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Title:  Compositions and methods for treatment of sexual dysfunction

United States Patent:  6,579,968

Issued:  June 17, 2003

Inventors:  Blood; Christine H. (Morristown, NJ); Shadiack; Annette M. (Sommerset, NJ); Bernstein; Joanna K. (North Brunswick, NJ); Herbert; Guy H. (Metuchen, NJ)

Assignee:  Palatin Technologies, Inc. (Cranbury, NJ)

Appl. No.:  606501

Filed:  June 28, 2000

Abstract

Compositions and methods are provided for treatment of sexual dysfunction in mammals, including male sexual dysfunction, such as erectile dysfunction, and female sexual dysfunction. In one embodiment, a peptide-based composition including the peptide sequence Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH is administered. Methods of administration include injection, oral, nasal and mucosal administration.

SUMMARY OF THE INVENTION (DISCLOSURE OF THE INVENTION)

The invention relates to a peptide that is a free acid or pharmaceutically acceptable salt thereof that includes the sequence His-Phe-Arg-Trp (SEQ ID NO:1), His-D-Phe-Arg-Trp, homologs of His-Phe-Arg-Trp (SEQ ID NO:1) or homologs of His-D-Phe-Arg-Trp. The peptide is preferably a cyclic peptide, and preferable has a terminal --OH at the carboxyl terminus. In a preferred embodiment, the peptide is Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH.

The invention also includes pharmaceutical compositions of matter, including a peptide of this invention and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a buffered aqueous carrier, and preferably a saline or citrate buffered carrier.

The peptide of this invention, and pharmaceutical compositions of this invention, may be used for stimulating sexual response in a mammal. The invention thus also includes a method for stimulating sexual response in a mammal, in which a pharmaceutically sufficient amount of a composition including His-Phe-Arg-Trp (SEQ ID NO:1), His-D-Phe-Arg-Trp, homologs of His-Phe-Arg-Trp (SEQ ID NO:1) or homologs of His-D-Phe-Arg-Trp is administered. In a preferred embodiment, the composition includes a peptide or pharmaceutically acceptable salt thereof of the formula Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH. The mammal may be male or female. In this method, the composition can also include a pharmaceutically acceptable carrier. The peptide or pharmaceutical composition may be administered by any means known in the art, including administration by injection, administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration and nasal administration. In a preferred embodiment, administration is by nasal administration of a metered amount of a formulation including an aqueous buffer, which buffer may be a saline or citrate buffer.

A primary object of the present invention is a melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction.

A second object is to provide a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of male sexual dysfunction, including erectile dysfunction.

Yet another object is to provide a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of female sexual dysfunction.

Yet another object is to provide a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction with substantially reduced incidence of undesirable side effects.

A primary advantage of the present invention is that it is efficacious at doses that do not cause deleterious side effects, such side effects including nausea, yawning, stretching, decreased appetite and other effects observed with Melanotan-II, or that causes decreased deleterious side effects as compared to Melanotan-II.

A second advantage of the present invention is that it provides compositions with a larger therapeutic window between desired therapeutic effects and the onset of undesired side effects than other melanocortin receptor-specific agents for the intended purpose.

Yet another advantage of the present invention is that it provides compositions with a greater safety margin between desired therapeutic effects and the onset of undesired side effects than other melanocortin receptor-specific agents for the intended purpose.

Yet another advantage of the present invention is that it provides a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction which is efficacious at significantly lower doses than Melanotan-II or other melanocortin receptor-specific agents.

Yet another advantage of the present invention is that it provides a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction which is pharmaceutically active more rapidly following administration than Melanotan-II or other peptide-based melanocortin receptor-specific agents.

Yet another advantage of the present invention is that it provides a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction which, because of increased efficacy at low doses, may be administered by delivery systems other than art conventional intravenous, subcutaneous or intramuscular injection, including but not limited to nasal delivery systems and mucous membrane delivery systems.

Other objects, advantages and novel features, and further scope of applicability of the present invention will be set forth in part in the detailed description to follow, taken in conjunction with the accompanying drawings, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS (BEST MODES FOR CARRYING OUT THE INVENTION)

In the listing of compounds according to the present invention, the amino acid residues have their conventional meaning as given in Chapter 2400 of the Manual of Patent Examining Procedure, 7th Ed. Thus, "Nle" is norleucine; "Asp" is aspartic acid; "His" is histidine;"D-Phe" is D-phenylalanine "Arg" is arginine; "Trp" is tryptophan; "Lys" is lysine; "Gly" is glycine; "Pro" is proline; "Tyr" is tyrosine, and "Ser" is serine. "Ac" refers to a peptide or amino acid sequence that is acetylated.

The invention provides deamidated .alpha.-MSH peptides, which are peptides that include the core .alpha.-MSH sequence His-Phe-Arg-Trp (SEQ ID NO:1), His-D-Phe-Arg-Trp, or homologs or analogs of either of the foregoing, in which the peptide is deamidated, which is to say that it does not include an --NH2 group at the carboxyl terminus. In a preferred embodiment, the deamidated .alpha.-MSH peptides of this invention have an --OH group at the carboxyl terminus, and are thus a free acid form of peptide.

In a preferred embodiment, the invention provides the peptide

Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH Compound 1

The peptide of Compound 1 has a formula of C50 H68 N14 O10, and a net molecular weight of 1025.18. This peptide may be synthesized by solid-phase means and purified to greater than 96% purity by HPLC, yielding a white powder that is a clear, colorless solution in water.

In general, the peptide compounds of this invention may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the compounds of this invention.

The peptides of this invention may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. Where the compounds of this invention include an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.

The invention provides a pharmaceutical composition that includes a peptide of this invention and a pharmaceutically acceptable carrier. The carrier may be a liquid formulation, and is preferably a buffered, isotonic, aqueous solution. Pharmaceutically acceptable carriers also include excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as hereafter described.

Routes of Administration. Because, in part, of the increased potency of Compound 1 and the other peptides of this invention, these peptides may be administered by means other than by injection. If it is administered by injection, the injection may be intravenous, subcutaneous, intramuscular, intraperitoneal or other means known in the art. The peptides of this invention may be formulated by any means known in the art, including but not limited to formulation as tablets, capsules, caplets, suspensions, powders, lyophilized preparations, suppositories, ocular drops, skin patches, oral soluble formulations, sprays, aerosols and the like, and may be mixed and formulated with buffers, binders, excipients, stabilizers, anti-oxidants and other agents known in the art. In general, any route of administration by which the peptides of invention are introduced across an epidermal layer of cells may be employed. Administration means may include administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration, nasal administration and the like. The dosage for treatment of male erectile dysfunction is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about an erection of the penis in a male. The dosage for treatment of female sexual dysfunction is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired response.

The peptides of this invention may be formulated or compounded into pharmaceutical compositions that include at least one peptide of this invention together with one or more pharmaceutically acceptable carriers, including excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired. Formulation excipients may include polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, manniton, sodium chloride or sodium citrate. For injection or other liquid administration formulations, water containing at least one or more buffering constituents is preferred, and stabilizing agents, preservatives and solubilizing agents may also be employed. For solid administration formulations, any of a variety of thickening, filler, bulking and carrier additives may be employed, such as starches, sugars, fatty acids and the like. For topical administration formulations, any of a variety of creams, ointments, gels, lotions and the like may be employed. For most pharmaceutical formulations, non-active ingredients will constitute the greater part, by weight or volume, of the preparation. For pharmaceutical formulations, it is also contemplated that any of a variety of measured-release, slow-release or time-release formulations and additives may be employed, so that the dosage may be formulated so as to effect delivery of a peptide of this invention over a period of time.

In general, the actual quantity of peptides of this invention administered to a patient will vary between fairly wide ranges depending upon the mode of administration, the formulation used, and the response desired.

Nasal or Intrapulmonary Administration. By "nasal administration" is meant any form of intranasal administration of any of the peptides of this invention. The peptides may be in an aqueous solution, such as a solution including saline, citrate or other common excipients or preservatives. The peptides may also be in a dry or powder formulation.

In an alternative embodiment, peptides of this invention may be administered directly into the lung. Intrapulmonary administration may be performed by means of a metered dose inhaler, a device allowing self-administration of a metered bolus of a peptide of this invention when actuated by a patient during inspiration.

The peptides of this invention may be formulated with any of a variety of agents that increase effective nasal absorption of drugs, including peptide drugs. These agents should increase nasal absorption without unacceptable damage to the mucosal membrane. U.S. Pat. Nos. 5,693,608, 5,977,070 and 5,908,825, among others, teach a number of pharmaceutical compositions that may be employed, including absorption enhancers, and the teachings of each of the foregoing, and all references and patents cited therein, are incorporated by reference.

If in an aqueous solution, the peptide may be appropriately buffered by means of saline, acetate, phosphate, citrate, acetate or other buffering agents, which may be at any physiologically acceptable pH, generally from about pH 4 to about pH 7. A combination of buffering agents may also be employed, such as phosphate buffered saline, a saline and acetate buffer, and the like. In the case of saline, a 0.9% saline solution may be employed. In the case of acetate, phosphate, citrate, acetate and the like, a 50 mM solution may be employed. In addition to buffering agents, a suitable preservative may be employed, to prevent or limit bacteria and other microbial growth. One such preservative that may be employed is 0.05% benzalkonium chloride.

It is also possible and contemplated that the peptide may be in a dried and particulate form. In a preferred embodiment, the particles are between about 0.5 and 6.0 .mu.m, such that the particles have sufficient mass to settle on the lung surface, and not be exhaled, but are small enough that they are not deposited on surfaces of the air passages prior to reaching the lung. Any of a variety of different techniques may be used to make dry powder microparticles, including but not limited to micro-milling, spray drying and a quick freeze aerosol followed by lyophilization. With micro-particles, the peptides may be deposited to the deep lung, thereby providing quick and efficient absorption into the bloodstream. Further, with such approach penetration enhancers are not required, as is sometimes the case in transdermal, nasal or oral mucosal delivery routes. Any of a variety of inhalers can be employed, including propellant-based aerosols, nebulizers, single dose dry powder inhalers and multidose dry powder inhalers. Common devices in current use include metered dose inhalers, which are used to deliver medications for the treatment of asthma, chronic obstructive pulmonary disease and the like. Preferred devices include dry powder inhalers, designed to form a cloud or aerosol of fine powder with a particle size that is always less than about 6.0 .mu.m. One type of dry powder inhaler in current use is Glaxo's Rotahaler.TM., which dispenses a unit dose of powder into a tube, and employs patient suction for inhalation of the powder. Other, more advanced and preferred dry powder inhalers have been or are in development, which include propellants and the like.

Microparticle size, including mean size distribution, may be controlled by means of the method of making. For micro-milling, the size of the milling head, speed of the rotor, time of processing and the like control the microparticle size. For spray drying, the nozzle size, flow rate, dryer heat and the like control the microparticle size. For making by means of quick freeze aerosol followed by lyophilization, the nozzle size, flow rate, concentration of aerosoled solution and the like control the microparticle size. These parameters and others may be employed to control the microparticle size.

In one preferred embodiment, a dry powder inhaler is employed which includes a piezoelectric crystal that deaggregates a dry powder dose, creating a small powder "cloud." Once the powder cloud is generated, an electricostatically charged plated above the powder cloud lifts the drug into the air stream. The user with one relatively easy breath can then inhale the powder. The device may be breath activated, utilizing a flow sensor that activates the electronic components upon the start of inhalation, and thereby eliminating the need for coordination of activation and breathing rhythms by the user.

Induction of Penile Response. Both Compound 1 and Melanotan-II induce penile erections in experimental rat models when administered by intravenous routes and by other routes, including nasal administration. However, Compound 1 is approximately 100-fold more potent than Melanotan-II for inducing penile erection in the rat model. In intravenous dosing studies, penile erection was induced by Compound 1 in a broad range of concentrations, from 0.5 .mu.g/kg of body weight to 25 .mu.g/kg of body weight. At intravenous doses of 2 .mu.g/kg of body weight, Compound 1 resulted in penile erection in 100% of rats tested, with approximately 50% of the rats having multiple erections during a 30 minutes observation period. By comparison, the optimal efficacious dose intravenously of Melanotan-II in the same rat model was 100 .mu.g/kg of body weight.

The therapeutic window (the range from the desired therapeutic effect to observed adverse effects) for Compound 1 is on the order of >1,000-fold, compared to a 3- to 4-fold therapeutic window for Melanotan-II. That is, the optimal efficacious dose of Melanotan-II is approximately one-third to one-fourth the dose that causes observed adverse effects. For Compound 1, the optimal efficacious dose is less than one-one thousandth the dose that causes observed adverse effects. The significantly greater therapeutic window for Compound 1 demonstrates that it is better tolerated than Melanontan-II.

The potency of Compound 1 is significantly higher than that of Melanotan-II, meaning that significantly less Compound 1 is required for a desired effect, as compared to Melanotan-II. For example, 2 .mu.g/kg of body weight of Compound 1 resulted in penile response by intravenous injection in rats, while 100 .mu.g/kg of body weight of Melanotan-II was required for an equivalent penile response. The significantly higher potency results in less product being required. It further permits utilization of alternative delivery routes, including dermal, nasal and similar delivery routes, wherein higher quantities of drug may be required in order to achieve the desired effect. For example, intranasal routes of administration typically have a bioavailability substantially less than that achieved with intravenous dosing, and thus more drug must be administered by intranasal routes in order to achieve the equivalent pharmacological response.

Significant commercial advantage for Compound 1 is demonstrated by the reduced effective dose, compared to Melanotan-II, as a treatment or diagnostic for erectile dysfunction. Among the potential commercial advantages of Compound 1 are improved effectiveness; lower costs of the product; improved convenience, particularly in that the lower dose permits non-conventional delivery methods that are not feasible with Melanotan-II doses; and improved safety with a decreased risk of side-effects.

Claim 1 of 7 Claims

What is claimed is:

1. A peptide selected from the group consisting of Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH and pharmaceutically acceptable salts of Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH.
 



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