Combination Therapy for Male Sexual Dysfunction

Abstract

Pharmaceutical formulations containing a serotonin reuptake inhibitor and a phosphodiesterase 5 inhibitor are provided for the treatment of premature ejaculation and the increase in intravaginal ejaculatory latency time. Specific formulations contain tadalafil (1-30 mg per dose) and escitalopram (1-30 mg) in daily dose and on-demand formulations.

Claims

1. A method for delaying the onset of ejaculation in a male subject comprising administering to the subject 18 milligrams (mg) of escitalopram or a salt thereof and 9 mg of tadalafil or a salt thereof on-demand prior to sexual activity, wherein the onset of ejaculation by the subject is delayed during sexual activity by greater than 10 minutes.

2. The method of claim 1, wherein the escitalopram and tadalafil are administered at the same time.

3. The method of claim 1, wherein the escitalopram and tadalafil are administered orally in a single pharmaceutical formulation.

4. The method of claim 1, wherein the on-demand administering is within 36 hours prior to sexual activity.

5. The method of claim 4, wherein the on-demand administering is from 30 minutes to 5 hours prior to sexual activity.

6. The method of claim 4, wherein the on-demand administering is from 2 hours to 24 hours prior to sexual activity.

7. The method of claim 4, wherein said escitalopram and said tadalafil are co-administered to said male subject within about 36 hours, within about 24 hours, within about 12 hours, within about 6 hours prior to sexual activity, or within about 2 hours prior to sexual activity.

8. The method of claim 1, wherein the escitalopram and tadalafil are administered as a rapid dissolve tablet comprising 2.75% (w/w) escitalopram oxalate USP 39 powder, 1.37% (w/w) tadalafil powder, 81.22% (w/w) rapid dissolve tablet base powder, 3.82% (w/w) micronized silica gel, 9.16% (w/w) polyethylene glycol 3350, 0.61% (w/w) acesulfame potassium powder, 0.46% steviol glycosides 95% powder, and 0.61% (w/w) raspberry powder flavor.

9. A method of treating premature ejaculation in a patient in need thereof comprising administering to the patient no more than about 36 hours prior to sexual activity an oral tablet comprising about 1-40 mg escitalopram or a salt thereof, and a pharmaceutically acceptable excipient.

10. The method of claim 9, wherein said oral tablet further comprises about 1-30 mg tadalafil or a salt thereof.

11. The method of claim 10, wherein said oral tablet is administered to said patient no more than about 24 hours, no more than about 12 hours, no more than about 6 hours, no more than about 4 hours, or no more than about 2 hours prior to sexual activity.

12. The method of claim 10, wherein said oral tablet contains about 1 mg, about 4.5 mg, about 9 mg, or about 27 mg of tadalafil and contains about 1 mg, about 9 mg, about 18 mg, or about 36 mg of escitalopram.

13. A method of treating premature ejaculation in a patient in need thereof comprising administering to the patient no more than about 36 hours prior to sexual activity a pharmaceutical composition comprising about 18 mg escitalopram or a salt thereof, about 9 mg tadalafil or a salt thereof, and a pharmaceutically acceptable excipient, wherein the onset of ejaculation by the patient is delayed during sexual activity by greater than 10 minutes.

14. The method of claim 13 wherein said pharmaceutical composition is administered to said patient about 30 minutes to about 5 hours prior to sexual activity.

15. The method of claim 13, wherein said pharmaceutical composition is administered to said patient about 2 hours to about 24 hours prior to sexual activity.

16. The method of claim 13, wherein the pharmaceutical composition comprises 2.75% (w/w) escitalopram oxalate USP 39 powder, 1.37% (w/w) tadalafil powder, 81.22% (w/w) rapid dissolve tablet base powder, 3.82% (w/w) micronized silica gel, 9.16% (w/w) polyethylene glycol 3350, 0.61% (w/w) acesulfame potassium powder, 0.46% steviol glycosides 95% powder, and 0.61% (w/w) raspberry powder flavor.

Description

DETAILED DESCRIPTION

[0060] Before the present invention is described, it is to be understood that this invention is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0061] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term “about”, when used in reference to a particular recited numerical value or range of values, means that the value may vary from the recited value by no more than 2%. For example, as used herein, the expression “about 100” includes 98 and 102 and all values in between (e.g., 98.00, 98.01, 98.02, 98.03, 98.04, . . . , 101.96, 101.97, 101.98, 101.99, 102.00).

[0062] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplar methods and materials are now described. All publications mentioned herein are incorporated herein by reference to describe in their entirety.

[0063] As used herein, the expression “pharmaceutical formulation” means a combination of at least one active ingredient (e.g., a small molecule, macromolecule, compound, etc. which is capable of exerting a biological effect in a human or non-human animal), and at least one inactive ingredient which, when combined with the active ingredient or one or more additional active or inactive ingredients, is suitable for therapeutic administration to a human or non-human animal. The term “formulation”, as used herein, means “pharmaceutical formulation” unless specifically indicated otherwise. The present invention provides at least two pharmaceutical formulations containing one therapeutic small molecule that may be combined or co-administered to a subject. The present invention also provides pharmaceutical formulations that contain at least two therapeutic small molecules. According to those embodiments of the present invention having at least two formulations, in one embodiment the therapeutic small molecule is a phosphodiesterase inhibitor in one formulation, and a serotonin reuptake inhibitor in the other formulation. In another embodiment, the therapeutic small molecule is an alpha-blocker in one formulation, and a serotonin reuptake inhibitor in the other formulation. According to those embodiments having a single formulation containing at least two therapeutic small molecules, in one embodiment one therapeutic small molecule is a phosphodiesterase inhibitor and the other therapeutic small molecule is a serotonin reuptake inhibitor. In another embodiment one therapeutic small molecule is an alpha-blocker and the other therapeutic small molecule is a serotonin reuptake inhibitor. Specifically, the present invention includes in one embodiment a pharmaceutical co-formulations that comprise: (i) a phosphodiesterase 5 inhibitor (PDE5i) (ii) a selective serotonin reuptake inhibitor; and (iii) one or more pharmaceutically acceptable excipients. Specifically, the present invention includes in another embodiment a pharmaceutical co-formulations that comprise: (i) an alpha-blocker; (ii) a selective serotonin reuptake inhibitor; and (iii) one or more pharmaceutically acceptable excipients. More specifically, the present invention includes in one embodiment a pharmaceutical co-formulation that comprises: (i) taladafil (ii) escitalopram; and (iii) one or more pharmaceutically acceptable excipients; and in another embodiment a pharmaceutical co-formulation that comprises: (i) tamsulosin (ii) escitalopram, and (iii) one or more pharmaceutically acceptable excipients.

[0064] Pharmaceutical compositions useful in the practice of the method of the invention include a therapeutically effective amount of an active agent, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.

[0065] Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, other natural sweeteners, sugar alcohol, steviol glycosides, artificial sweeteners (i.e., acesulfame potassium, aspartame, saccharin, and sucralose), natural and artificial flavorings, gelatin, malt, rice, flour, chalk, silica gel (micronized), sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, polyethylene glycol (e.g., 3350), anticaking agents (e.g., tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminium silicate, calcium aluminosilicate, bentonite, aluminium silicate, stearic acid, polydimethylsiloxane), water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations, rapidly dissolving oral (buccal) tablets and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.

[0066] The active agents of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. Pharmaceutically acceptable counter ions include inter alia hydrochloride, sodium, sulfate, acetate, phosphate or diphosphate, chloride, potassium, maleate, calcium, citrate, mesylate, nitrate, succinate, tartrate, aluminum, and gluconate. In one embodiment, for example, the escitalopram is an escitalopram oxalate.

[0067] The amount of each active agent of the invention that will be effective in the treatment of premature ejaculation can be determined by standard clinical techniques based on the present description. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the condition, and should be decided according to the judgment of the practitioner and each subject's circumstances. However, suitable dosage ranges for oral administration are generally about 35-500 micrograms of each active agent (e.g., tadalafil and escitalopram) per kilogram body weight. Other suitable dosage ranges for oral administration are generally about 1-30 milligrams of each active agent (e.g., tadalafil or Acesulfame potassium, aspartame, saccharin, and sucralose, and escitalopram) per dose. Suitable dosage ranges for intranasal administration are generally about 0.01 ρg/kg body weight to 1 mg/kg body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0068] For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in vitro. Such information can be used to more accurately determine useful doses in humans. Initial dosages can also be estimated from in vivo data, e.g., animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.

[0069] Dosage amount and interval may be adjusted individually to provide plasma levels of the compounds that are sufficient to maintain therapeutic effect. A person having ordinary skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

[0070] The amount of compound administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. The therapy may be repeated intermittently while symptoms are detectable or even when they are not detectable. The therapy may be provided alone or in combination with other drugs.

[0071] According to certain embodiments of the invention, the pharmaceutical formulation is formulated as a formulation to be administered once daily to a subject suffering from premature ejaculation or desiring to increase intravaginal ejaculatory latency time (IELT). In a preferred formulation, approximately 9 mg of the PDE5i tadalafil (free form or salts) is combined with approximately 18 mg escitalopram (free form or salts, e.g., oxalate) and one or more pharmaceutically acceptable excipients. In another preferred formulation, approximately 0.4 mg of the alpha-blocker tamsulosin (free form or salts) is combined with approximately 18 mg escitalopram (free form or salts, e.g., oxalate) and one or more pharmaceutically acceptable excipients.

[0072] According to certain embodiments of the invention, the pharmaceutical formulation is formulated as a formulation to be administered on-demand to a subject suffering from premature ejaculation or desiring to increase intravaginal ejaculatory latency time (IELT). In a specific formulation for on-demand administration, approximately 6.9 mg of the PDE5i tadalafil (free form or salts) is combined with approximately 9.6 mg escitalopram (free form or salts) and one or more pharmaceutically acceptable excipients. In another specific formulation for on-demand administration, approximately 6.9 mg of the PDE5i tadalafil (free form or salts) is combined with approximately 19.2 mg escitalopram (free form or salts) and one or more pharmaceutically acceptable excipients. In another specific formulation for on-demand administration, approximately 13.8 mg of the PDE5i tadalafil (free form or salts) is combined with approximately 19.2 mg escitalopram (free form or salts) and one or more pharmaceutically acceptable excipients. In yet another specific formulation for on-demand administration, approximately 9 mg of the PDE5i tadalafil (free form or salts) is combined with approximately 18 mg escitalopram (free form or salts) and one or more pharmaceutically acceptable excipients.

[0073] In a specific formulation for on-demand administration, approximately 0.2 mg of the alpha-blocker tamsulosin (free form or salts) is combined with approximately 9.6 mg escitalopram (free form or salts) and one or more pharmaceutically acceptable excipients. In another specific formulation for on-demand administration, approximately 0.2 mg of the alpha-blocker tamsulosin (free form or salts) is combined with approximately 19.2 mg escitalopram (free form or salts) and one or more pharmaceutically acceptable excipients. In another specific formulation for on-demand administration, approximately 0.4 mg of the alpha-blocker tamsulosin (free form or salts) is combined with approximately 19.2 mg escitalopram (free form or salts) and one or more pharmaceutically acceptable excipients. In yet another specific formulation for on-demand administration, approximately 0.4 mg of the alpha-blocker tamsulosin (free form or salts) is combined with approximately 18 mg escitalopram (free form or salts) and one or more pharmaceutically acceptable excipients.

[0074] The excipients for each formulation depend in part on the route of administration (parenteral, nasal, buccal) and the desired properties of the formulation, such as extended release, rapid oral dissolution, enteric coating, comingled or bilayered agents, etc.

[0075] For orally disintegrating tablets, the tablet may comprise microcrystals of active agent (coated or uncoated), at least one disintegration agent and at least one other excipient, such as water soluble component, water-insoluble component, viscosity enhancer, and/or gel forming component, and optionally a surfactant (e.g., polysorbate). The other excipient may comprise a mixture of powders and compressible microparticles to facilitate tablet pressing.

[0076] For example, the disintegration agent may comprise 0.5% to 30%, 1 to 20%, 2 to 15% or 3 to 15% by weight of the mass of the tablet, and the soluble component, insoluble component, gel forming component, and/or viscosity enhancer may comprise 40 to 90% by weight of the mass of the tablet. Disintegration agents may include for example maize starch or modified starches, cross-linked polyvinyl pyrrolidone, sodium carboxymethylcellulose, sodium starch glycolate, crospovidone, and the like. Evervescent agents may also be incorporated into the formulation.

[0077] Useful soluble components include polyols, such as mannitol, xylitol, sorbitol, maltitol, and the like; and sugars, such as sucrose, lactose, maltose, and the like. Useful insoluble components include di- or tri-basic calcium phosphate, organic fillers (e.g., microcrystalline cellulose, PVP), water insoluble lubricants (e.g. magnesium stearate, sodium stearyl fumarate, stearic acid or glyceryl behenate) and/or glidants (e.g., talc, silicon dioxide). Useful gelling, swelling, and viscosity enhancers include guar gum, xanthan gum, alginates, dextran, pectins, polysaccharides, sodium or calcium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like.

[0078] In one embodiment, an orally dissolving tablet containing the PDEi or alpha-blocker and the SRI contains a rapid dissolve tablet base powder, micronized silica gel, polyethylene glycol 3350, acesulfame potassium, steviol glycosides, and flavorings. Rapid dissolve tablet base powders are well-known in the art are generally available though commercial vendors, such as: ZYDIS® (Catalant, Inc., Swindon, UK), ORAL BASE A (Fagron, Inc., St. Paul, Minn.), MEDI-RDT BASE (Medisa Network, Inc., St. Laurent, QC), RDT-PLUS™ (PCCA, Houston, Tex.), and DISINTEQUIK™ ODT (Kerry, Beloit, Wis.).

EXAMPLES

[0079] Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only to the appended claims.

[0080] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

Example 1: Rapid Dissolve Escitalopram/Tadalafil Tablets

[0081] The following powdered ingredients were combined: 2.75% (w/w) escitalopram oxalate USP 39 powder, 1.37% (w/w) tadalafil powder, 81.22% (w/w) rapid dissolve tablet base powder, 3.82% (w/w) micronized silica gel, 9.16% (w/w) polyethylene glycol 3350, 0.61% (w/w) acesulfame potassium powder, 0.46% steviol glycosides 95% powder, and 0.61% (w/w) raspberry powder flavor.

[0082] The powder was thoroughly mixed and pressed into a Rapid Dissolve Powder Mold (Torpac, Inc., Fairfield, N.J.) with about 0.6-0.7 g of powder per tablet. The Rapid Dissolve Powder Mold bottom plate was then baked in a convection oven at 110° C. for 30 minutes. Once cooled to room temperature the tablets are packaged in an amber round blister pack with appropriate labeling of ingredients. Each rapid dissolve tablet contains about 9 mg of tadalafil and about 18 mg escitalopram oxalate.

Example 2: Rapid Dissolve Escitalopram/Tamulosin Tablets

[0083] The following powdered ingredients were combined: 2.78% (w/w) escitalopram oxalate USP 39 powder, 0.06% (w/w) tamulosin powder, 82.30% (w/w) rapid dissolve tablet base powder, 3.87% (w/w) micronized silica gel, 9.28% (w/w) polyethylene glycol 3350, 0.62% (w/w) acesulfame potassium powder, 0.46% steviol glycosides 95% powder, and 0.62% (w/w) raspberry powder flavor.

[0084] The powder is thoroughly mixed and pressed into a Rapid Dissolve Powder Mold (Torpac, Inc., Fairfield, N.J.) with about 0.6-0.7 g of powder per tablet. The Rapid Dissolve Powder Mold bottom plate is then baked in a convection oven at 110° C. for 30 minutes. Once cooled to room temperature the tablets are packaged in an amber round blister pack with appropriate labeling of ingredients. Each rapid dissolve tablet will contain about 0.4 mg of tamsulosin and about 18 mg escitalopram oxalate.

Example 3: Clinical Test of Tadalafil/Escitalopram Oxalate 9 mg/18 mg Dosage

[0085] Patients were selected based upon their response to a self-administered questionnaire designed to evaluate key elements of premature ejaculation (PE), including (1) self-estimated intravaginal ejaculation latency time (IELT), (2) personal control, (3) levels of distress, and (4) interpersonal difficulty. The decision to initiate therapy for PE was at the discretion of a licensed physician. Exclusion criteria included use of phosphodiesterase-5 enzyme inhibitor, organic nitrates, antidepressant medications, antipsychotic medications, and agents with serotonergic effects. Patients were prescribed escitalopram/tadalafil (18/9 mg) orally disintegrating tablets (ODT) and instructed to use one ODT 2 to 24 hours prior to sexual intercourse, and no more than one ODT in a 24 hour period. The self-administered questionnaire was re-administered following the use of four ODTs.

[0086] A total of thirteen patients were included in this initial analysis. The median age was 36 years old (interquartile range (IQR) 26-40 years). The escitalopram/tadalafil combination improved IELT in 100% of patients. Moreover, there was a significant reduction in the number of patients reporting an IELT of 3 minutes or less post-treatment versus pre-treatment (0% vs. 69%; p<0.001). Additionally, significantly more patients reported a delay in IELT of greater than 10 minutes post-treatment compared to pre-treatment (69% vs. 0%; p<0.001). The majority of patients (69%) reported an improvement in composite patient-reported outcome measures (perceived control, personal distress, and interpersonal difficulty) post-treatment with escitalopram/tadalafil. More patients gave ratings of “very poor” or “poor” for control over ejaculation pre-treatment versus post-treatment (38% pre- vs. 8% post-treatment). More patients gave ratings of “very” or “extremely” for personal distress pre-treatment versus post-treatment (38% pre- vs. 15% post-treatment).

[0087] Ninety one percent of patients reported a noticeable improvement in sexual ability and/or performance after treatment with escitalopram/tadalafil and 77% of patients reported an improvement in overall satisfaction with sexual experience. Of the 13 patients analyzed, three reported a failure to ejaculate post-treatment. Common side effects reported included bad taste (8%, n=1), nausea/vomiting (8%, n=1), and headache (15%, n=2).

[0088] Overall, treatment with escitalopram/tadalafil was well tolerated and resulted in improvements of both IELT and patient-reported outcome measures in men with PE.

Example 4: Clinical Test of Tamulosin/Escitalopram Oxalate 0.4 mg/18 mg Dosage

[0089] Patients are selected based upon their response to a self-administered questionnaire designed to evaluate key elements of premature ejaculation (PE), including (1) self-estimated intravaginal ejaculation latency time (IELT), (2) personal control, (3) levels of distress, and (4) interpersonal difficulty. The decision to initiate therapy for PE is at the discretion of a licensed physician. Exclusion criteria include use of alpha-blockers, phosphodiesterase-5 enzyme inhibitor, organic nitrates, antidepressant medications, antipsychotic medications, and agents with serotonergic effects. Patients are prescribed escitalopram/tamsulosin (18/0.4 mg) orally disintegrating tablets (ODT) and are instructed to use one ODT 2 to 24 hours prior to sexual intercourse, and no more than one ODT in a 24-hour period. The self-administered questionnaire is re-administered following the use of four ODTs.