and a Syringe or any other Suitable device. An example of a fatty alcohol Such as cetyl or Stearyl alcohol; the aqueous hypodermic Syringe useful herein, that can be used for phase usually, although not necessarily, exceeds the oil Simultaneous injection into both corpora, is described in phase in Volume, and generally contains a humectant. The U.S. Pat. No. 4,127,118. The injection is made on the emulsifier in a cream formulation is generally a nonionic, dorsum of the penis by placement of the needle to the side anionic, cationic or amphoteric Surfactant. The Specific of each dorsal vein and inserting it deep into the corpora. ointment or cream base to be used, as will be appreciated by The active ingredient can be administered in a pharma those skilled in the art, is one that will provide for optimum 35 ceutical formulation Suitable for transurethral drug delivery. drug delivery. AS with other carriers or vehicles, an ointment The formulation contains one or more Selected carriers or base should be inert, Stable, nonirritating and nonsensitizing. excipients, Such as water, Silicone, waxes, petroleum jelly, Formulations for buccal administration include tablets, polyethylene glycol, propylene glycol, liposomes, Sugars lozenges, gels and the like. Alternatively, buccal adminis Such as mannitol and lactose, and/or a variety of other tration can be effected using a transmucosal delivery System 40 materials, with polyethylene glycol and derivatives thereof as known to those skilled in the art. particularly preferred. It may be desirable to incorporate a transurethral permeation enhancer in the urethral dosage Pharmaceutical compositions Suitable for parenteral form. Examples of Suitable transurethral permeation enhanc administrations comprise the active ingredient in combina ers include dimethylsulfoxide, dimethyl formaminde, N,N- tion with one or more pharmaceutically-acceptable Sterile 45 dimethylacetamide, decylmethylsulfoxide, polyethylene isotonic aqueous or non-aqueous Solutions, dispersions, Sus glycol monolaurate, glycerol monolaurate, lecithin, the pensions or emulsions, or Sterile powders or other Solid 1-Substituted azacycloheptan-2-ones, particularly 1-n-dode forms which may be reconstituted into sterile injectable cylcyclazacycloheptan-2-one (available under the trademark Solutions or dispersions just prior to use, which may contain AZone(R) from Nelson Research & Development Co., Irvine, antioxidants, buffers, Solutes which render the formulation 50 Calif.), SEPAGE) (available from Macrochem Co., Lexington, isotonic with the blood of the intended recipient or Suspend Mass.), alcohols (e.g., ethanol), detergents (Such as Tergi ing or thickening agents. tol(R), Nonoxynol-9(R) and TWEEN-80(R) and the like. Tran Examples of Suitable aqueous and nonaqueous carriers Surethral formulations may additionally include one or more which may be employed in the pharmaceutical compositions enzyme inhibitors effective to inhibit drug-degrading include water, ethanol, polyols (such as glycerol, propylene 55 enzymes which may be present in the urethra. Additional glycol, polyethylene glycol, and the like), and Suitable optional components include excipients, preservatives (e.g., mixtures thereof, vegetable oils, Such as olive oil, and antioxidants), chelating agents, Solubilizing agents (e.g., injectable organic esters, Such as ethyl oleate. Proper fluidity Surfactants), and the like, as will be appreciated by those can be maintained, for example, by the use of coating skilled in the art of drug formulation preparation and deliv materials, Such as lecithin, by the maintenance of the 60 ery. required particle size in the case of dispersions, and by the Transurethral drug administration, as explained in PCT use of Surfactants. application WO 91/16021, can be carried out in a number of These compositions may also contain adjuvants Such as different ways using a variety of urethral dosage forms. For Wetting agents, emulsifying agents and dispersing agents. It example, the drug can be introduced into the urethra from a may also be desirable to include isotonic agents, Such as 65 flexible tube, Squeeze bottle, pump or aeroSol Spray. The Sugars, Sodium chloride, and the like in the compositions. In drug may also be contained in coatings, pellets or Supposi addition, prolonged absorption of injectable pharmaceutical tories which are absorbed, melted or bioeroded in the US 6,974,839 B2 10 urethra. In certain embodiments, the drug is included in a preparation of tramadol marketed under the brand name coating on the exterior Surface of a penile insert. Drug ULTRAME) consists of a mixture of the R.R and S.S isomers delivery devices for administering a drug transurethrally are of tramadol hydrochloride. described in U.S. Pat. No. 6,037,360 and PCT application WO 91/16021. EXAMPLES Urethral Suppository formulations containing polyethyl ene glycol or a polyethylene glycol derivative can be used as Example 1 the urethral dosage form, and may be conveniently formu lated using conventional techniques, e.g., compression Tramadol Hydrochloride Delays Ejaculation molding, heat molding or the like, as will be appreciated by 1O those skilled in the art and as described in the pertinent A tramadol material at doses of 10 mg and higher, taken literature and pharmaceutical texts. See, for example, Rem approximately 30–60 minutes prior to Sexual intercourse by ington. The Science and Practice of Pharmacy, 19th Ed. the male partner delays ejaculation significantly. It was (Easton, Pa. Mack Publishing Co., 1995), which discloses observed, for example, that a dose of 25 mg tramadol typical methods of preparing pharmaceutical compositions hydrochloride (one-half of a 50 mg ULTRAM tablet, Ortho in the form of urethral Suppositories. It is also preferred that 15 McNeil Pharmaceutical, Inc., Raritan, N.J.) taken orally urethral Suppositories contain one or more Solubilizing 30-60 minutes prior to Sexual intercourse delayed ejacula agents (e.g., a nonionic, anionic, cationic or amphoteric tion by a normal male subject by at least 10-15 minutes. At surfactant) effective to increase the solubility of the active doses of 50-100 mg, a similar effect was observed. How ingredient in the polyethylene glycol or other transurethral ever, it was associated with drowsiness, lightheadedness, dry vehicle. mouth and a Sense of slight euphoria (opioid effect) and, at It may be desirable to deliver the active ingredient in a 100 mg, Sometimes ejaculation/orgasm was not achieved. urethral dosage form which provides for controlled or SuS From these observations, it was concluded that a dose of tained release of the agent. In Such a case, the dosage form 10-50 mg of a tramadol material, preferably 15-35 mg, typically comprises a biocompatible, biodegradable mate most preferably 25 mg, can delay ejaculation significantly rial, typically a biodegradable polymer. Examples of Such 25 and can be used to treat (prevent or reduce) premature polymers include polyester, polyalkylcyanoacrylate, poly ejaculation. orthoester, polyanhydride, albumin, gelatin and Starch. AS explained, for example, in PCT application WO 96/40054, I claim: these and other polymers can be used to provide biodegrad 1. A method of delaying ejaculation during Sexual inter able microparticles which enable controlled and Sustained course comprising administering orally to a human male drug release, in turn minimizing the required dosing fre who Suffers from premature ejaculation prior to the Sexual quency. intercourse an effective amount of a compound Selected The method of intraurethral administration may involve from the group consisting of tramadol, a pharmaceutically an “active' delivery mechanism Such as iontophoresis, elec acceptable form of tramadol, tramadol-oxide, a pharmaceu troporation or phonophoresis. Devices and methods for tically-acceptable form of tramadol N-oxide, O-desmethyl delivering drugs in this way are well known in the art. 35 tramadol, a pharmaceutically-acceptable form of O-desm Iontophoretically assisted drug delivery is, for example, ethyl tramadol and mixtures of the foregoing. described in PCT application WO 96/40054. Briefly, the 2. The method of claim 1 wherein the compound is active agent is driven through the urethral wall by means of tramadol or a pharmaceutically-acceptable Salt thereof. an electric current passed from an external electrode to a 3. The method of claim 2 wherein the tramadol is (+) Second electrode contained within or affixed to a urethral 40 cis-tramadol or a pharmaceutically-acceptable Salt thereof. probe. 4. The method of claim3 wherein a dose of from about 10 The pharmaceutical formulations of the tramadol material to about 50 milligrams of the tramadol or the pharmaceuti may be presented in unit-dose or multi-dose Sealed contain cally-acceptable Salt thereof is administered to the male. ers, for example, ampules and vials, and may be stored in a 5. The method of claim 4 wherein a dose of from about 15 lyophilized condition requiring only the addition of the 45 Sterile liquid carrier, for example water for injection, imme to about 35 milligrams of the tramadol or the pharmaceuti diately prior to use. Extemporaneous injection Solutions and cally-acceptable Salt thereof is administered to the male. Suspensions maybe prepared from Sterile powders, granules 6. The method of claim 4 wherein a dose of about 25 and tablets of the type described above. milligrams of the tramadol or the pharmaceutically-accept Pharmaceutical compositions containing a tramadol mate 50 able Salt thereof is administered to the male. rial and methods of making the pharmaceutical composi 7. The method of claim 3 whereina (+)-enantiomer of the tions have been described. See, e.g., U.S. Pat. Nos. 3,652, cis-tramadol or the pharmaceutically-acceptable Salt thereof 589, 3,830,934, 5,223,541, 5,591,452, 5,601,842, 5,728,885, is administered to the male. 6,017,963, 6,090,856, and 6,156,342, the complete disclo 8. The method of claim 3 whereina (-)-enantiomer of the Sures of which are incorporated herein by reference. More 55 cis-tramadol or the pharmaceutically-acceptable Salt thereof over, pharmaceutical compositions containing tramadol and is administered to the male. pharmaceutically-acceptable Salts thereof are manufactured 9. The method of claim 3 wherein the tramadol material and sold worldwide. In the United States, (+)-cis-2-(dim ethylamino)methyl-1-(3-methoxyphenyl)-cyclohexanol is (t) cis-tramadol hydrochloride. hydrochloride for oral administration is available from 10. The method of claim 9 wherein a dose of from about Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J. 08869, as 60 10 to about 50 milligrams of the tramadol hydrochloride is ULTRAM tablets. Each ULTRAM tablet contains 50 mg administered to the male. (t)cis-2- (dimethylamino)methyl-1-(3-methoxyphenyl)- 11. The method of claim 10 wherein a dose of from about cyclohexanol hydrochloride and a number of inactive ingre 15 to about 35 milligrams of the tramadol hydrochloride is dients (corn Starch, hydroxypropyl methylcellulose, lactose, administered to the male. magnesium Stearate, microcrystalline cellulose, polyethyl 65 12. The method of claim 10 wherein a dose of about 25 ene glycol, polySorbate 80, Sodium Starch glycolate, tita milligrams of the tramadol hydrochloride is administered to nium dioxide and wax). It is understood the commercial the male. US 6,974,839 B2 11 12 13. The method of any one of claims 1-12 or 14-17 16. The method of claim 10 wherein a dose of from about wherein the compound is administered from about 30 min 10 to about 35 milligrams of the tramadol or the pharma utes to about 60 minutes prior to Sexual intercourse. ceutically-acceptable Salt thereof is administered to the 14. The method of claim 4 wherein a dose of from about male. 10 to about 35 milligrams of the tramadol or the pharma ceutically-acceptable Salt thereof is administered to the 17. The method of claim 10 wherein a dose of from about male. 25 to about 35 milligrams of the tramadol or the pharma 15. The method of claim 4 wherein a dose of from about ceutically-acceptable Salt thereof is administered to the 25 to about 35 milligrams of the tramadol or the pharma male. ceutically-acceptable Salt thereof is administered to the 10 male.