WO2017100324A1 - Traitement d'association pour traiter les troubles de la baisse du désir sexuel chez la femme - Google Patents

Traitement d'association pour traiter les troubles de la baisse du désir sexuel chez la femme Download PDF

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WO2017100324A1
WO2017100324A1 PCT/US2016/065384 US2016065384W WO2017100324A1 WO 2017100324 A1 WO2017100324 A1 WO 2017100324A1 US 2016065384 W US2016065384 W US 2016065384W WO 2017100324 A1 WO2017100324 A1 WO 2017100324A1
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tablet
apomorphine
phentolamine
capsule
sexual
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Joseph S. Podolski
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Repros Therapeutics Inc
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Repros Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the application is directed to the compositions and methods useful in modulating the human female sexual response on demand.
  • the human sexual response in both males and females results from a complex interplay of psychological, hormonal, and other physiological influences.
  • One important aspect of human sexual response that is common to both men and women is the erectile response which itself results from the interplay between the autonomic nervous system, the endocrine system, and the circulatory system. Failure of the erectile response in both men and women results in impotence.
  • male erectile dysfunction has generated a great deal of research resulting in the discovery and development of a number of drugs and methods for alleviating male impotence, similar progress in modulating the female erectile response has garnered much less attention.
  • libido Female hypoactive sexual desire disorders (HSDD) afflict approximately 40% of women and there are few treatment options. HSDD is more prevalent in older women and is a progressive and widespread condition. Common symptoms include lack of vaginal dilation, lubrication or tumescence, little interest in or thoughts of sex and littld pleasure in sex.
  • HSDD is generally considered to encompass elements of both sexual arousal disorder and sexual desire disorder, illustrating the degree to which potency and libido are intertwined in the female human sexual response.
  • An effective therapy for HSDD must be capable of modulating both potency and libido to be effective.
  • sildenafil Viagra®
  • sildenafil is of limited efficacy in women. In women, sildenafil works by decreasing cyclic guanosine
  • Libido is frequently correlated with levels of serum testosterone, which may account for the observed differences in effectiveness of sildenafil in younger and older women.
  • hormone replacement therapy involving administration of exogenous estrogen, which serves to raise testosterone in post-menopausal women, is often recommended, in part, to alleviate the symptoms of HSDD.
  • LibiGel® BioSante Biopharmaceuticals
  • TBS-2 Trimel Biopharma SRL
  • Combination drugs such as Lybrido (Emotional Brain NY, Inc.), which is a combination of testosterone and sildenofil, and Lybridos (Emotional Brain NY, Inc.), a combination of testosterone and buspirone (a 5HT 1 A receptor antagonist that also binds dopamine type 2 receptors) are also available, but have had only limited success in treating female hypoactive sexual desire disorder. More recently, ilibanserin (Addyi®, Sprout Pharmaceuticals, Inc.), another compound with affinity for 5HT1 A and 5HT2 receptors was approved as an oral treatment for women suffering from hypoactive sexual desire disorder and has proven effective in increasing libido.
  • the present invention provides improved compositions and methods for modulating the female human sexual response by administering two or more pharmaceutically active agents to the circulation, the combination of which results in improved sexual responsiveness, for example, by improving blood flow to the genitalia by various physiological mechanisms.
  • the female human sexual response is modulated on demand by the administration of an effective response modulating amount of two or more pharmaceutically active agents one of which is an alpha-adrenergic antagonist and the other a dopaminergic agonist, together in an orally administrable formulation.
  • the formulation comprises the pharmaceutically active agents in an orally administrable tablet.
  • Another aspect of the present invention is directed to a combination of a first pharmaceutically active agent and a second pharmaceutically active agent wherein the first pharmaceutically active agent is an alpha-adrenergic antagonist selected from the group consisting of phentolamine, phentolamine mesylate, phentolamine hydrochloride, or any pharmaceutically acceptable salt thereof, and wherein the second pharmaceutically active agent is a dopaminergic agonist selected from the group consisting of buspirone, flibanserin or apomorphine.
  • a preferred first pharmaceutically active agent is phentolamine mesylate.
  • a preferred dopaminergic agonist useful in the practice of the invention is apomorphine in any of its pharmaceutically useful forms, including but not limited to apomorphine hydrochloride.
  • the invention also contemplates formulations comprising an alpha- adrenergic antagonist such as phentolamine mesylate in combination with an agent which activates 5- ⁇ 1 ⁇ receptors in a human subject to disinhibit norepinephrine and dopamine release.
  • an alpha- adrenergic antagonist such as phentolamine mesylate
  • an agent which activates 5- ⁇ 1 ⁇ receptors in a human subject to disinhibit norepinephrine and dopamine release.
  • two or more pharmaceutically active agents may be separately administered so long as the two or more agents are present in the circulation simultaneously so as to exert their combined effects.
  • a preferred oral formulation comprises in combination, at least a first and a second pharmaceutically active agent in a rapidly dissolving orally administrable tablet.
  • Preferred rapidly dissolving tablets have disintegration times from about 1 minute to about 10 minutes. Most preferred are rapidly dissolving tablets having the disintegration times of less than one minute.
  • Preferred oral doses of phentolamine mesylate in the formulations of the present invention are preferably from about 5 mg to about 100 mg.
  • Preferred oral doses of apomorphine in the same tablet are preferably from about 5 mg to about 50 mg.
  • Apomorphine has been described as effective in improving the sexual experience of women suffering from hypoactive sexual desire disorder. However, best results were obtained when apomorphine was administered (sub-lingual) on a daily basis (2-3 mg/daily). Under this regimen 20 of 37 women completing the two week trial period reported improvements in sexual satisfaction. In contrast, only 6 of 55 women receiving apomorphine (2-3 mg sub-lingual) on an "as needed" or "on demand” basis prior to sexual activity reported any improvement in sexual satisfaction. Thus, although apomorphine appears to be effective in treating some aspects of female hypoactive sexual desire disorder it requires daily administration. See Caruso et al., Placebo-Controlled Study on Efficacy and Safety of Daily
  • flibanserin has received approval for use in treating female hypoactive sexual desire disorder.
  • Administration of flibanserin is on a daily basis, and as with sub-lingual administration of apomorphine, does not appear to be effective as an "on demand" therapy. See Borsini and Evans, Treating Sexual Desire Disorder with Flibanserin. U.S. Patent Application No. 8,227,471.
  • the present invention is directed to methods for improving the sexual response in women (i.e., excitation, plateau, and orgasmic phases of the female sexual response) on demand by oral administration of an effective amount of the compositions of the present invention.
  • compositions of the present invention are also useful in preparation for sexual intercourse by virtue of their ability to improve the sexual response in females in less than one hour after administration.
  • the therapeutic treatment must minimize side effects associated with alpha-adrenergic antagonists and dopaminergic agonists.
  • alpha- andrenergic antagonists such as phentolamine mesylate can cause rhinitis, headache and tachycardia.
  • dopaminergic agonists such as apomorphine can induce headache, dizziness, hypotension, nausea and vomiting.
  • side effects are inimical to use of such agents as an "on demand" therapy for enhancing the female sexual response.
  • therapeutics can be delivered in a manner and mode which avoids such side-effects these therapeutic cannot be used to effectively treat female hypoactive sexual desire disorder.
  • An important aspect of the present invention is that the claimed dosages represent the levels at which the combination of alpha-adrenergic antagonists and dopaminergic agonists have maximum effect on the female sexual response with minimal side effects, thus identifying the critical point of maximal therapeutic effect.
  • the present invention is also directed to the use of at least a first and a second pharmaceutically active agent, or a combination of pharmaceutically active agents or any of their pharmaceutically accepted salts, one of which potentiates the sexual response improving ability of one or more of the other agents.
  • the pharmaceutically active agents may, in combination, be used for the manufacture of a medicament for oral administration to a human subject to improve, on demand, the sexual response and, more particularly, to improve response to sexual stimulation.
  • the present invention is also directed to the use of at least a first and a second pharmaceutically active agent, or a combination of pharmaceutically active agents, one of which potentiates the sexual response improving ability of one or more of the other agents.
  • the pharmaceutically active agents may, in combination, be used for the manufacture of a medicament for oral administration to a female to improve, on demand, the sexual response and, more particularly, to improve response to sexual stimulation.
  • First pharmaceutically active agents useful for manufacturing the medicament include, but are not limited to alpha-adrenergic antagonists. More particularly, the pharmaceutically active agents include phentolamine mesylate, and phentolamine hydrochloride.
  • Second pharmaceutically active agents useful for manufacturing the medicament include, but are not limited to norepinephrine and dopamine reuptake inhibitors and dopaminergic agonists. More particularly, the pharmaceutically active agents include buspirone, flibanserin and apomorphine.
  • any of the pharmaceutically active agents useful in the practice of the invention may be used as a free base, pharmaceutically acceptable salts, hydrates, and other forms such as described with respect to phentolamine.
  • Figure 1 illustrates the pharmacokinetic time course of apomorphine present in serum of human subjects administered apomorphine (2 mg and 4 mg doses) and a combination of phentolamme (40 mg) and apomorphine (6 mg). While the maximum peak of circulating apomorphine occurs at about the same time (30-45 minutes after administration) in each example, the overall amplitude of the 6 mg apomorphine administered in combination with phentolamme is less than that of the 4 mg dose of apomorphine administered alone. Also, the time required to clear apomorphine administered in conjunction with phentolamine is less than that required to clear even a 2 mg dose of apomorphine delivered alone.
  • Figure 2 depicts the range of circulating apomorphine measured in serum of human subjects administered with apomorphine (2 mg and 4 mg doses) and a combination of phentolamine (40 mg) and apomorphine (6 mg). The data indicate that in the presence of phentolamine the observed range of circulating apomorphine is proportionally much narrower than that observed in subjects in which apomorphine is administered alone.
  • the present invention encompasses a combination of an alpha-andrenergic inhibitor, such as phentolamine mesylate, and a dopaminergic agonist, such as apomorphine, in an "on demand" formulation that can be orally administered prior to sexual activity to overcome symptoms of female hypoactive desire disorder.
  • an alpha-andrenergic inhibitor such as phentolamine mesylate
  • a dopaminergic agonist such as apomorphine
  • Figure 1 depicts the time course of apomorphine detected in the blood after administration of rapid release tablet containing 40 mg of phentolamine and 6 mg apomorphine, as described in Example 1 , to a human subject.
  • the serum level of apomorphine rises rapidly and reaches a maximal level at approximately 30-45 minutes after administration and then declines gradually as the active compound is metabolized. Complete washout required approximately 4 hours. This is similar to the serum profile exhibited by phentolamine (see Table 8 of Lowery, Methods and Formulations for Modulating the Human Sexual Response.
  • FIG. 2 illustrates the range of serum apomorphine observed in human subjects upon administration of apomorphine with and without co-administration of phentolamine.
  • concentration range varied to a much greater degree than when apomorphine and phentolamine were co-administered.
  • the average amount of apomorphine detected in serum was lower from 6 mg apomorphine in combination with 40 mg phentolamine than in serum from subjects administered 4 mg of apomorphine without concomitant administration of phentolamine. This further indicates that co-administration of phentolamine and apomorphine serves to regulate the availability of apomorphine in the blood stream to desired therapeutic levels.
  • Co-administration of an alpha-adrenergic antagonist such as phentolamine mesylate and a dopaminergic agonist such as apomorphine produces a rapid increase in the concentration of the dopaminergic agonist within a limited concentration range and facilitates washout of the compound over a shorter period of time than administration of the dopaminergic compound alone.
  • This profile is ideal for use in treatment of female human sexual desire disorder in that it provides limited, but effective dosing on demand.
  • compositions for the rapid delivery of pharmaceutically active agents to the systemic circulation thereby allowing a rapid (on demand) onset of improved female erectile response to sexual stimulation.
  • the composition comprises a combination of two or more pharmaceutically active agents.
  • one of the two or more agents is an alpha-adrenergic antagonist and the other is a norepinephrine and dopamine reuptake inhibitors and/or a dopaminergic agonist.
  • the invention is also directed to other oral ly administered formulations for "on demand" improvement in female erectile response to sexual stimulation including chewable tablets, effervescent formulations, wafers, chewing gum, solutions, lozenges, troches, powders, solutions, suspensions, emulsions, or encapsulated powders or encapsulated crystals which capsule can be ol ' the gelatin type or other types.
  • the compositions may be administered by other than the oral route although the oral route is preferred.
  • the composition may be administered topically, transmucosally, transdermal ly, and by other methods via other drug delivery media.
  • Other drug delivery media may also be used to administer the compositions of the invention including suppositories (rectal or vaginal), creams, gels, or other drug delivery media well known in the art.
  • Exemplary formulations of a rapidly dissolving tablet that includes the alpha-adrenergic antagonist phentolamine mesylate and the dopaminergic agonist apomorphine are set out below.
  • croscarmellose sodium NF available as Ac-Di-Sol®, from FMC Corporation
  • croscarmellose sodium NF available as Ac-Di-Sol®, from FMC Corporation
  • Tablets useful in the practice of the present invention may include other pharmaceutical excipients, pharmaceutically acceptable salts, carriers, and other substances well known in the art.
  • Buffering agents, flavoring agents, and inert fillers such as lactose, sucrose, corn starch, binders such as acacia, cornstarch, or gelatin.
  • Disintegrants such as potato starch and analgetic acid as well as other commercially available disintegrants including Explotab® sodium starch glycolate, Polyplasdone XL® crospovidone NF, Starch 1500® pregelatinized starch NF.
  • vasodilator agent itself.
  • Formulations useful in the practice of the present invention may vary so long as the formulation maintains the properties of rapid dissolution and improved bioavailability of the active ingredient or ingredients.
  • a rapidly disintegrating tablet formulation is described in Pebley, et al., Rapidly disintegrating tablet.
  • U.S. Pat. No. 5,298,261 (the '261 patent) which is incorporated herein by reference.
  • the '261 patent describes a rapidly dissolving tablet comprising a drug and a matrix network that has been vacuum-dried below the equilibrium freezing point of the matrix but above its collapse temperature.
  • the matrix network set out in the '261 patent preferably includes a gum, a carbohydrate, and the drug.
  • Preferred gums include acacia, guar, xanthine, carrageenan, or tragacanth.
  • Preferred carbohydrates described in the '261 patent include mannitol, dextrose, sucrose, lactose, maltose, maltodextrin, or corn syrup solids.
  • Alternate rapid release formulations suitable for on demand treatment of female hypoactive sexual desire disorder may comprise different norepinephrine and dopamine reuptake inhibitors and dopaminergic agonists. Compounds such as busprione and flibanserm may be incorporated into the formulations as depicted in Tables 4 and 5, respectively. The dose of such alternate norepinephrine and dopamine reuptake inhibitors and dopaminergic agonists may be adjusted to optimize the effectiveness of combining the drug with an alpha-adrenogeric antagonist such as phentolamine.
  • an alpha-adrenogeric antagonist such as phentolamine.
  • norepinephrine and dopamine reuptake inhibitors and/or dopaminergic agonists contemplated by the invention may have bioavailability characteristics that differ from phentolamine mesylate.
  • the foregoing information identified particular characteristics useful in optimizing the certain orally administrable formulations of the invention.
  • the present invention also includes a chewable tablet formulation shown in Table 6.
  • a number of pharmaceutically active agents may be used in the compositions according to the practice of the present invention based on their demonstrated efficacy as norepinephrine and dopamine reuptake inhibitors and/or dopaminergic agonists.
  • Useful drugs include those generally classified as alpha- adrenergic antagonist, norepinephrine and dopamine reuptake inhibitors, dopaminergic agonists, and those agents which exhibit direct relaxation of vascular smooth muscle.
  • exemplary alpha-adrenergic antagonists useful in the compositions of the present invention include phentolamine hydrochloride and phentolamine mesylate. Phentolamine mesylate is preferred in the practice of the present invention.
  • a preferred dopaminergic agonist useful in the compositions of the invention is apomorphine.
  • these pharmaceutically active agents are administered in rapidly dissolving orally administered formulation or other formulations such as troches, lozenges, chewable tablets, effervescent formulation, powders, solutions, and other formulations that provide for rapid delivery of the active agent to the systemic circulation and which provide rapid improvement of the female erectile response according to the present invention.
  • formulation or other formulations such as troches, lozenges, chewable tablets, effervescent formulation, powders, solutions, and other formulations that provide for rapid delivery of the active agent to the systemic circulation and which provide rapid improvement of the female erectile response according to the present invention.
  • the combinations of pharmaceutically active agent according to the present invention may be administered in other orally available dosage forms or by way of other drug delivery media as discussed in more detail above.
  • a preferred embodiment of the invention comprises about 5 mg to about 100 mg phentolamine mesylate in combination with about 5 mg to about 10 mg apomorphine.
  • the optimal dosage for the specific route of administration can be determined by measuring baseline arterial blood flow in genital circulation of the patient prior to administration of the drug using a doppler ultrasound velocimeter as described in Bcchara, et al., A Double-Blind Randomized Placebo controlled study comparing the Objective and Subjective Changes in Female Sexual Response Using Sublingual Apomorphine. Journal of sexual Medicine 1 :209 (2004). Other methods such as thermography,
  • plethysmography, radiometric or scintigraphic methods, and other methods well known in the art may also be utilized to assess blood flow in the genitalia. See Boolell et al., Sildenafil, a novel effective oral therapy for male erectile dysfunction. British Journal of Urology, 78:257 ( 1 996) and Boolell et al., Sildenafil: an orally active, type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. International Journal of Impotence Research 8:47 ( 1996). Having established base line blood flow, various dosages of the respective vasodilators may be administered using the compositions encompassed by the present invention and their effect on blood flow may be measured. In addition, individual patients may be titrated with various dosages of the respective vasodilators until the optimum dosage is determined.
  • Preferred embodiments of the present invention for use in the treatment of female hypoactive sexual desire disorders involves administration of from about 5 mg to about 100 mg of phentolamine mesylate and about 5 to about 10 mg apomorphine in a rapidly dissolving oral formulation of the present invention from about 1 minute to about 1 hour prior to, and in preparation for intercourse.
  • a preferential formulation involves administration of 40 mg of phentolamine mesylate and 6 mg apomorphine in a rapidly dissolving formulation to achieve peak serum apomorphine levels within an hour of administration ( Figure 1 ), where peak levels represent 0.63 ng/ml and 2.11 ng/ml apomorphine. Shown in Figure 2.
  • Tachycardia 1.5% 0% 0/10 0.6%
  • the female erectile response takes place when under physical or psychological stimulation, blood flow to the genitalia increases by virtue of relaxation of smooth muscles in the arteries serving the genitalia. This physical response is enhanced by increased libido.
  • compositions and methods of the present invention may be used to improve or enhance the sexual response in women whose sexual response is impaired as evidenced by diminished capacity to produce sufficient vaginal lubrication to facilitate comfortable penile penetration and by other symptoms of impaired sexual responsiveness that may be correlated with the erectile response.
  • compositions and methods of the present invention may be used to enhance the normal female sexual response.
  • the "on demand” aspect of the present invention will allow a more rapid response to sexual stimulation along with heightened sensation associated with excitement, plateau, and orgasmic stages of the female sexual response by virtue of the increased blood flow to the tissues.
  • the appropriate doses of the particular combinations of pharmaceutically active agents may be readily determined as described above.
  • the female response may be measured using methods described in Masters, W. H. and Johnson, V. E., Human Sexual Response, Little, Brown, and Co., Boston (1966) which is incorporated herein by reference.
  • thermography using for example an isothermal blood flow transducer, radioscintigraphic methods, and photoplethysmography may be used as well as other methods well known in the art.
  • measuring the contraction of the distal third as is characteristic of the plateau phase of female sexual response of the vagina may be measured using methods and equipment well known in the art including but not limited to strain gauges or other devices for measuring muscular contraction or muscle tension.
  • Enhanced sexual response may also be measured in a more subjective manner by simply asking the female subject to describe any change in sensation brought about by administration of an alpha-adrenergic antagonist such as phentolamine mesylate and a dopaminergic agonist such as apomorphine the by the methods of the present invention.
  • Appropriate placebo controls should also be conducted to ascertain whether or not the effort is directly attributable to the administration of the vasodilator.

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Abstract

L'invention concerne des compositions et méthodes améliorées destinées à moduler la réponse sexuelle chez la femme dans le traitement d'une baisse du désir sexuel, comprenant une association d'un antagoniste alpha-adrénergique et d'un inhibiteur du recaptage de la norépinéphrine et de la dopamine et/ou un agoniste dopaminergique. L'association conduit à une augmentation synergique de la réponse érectile chez la femme accompagnée d'une augmentation simultanée de la libido, permettant de fournir un traitement thérapeutique sur demande de la baisse du désir sexuel chez la femme.
PCT/US2016/065384 2015-12-10 2016-12-07 Traitement d'association pour traiter les troubles de la baisse du désir sexuel chez la femme Ceased WO2017100324A1 (fr)

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CN112603587A (zh) * 2020-12-09 2021-04-06 山东第一医科大学附属省立医院(山东省立医院) 一种用于评价治疗血管性ed的药物的动物模型的构建方法

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US5731339A (en) * 1995-04-28 1998-03-24 Zonagen, Inc. Methods and formulations for modulating the human sexual response
US20040214824A1 (en) * 1999-01-06 2004-10-28 Pharmacia & Upjohn Company Method of treating sexual disturbances
US20070072872A1 (en) * 2001-10-20 2007-03-29 Boehringer Ingelheim Pharma Kg Treating sexual desire disorders with flibanserin
US20070071818A1 (en) * 2002-09-19 2007-03-29 Ardana Bioscience Limited Effervescent formulations comprising apomorphine
US20070191320A1 (en) * 1998-12-10 2007-08-16 Nexmed Holdings, Inc. Methods of treatment for female sexual arousal disorder

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4640921A (en) * 1986-02-04 1987-02-03 Bristol-Myers Treatment of sexual dysfunction with buspirone
US5731339A (en) * 1995-04-28 1998-03-24 Zonagen, Inc. Methods and formulations for modulating the human sexual response
US20070191320A1 (en) * 1998-12-10 2007-08-16 Nexmed Holdings, Inc. Methods of treatment for female sexual arousal disorder
US20040214824A1 (en) * 1999-01-06 2004-10-28 Pharmacia & Upjohn Company Method of treating sexual disturbances
US20070072872A1 (en) * 2001-10-20 2007-03-29 Boehringer Ingelheim Pharma Kg Treating sexual desire disorders with flibanserin
US20070071818A1 (en) * 2002-09-19 2007-03-29 Ardana Bioscience Limited Effervescent formulations comprising apomorphine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112603587A (zh) * 2020-12-09 2021-04-06 山东第一医科大学附属省立医院(山东省立医院) 一种用于评价治疗血管性ed的药物的动物模型的构建方法

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