EP0998289A1 - Zusammensetzung und verfahren zur ergänzung von testosteron bei frauen mit testosteronmanel - Google Patents

Zusammensetzung und verfahren zur ergänzung von testosteron bei frauen mit testosteronmanel

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Publication number
EP0998289A1
EP0998289A1 EP98904894A EP98904894A EP0998289A1 EP 0998289 A1 EP0998289 A1 EP 0998289A1 EP 98904894 A EP98904894 A EP 98904894A EP 98904894 A EP98904894 A EP 98904894A EP 0998289 A1 EP0998289 A1 EP 0998289A1
Authority
EP
European Patent Office
Prior art keywords
testosterone
androgenic steroid
methyltestosterone
group
esters
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98904894A
Other languages
English (en)
French (fr)
Inventor
Susan Rako
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Actavis Laboratories UT Inc
Original Assignee
Theratech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Theratech Inc filed Critical Theratech Inc
Publication of EP0998289A1 publication Critical patent/EP0998289A1/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

Definitions

  • compositions and methods for their administration that would enable women exhibiting symptoms of testosterone deficiency to take supplemental amounts of and androgenic steroid in such a manner as to restore physiological testosterone levels and promote the return of sexual health and activity, promote feelings of well-being, promote cardiovascular and coronary health, maximize muscle tone and inhibit bone loss.
  • the present invention is- drawn to the attaining of these desires.
  • the present invention relates to compositions and methods for providing androgenic steroids in effective amounts to women who are in need of supplementation, such as women whose total serum testosterone or free testosterone levels are less than optimal or significantly below normal physiological levels due to menopause and/or natural aging or as a result of hysterectomy or ovarian failure (e.g., consequent to chemotherapy) , or adrenal insufficiency.
  • a topical formulation comprising effective amounts of androgenic steroids in a pharmaceutically acceptable carrier, is applied to the genital mucosa for a period of time sufficient to overcome or ameliorate symptoms of testosterone deficiency.
  • the invention also relates to a method of progressively providing androgenic steroids in effective amounts to women who are in need of testosterone supplementation, by means of first applying to the genital mucosa effective amounts of androgenic steroids in a pharmaceutically acceptable carrier for a time sufficient to bring the testosterone level to within physiological ranges as determined by serum blood levels ("total testosterone") or serum free testosterone unbound to sex hormone binding globulin ("free testosterone"). Once the testosterone levels are within physiological ranges, the topical application to the genital mucosa is replaced by the oral, transdermal or parenteral administration of lower amounts of androgenic steroids to maintain the testosterone levels within the desired physiological ranges.
  • testosterone deficiency a condition in which testosterone deficiency is a chronic obstructive obstructive obstructive pulmonary disease.
  • symptoms might include, but not be limited to, global loss of sexual desire, decreased sensitivity to sexual stimulation in the nipples and in the clitoris, decreased arousability and capacity for orgasm, diminished vital energy and sense of well-being, and, loss of muscle tone.
  • Some women also notice other symptoms such as thinning and loss of pubic hair, genital atrophy not responsive to estrogen, dry and brittle scalp hair, and, dry skin.
  • testosterone supplementation for a female patient be based on a diagnosis by a physician who prescribes the mode of application, dosage and duration of treatment.
  • the transdermal administration of between about 50 to 500 ⁇ g of testosterone per day is usually sufficient to maintain serum blood levels of between about 15 to 80 ng/dl.
  • the daily dosage of methyltestosterone, administered orally is suggested to be between about 100 to 800 ⁇ g (i.e. 0.10 to 0.80 mg/day) .
  • testosterone agent or testosterone (when used generically) , must be taken in context and are generally meant to encompass any androgenic steroid that is functional in reducing symptoms of testosterone deficiency in females.
  • testosterone are representative of androgenic steroids.
  • testosterone methyltestosterone and esters thereof are preferred.
  • esters include the propionate, phenylacetate, enanthate and cypionate esters of testosterone and methyltestosterone.
  • Serum, or total, testosterone or free testosterone determined by analysis of blood or other body fluids will generally refer to natural testosterone.
  • the dosage of the testosterone agent must be sufficient to overcome the deficiency being monitored or treated without administering too great a dosage.
  • Too high a dosage of testosterone, or application of a dosage for too long a period of time may be manifest by symptoms of testosterone excess, i.e. irritability, clitoral enlargement, increased facial hair and lowering of the voice.
  • symptoms of testosterone excess i.e. irritability, clitoral enlargement, increased facial hair and lowering of the voice.
  • the initiating of testosterone supplementation in that area quickly provides vitalization of the genitalia as well as providing systemic delivery of testosterone to other areas.
  • the blood circulation is improved and testosterone receptors become well supplied with the concomitant increase in sexual sensation and gratification. A sense of well-being and self awareness usually results.
  • the compounding of a formulation for topical application to the genital mucosa may be in various forms, e.g. a solution, emulsion, cream, gel, ointment, paste and the like.
  • concentration of testosterone or other androgenic steroid will be between about 0.01 and 2.5% by weight of the formulation with concentrations of between about 0.1 and 1.0% being preferred.
  • the carrier used may be a solvent for testosterone or a vehicle in which the testosterone may be uniformly dissolved or suspended.
  • pharmaceutically acceptable carrier a vehicle or carrier in which the androgenic steroid, and any other ingredients such as enhancers and/or solvents, along with any other additives, are contained in a single or phase separated fluid state.
  • fluid is meant a composition that is not solid but may be present in varying degrees or states of viscosity.
  • the carrier per se may serve as a solvent or a solvent or co-solvent may be added.
  • Carriers can be water or organic based and may contain a mixture of liquids or solvents appropriately gelled or thickened.
  • such carriers may comprise, but are not limited to, solutions, suspensions, emulsions, gels, ointments, creams, pastes or any other similar state which permits the outward diffusion of testosterone or other androgenic steroid and any enhancer, solvent or other additives as desired.
  • the continuous phase forming such carriers can vary from hydrophilic to hydrophobic depending upon the desired combination.
  • Representative inert ingredients other than water include, but are not limited to, polypropylene glycol, polyethylene glycol, polyvinyl alcohols, petrolatum, polyvinylpyrrolidone, mineral oil, silicone oil, ethylene-vinyl acetate polymers or other low molecular weight polymers soluble in water, C 2 -C 8 lower alcohols or suitable solvents.
  • the formulation may contain a solvent (or solvents) and an absorption enhancer (or enhancers) .
  • the formulation can also comprise preservatives, fragrances and/or stabilizers .
  • the androgenic steroid is in the form of natural testosterone, methyltestosterone, and esters thereof such as testosterone or methyltestosterone propionate, cypionate, or enanthate.
  • Suitable enhancers include those conventionally used in the art. Representative of these are C g to C 18 fatty acids, C x to C 8 esters of C 8 to C 18 fatty acids, C 8 to C 18 fatty alcohols, sorbate esters and salts, glycerol esters of fatty acids, C 7 to C 22 fatty acid esters of ⁇ - hydroxy acids and mixtures of any of the above. Enhancers may be present in any functional amount and will generally be present in amounts of between about 0.01 and 30% by weight.
  • solvents can serve as both solvents and enhancers .
  • Representative of these are C 2 to C 7 alcohols, C 3 or C 4 diols, ethoxydiglycol , DMSO, DMF, DMA, l-n-dodecyl-cyclazacyclohept n-2-one, N-methyl- pyrrolidone, N- (2-hydroxyethyl) pyrrolidone and the like.
  • solvents may be present in any functional amount. Since some solvents may actually function as the carrier vehicle, it is not practical to restrict the amount of solvent to any numerical range except to state that "effective amounts" may be utilized.
  • additives such as thickening agents, gums, fragrances, stabilizers, agents to increase the solubility of androgenic steroids (e.g. cyclodextrins, etc.), and the like can also be incorporated into the formulation.
  • the absorption enhancer or enhancers render the androgenic steroid more readily available by enabling or enhancing its uptake into genital mucosal cells or the surrounding skin. This facilitates delivery to the genital mucosa or the skin and absorption of the androgenic steroid utilized.
  • topical formulations comprise from about
  • testosterone can comprise any concentration within this range which is appropriate to produce the desired effects. The lowest concentration that can bring about the desired effects is preferred. In that regard formulations comprising from about 0.05% to about 1% testosterone are preferred. While the invention encompasses the utilization of testosterone, methyltestosterone and esters thereof it may be beneficial to utilize methyltestosterone when administered concurrently with estrogens or when it is preferred estradiol levels be maintained as low as possible. Methyltestosterone does not tend aromatize in si tu into estradiol whereas small amounts of testosterone may be converted to estradiol.
  • methyltestosterone is of particular value, for example, in women who develop testosterone deficiency as a result of ovarian failure following chemotherapy for breast cancer and who need to keep their estrogen levels as low as possible.
  • methyltestosterone that is not intended to be a limitation on the invention as other androgenic steroids may also be utilized to bring about the desired results but may need to be monitored more carefully.
  • a dosage of between 0.25 and 0.5 mg methyltestosterone/0.1 ml transmucosal cream is used.
  • the concentration of methyltestosterone in the topical preparation is between 0.25 and 0.5% by weight.
  • the concentration most appropriate for a particular woman can be determined empirically (e.g., by varying the concentration and assessing the resulting effects on genital atrophy and sexual sensitivity) .
  • a formulation comprising an androgenic steroid, such as methyltestosterone, at an appropriate concentration is applied to the genital mucosa in sufficient quantity and for sufficient time, as the patient is monitored by her physician, to reduce genital atrophy and bring about a reduction in the symptoms of testosterone deficiency.
  • an androgenic steroid such as methyltestosterone
  • topical genital administration is reduced and supplemented by oral, transdermal or parenteral administration of low doses of the androgenic steroid, such as methyltestosterone, in sufficient quantity to maintain the benefits obtained from the use of the topical genital formulation.
  • the oral dose of methyltestosterone is in the range of .1 mg to .8 mg per day and the transdermal dose of testosterone, as noted in U.S. Patent 5,460,820, is in the range of 0.05 to 0.5 mg per day for testosterone.
  • the transdermal or parenteral dose for methyltestosterone or oral or parenteral dosages testosterone may require minor adjustments.
  • the overall ranges for testosterone and methyltestosterone given above overlap considerably such that a general dosage range of testosterone or methyltestosterone, in any administered form, of from about 0.01 to 1.0 mg/day should be suitable.
  • this range may vary for any given androgenic steroid according to its relative potency and bioavailability . Therefore the key to the exact amount is that of functionality. Any androgenic dosage that is equivalent to 0.01 to 1.0 mg/day of testosterone or methyltestosterone should be effective.
  • the formulation of the present invention provides a means by which the health of the genital mucosa and sexual sensitivity of the clitoris and vagina can be improved and other systemic benefits of improved testosterone levels can also be achieved.
  • compositions described are for topical application to the genitals, particularly the genital mucosa, and to the adjacent skin.
  • the formulation comprises an androgenic steroid suitable for testosterone supplementation as noted above in combination with a pharmaceutically acceptable carrier. More than one androgenic steroid or form of testosterone can be included in a single formulation (e.g., to provide forms which can vary in their availability) . Testosterone, methyl testosterone and their esters, as noted above, are preferred androgenic steroid agents.
  • a cream base such as that available from Professional Compounding Centers of American, Inc. ("PCCA") and referred to as PLO gel or Pluronic Lecithin Organogel can be used.
  • the PCCA base includes: soya granular lecithin; Poloxamar 407, NF : isopropyl palmitate, NF; purified water, USP; alcohol, USP; sorbic acid, NF and potassium sorbate, NF .
  • a cream base referred to as
  • Pharmavan cream and available from The Apotherecary, (Keene, NH) , is used in Examples 1-14 below.
  • Pharmavan cream includes; cetyl alcohol NF (1.0%); stearic acid NF (16.0%); isopropyl myristate (5.0%); polyoxyl 40 stearate NF (1.0%); stearyl alcohol NF (1.0%); potassium sorbate (0.1%) and distilled water (qs 100.0%).
  • the cream base is made by combining the cetyl alcohol NF, stearic acid NF, isopropyl myristate, polyoxyl 40 stearate NF and stearyl alcohol NF and heating the resulting combination to 75°C.
  • the potassium sorbate is dissolved in 75% of the distilled water, heated to 75°C and the xanthene gum is dispersed in this potassium sorbate/distilled water mixture.
  • the two combinations of components are combined, preferably by adding the potassium sorbate/water/xanthene gum combination to the cetyl alcohol-containing combination.
  • the resulting combination (which contains all of the components described above) is homogenized and mixed at slow speed until it is of uniform consistency and makeup.
  • the pH is adjusted, if needed, to be within a range of 4.0 to 5.5 and, preferably, between pH about 4.5 and about 5.0. Sufficient additional distilled water is added (qs to volume) and mixing is carried out to produce a uniform consistency.
  • a methyltestosterone topical cream is produced by combining methyltestosterone, ethoxydiglycol and the Pharmavan cream described above.
  • a methyltestosterone topical cream containing 0.5 mg methyltestosterone/0.1 ml cream can be produced by combining 0.150 gm methyltestosterone, 10.0 ml ethoxydiglycol and Pharmavan cream qs 30.0 ml.
  • the androgenic steroid-containing formulation is applied topically to the genital mucosa, in an effective quantity (a sufficient quantity to improve the health of the genital mucosa and supply testosterone to local testosterone receptors) .
  • Testosterone such as methyltestosterone
  • in the formulation is absorbed, resulting in increased systemic levels and attendant benefits (e.g., restoration of vital energy, sexual libido, capacity for orgasm and intensity of orgasm, sensitivity to sexual stimulation in the nipples, improvement of muscle tone, improved moisture in skin and hair, increased deposition of bone, stimulation of red blood cell production and improvements in mood and sense of well-being) .
  • topical formulation is applied one or more times a day for a sufficient number of days (e.g., 1 week to 3 months and, generally 3-9 weeks) to produce the desired effect.
  • topical genital application is reduced or discontinued and oral or transdermal supplementation with an appropriate low dosage of the same or different androgenic steroid is begun, in order to maintain blood levels of testosterone sufficient to maintain the effects achieved as a result of topical application.
  • application to the genital mucosa can be discontinued and a low dose of testosterone can be administered orally, transdermally or parenterally, in an amount sufficient to maintain the desired blood levels.
  • methyltestosterone will be administered orally at a dose of from about 0.10 mg to about 0.80 mg per day; the dose will be adjusted according to an individual woman's needs. In a particular embodiments of Examples 1-14, the dose will be from about 0.3 mg to about 0.6 mg per day.
  • Methyltestosterone capsules e.g., capsules containing 0.05 mg, 0.10 mg, 0.25 mg or 0.50 mg methyltestosterone
  • the dose of oral methyltestosterone can be taken in a single daily dose or in two or more smaller quantities.
  • testosterone supplementation is exemplary of the results obtained using testosterone supplementation according to the invention.
  • the formulation applied was compounded as described above, i.e. methyltestosterone, ethyoxydiglycol and Pharmvan cream.
  • EXAMPLE 1 Patient A is a 41 year old woman who had a hysterectomy three years prior. She had huge fibroid tumors of the uterus weighing up to five pounds . Her ovaries were not removed. She described herself prior to the surgery as a very sexually active woman in a satisfying relationship with a wonderful man. Following her surgery, she lamented that she "feels nothing" sexually. She has noticed some loss of scalp hair but not much change in pubic hair . She complained that she has a loss of general vital energy and is very distressed about lack of sexual feeling, pleasure and libido .
  • Patient A was treated with topical methyltestosterone cream 0.25%, .1 ml applied to the genital mucosa each night after bathing and, after 4 days, she noted an appreciable improvement in genital sexual sensitivity and pleasure on stimulation. After three weeks she stated that her sexual vitality had been restored and that she "feels like herself again.”
  • Patient B is a 53 year old woman whose menstrual periods stopped three years ago, when she was age 50. She complained of changes in her personality, having rageful feelings, being forgetful, unable to concentrate, having no energy and was most troubled because she had no sexual feelings at all. Her sexual feelings had been waning somewhat for several years. She reported she last felt fully well and sexually alive when she was about 40. She had previously enjoyed a very good sexual relationship with her husband but now had no sexual interest at all. She stated that she took estrogen for 3-4 months about a year ago but stopped because she got nervous about potential breast cancer risks. On a mammogram, some calcifications showed up, but were negative for cancer on needle biopsy. Patient B complained of having hot flashes and disrupted sleep.
  • Patient C is a 39 year old woman complaining of decreases clitoral and vaginal sensitivity, low libido and dyspareunia. For the past year, she also had a depressed mood, and her energy level was quite low.
  • Serum testosterone was low at 14.0 ng/dl, and serum free testosterone was low at .3 pg/ml. Thyroid hormone levels were within normal limits.
  • Patient D is a 60 year-old- woman who has never been treated with estrogen, and sought professional advice complaining of the decline in her energy and her sex drive.
  • Her last menstrual flow was at about age 50. She had not had sexual intercourse since she was about age 51. She had vaginal dryness .
  • Serum estradiol was ⁇ 20 pg/ml.
  • Serum testosterone was 12 ng/dl.
  • a free testosterone level was .74 pg/ml.
  • Patent E is a 46 year old woman who, at age 38, had a total hysterectomy and bilateral salpingo-oophorectomy for ovarian cyst and severe endometriosis . She was subsequently placed on the Climara patch 0.1 mg. On the estrogen treatment, she developed migraine headaches once weekly which were severe and associated with vomiting. These were treated with Imitrex 25 mg . She came in complaining of markedly decreased sex drive.
  • Patient F is a 40 year old woman who had a hysterectomy and bilateral salpingo-oophorectomy five years ago for bad menstrual periods, severe endometriosis, and painful intercourse. She had enjoyed an active sex life and had a good sex drive prior to the surgery, although intercourse had been painful due to the endometriosis. Following the surgery, she was placed on Premarin .625 mg per day. During the 2 year period previous to her visit, she had suffered a complete loss of sexual libido and activity. During the previous year, she has had increasing problems with insomnia and frequent headaches. Her weight has increased 30-40 lbs in the past five years, and she was much less active than she had been previously.
  • a serum estradiol was 186 pg/ml, a total testosterone was low normal at 18 ng/dl, and the free testosterone was the low end of the normal range at 1.05 pg/ml. Thyroid function studies were within normal limits.
  • the patient was started on methyltestosterone .25% cream, .1 ml applied to the genital mucosa daily. On her return in 8 weeks, she was pleased to report increased sexual sensitivity and desire, better energy and sleep. She has begun to exercise, and reports improved muscle tone and a weight loss of 4 pounds .
  • Patient G is a 41 year old woman who was still menstruating regularly, with periods every 28 days, but who reported loss of sexual libido and was very distressed that she had lost most of her pubic hair. Migraine headaches, which she has had since she was a teenager, had become more problematic. She noted muscle weakness, and had also gained 20-25 pounds and had noted a marked decline in her energy level . She had also been having some problems with concentration.
  • Her serum testosterone was quite low at 1.9 ng/dl, and a free testosterone was low at 0.79 pm/ml.
  • EXAMPLE 8 Patient H is a 43 year old woman suffering severe depression and loss of sexual libido and pleasure since a hysterectomy and bilateral salpingo-oophorectomy four years ago for large uterine myomata. She had been treated with a variety of estrogen preparations, including Ogen and Estraderm. She had a trial of an androgen implant at one time to determine if it would be beneficial. She did not notice improvement in mood or libido and felt agitated (possibly from too high a blood level of testosterone) . She had been treated for major depressive disorder with multiple antidepressants including Zoloft, Desyrel, Parnate, Wellbutrin, Anafranil, Prozac, lithium, Ritalin, Risperidone, and ETC.
  • multiple antidepressants including Zoloft, Desyrel, Parnate, Wellbutrin, Anafranil, Prozac, lithium, Ritalin, Risperidone, and ETC.
  • Serum estradiol was 38.6 pg/ml, total testosterone level was low at 4.9 ng/dl and free testosterone was 0.24 pg/ml. Thyroid hormone levels were within normal limits. Increasing her estradiol by prescribing Estraderm 0.1 mg resulted in some improvement in her depression. Six weeks later, she was started on methyltestosterone topical cream 0.25% at .1 ml applied to the genital mucosa daily. After 6 weeks, the patient reported better energy and improvement in sexual sensitivity and libido.
  • Patient I is a 48 year old woman with a history of carcinoma of the breast diagnosed when she was 40 and treated with chemotherapy.
  • the carcinoma was found to be estradiol receptor negative, progesterone positive.
  • she became menopausal and her libido declined.
  • She also noted a decline in her energy and increase in symptoms of depression.
  • She was taking Zoloft 50 mg daily and was using Estrace vaginal cream once weekly.
  • Serum estradiol was very low at 29 pg/ml. Interestingly enough, serum and free testosterone levels were within normal limits at 33 ng/dl and 1.7 pg/ml, respectively. Thyroid hormone levels, prolactin and DHEA-S evaluations were within normal limits.
  • Patient J is a 50 year old perimenopausal woman who had been taking a contraceptive (Norinyl) , containing ethinyl estradiol and norethindrone . Prior to starting the oral contraceptive, she had been experiencing some hot flashes. While taking the oral contraceptive, her sex drive had decreased. She was having painful intercourse, and she had also noted some loss of pubic hair . Laboratory evaluation showed that she had no measurable total testosterone, and virtually no serum free testosterone (.25 pg/ml).
  • a contraceptive Nethinyl
  • the oral contraceptive was discontinued and she was placed on Premarin 0.9 mg per day and topical methyltestosterone .25% cream, 0.1 ml per day to be applied to her genital mucosa.
  • Patient K is a 55 year old woman who has been on hormone replacement therapy since age 42, when she began suffering from night sweats and vaginal dryness. At the time of consultation, she was using Estraderm 0.05 mg twice weekly. She had had problems with mild depression for many years, but it had been worse since she had been menopausal. She had been taking Prozac 20 mg daily for the past seven years. She had had poor libido for more than 8 years . Serum estradiol was 47.3 pg/ml, serum total testosterone was less than 20 ng/dl and free testosterone was very low at 0.48 pg/ml. Serum T3 , T4 , free T4 and TSH levels were within the normal range.
  • Estraderm dosage was increased to 0.1 mg twice weekly. After 6 weeks, she noted mild improvement in the vaginal dryness, but no improvement in sexual libido or sensitivity. She was started on methyltestosterone 0.25% cream, 0.1 ml per day applied to the genital mucosa. After 6 weeks, she reported improvement in sexual sensitivity and return of libido. She also noted markedly improved vaginal lubrication on intercourse.
  • Patient L is a 50 year old woman complaining of low energy, mood problems, and depression. She had been taking Wellbutrin 300 mg daily for the past 3-4 years. Her sex drive was low and she was unable to have an orgasm. Her sexual activity had declined gradually over the past 10 years. When she was younger she enjoyed a very active sex life. She still had slight menstrual periods about every three weeks .
  • EXAMPLE 13 Patient M is a 48 year old woman who, two years previous, had a total hysterectomy with bilateral salpingo-oophorectomy because of fibroids. Following the surgery, she was placed on Premarin 0.625 mg .
  • the dosage was increased to .9 mg daily. Subsequently, about one year previous, the dosage was decreased to 0.625 mg because of her concerns regarding the risk of breast cancer.
  • her serum estradiol was 75 pg/ml, serum total testosterone was low at 11.6 ng/dl, and serum free testosterone was virtually absent at 0.2 pg/ml.
  • the patient was started on methyltestosterone .25% cream 0.1 ml applied daily to the genital mucosa. Returning after 6 weeks, she reported the return of sexual sensitivity, markedly improved sexual libido and capacity for orgasm. She also noted a marked improvement in general energy.
  • Patient N is a 57 year old woman who, at age 45, began to notice mood changes and decline in energy. At that time, she was also having the onset of heavy menstrual bleeding, was told that she had myomata and needed a hysterectomy. When she was 47, a bilateral salpingo-oophorectomy and total hysterectomy was performed. Following the surgery, her moods worsened and she had a marked decline in her sex drive. She is unable to have an orgasm. She was sent to a psychiatrist and was treated with tricyclics, Nardil,
  • Patient 0 is a 51 year old woman who had her last menstrual period one year previous. She reported that when she was 47, having irregular menstrual periods with light flow. She experienced a loss of sexual libido and general energy over a period of several months. She noted a significant loss of pubic hair and flaccidity of her labia. Scalp hair was dry and breaking. For the previous 18 months she had been taking Premarin .625 mg. and cycling with Provera 10 mg for ten days each month. She reported a feeling of "flatness" and lack of zest and experienced no sexual sensation in nipples or genitals .
  • Carrier A is the Pharmvan cream carrier given above as used in Examples 1-14.
  • Carrier B is a gelled base comprising ethanol/water/glycerin (50:20:30 volume) gelled with 1.5% w hydroxypropyl cellulose and containing about 2.5% w of an oleic acid ester of glycerol as an enhancer.
  • Carrier C is a petrolatum base containing 2% isopropyl palmitate as an enhancer.
  • Oral Tablet A is a sugar coated tablet containing the specified amount of methyl testosterone in an inert lactose/magnesium stearate/microcrystalline cellulose carrier.
  • Oral Tablet B is a pressed tablet containing the specified amount of fluoxymesterone in a calcium stearate/corn starch carrier.
  • Injectable solution A is a testosterone cypionate ester uniformly contained in a cottonseed oil/benzyl alcohol solution stabilized by benzyl benzoate.
  • Transdermal patch A is a matrix patch as described in U.S. Patent 5,460,820 formulated to deliver 100 ⁇ g/day of testosterone.
  • the designated topical formulation is applied one or more times daily to the genital mucosa for a time sufficient to alleviate the symptoms of testosterone deficiency.
  • the topical treatment is replaced by an oral, transdermal or parenteral maintenance formulation administered using the formulation and/or dosage indicated.
  • Topical formulation 0.2% w. natural testosterone in Carrier B
  • Topical formulation 0.15% w. micronized testosterone propionate in Carrier C
  • Topical formulation 0.3% w. testosterone in Carrier A
  • Topical formulation 0.15% w. testosterone enanthate in Carrier C
  • Topical formulation 0.05% w. testosterone enanthate in Carrier A
  • Topical formulation 0.15% w. dehydroepiandrosterone in
  • Example 22 Topical formulation: 0.2% w. testosterone in
  • Topical formulation 0.1% w. methyltestosterone propionate in Carrier A
  • Topical formulation 0.12% 50/50 ratio of testosterone and testosterone propionate in Carrier B

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EP98904894A 1997-02-07 1998-02-05 Zusammensetzung und verfahren zur ergänzung von testosteron bei frauen mit testosteronmanel Withdrawn EP0998289A1 (de)

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US466424 1995-06-06
US3747397P 1997-02-07 1997-02-07
US374737 1997-02-07
US3971797P 1997-02-12 1997-02-12
US39717 1997-02-12
US4664297P 1997-05-16 1997-05-16
PCT/US1998/002089 WO1998034621A1 (en) 1997-02-07 1998-02-05 Composition and method for supplementing testosterone in women with symptoms of testosterone deficiency

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Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968547A (en) 1997-02-24 1999-10-19 Euro-Celtique, S.A. Method of providing sustained analgesia with buprenorphine
US20020013304A1 (en) * 1997-10-28 2002-01-31 Wilson Leland F. As-needed administration of an androgenic agent to enhance female sexual desire and responsiveness
US6465445B1 (en) * 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US6428769B1 (en) * 1999-05-04 2002-08-06 Aradigm Corporation Acute testosterone administration
NZ536633A (en) * 2000-08-30 2006-03-31 Unimed Pharmaceuticals Inc Percutaneous delivery of testosterone via a hydroalcoholic gel as a method of increasing testosterone and related steroid concentrations in women
MXPA03001858A (es) * 2000-08-30 2004-05-21 Unimed Pharmaceuticals Inc Metodo para el tratamiento de la disfuncion erectil e incremento en el libido del hombre.
US6503894B1 (en) 2000-08-30 2003-01-07 Unimed Pharmaceuticals, Inc. Pharmaceutical composition and method for treating hypogonadism
WO2004091631A1 (en) * 2002-03-15 2004-10-28 Unimed Pharmaceuticals, Inc. Androgen pharmaceutical composition and method for treating depression
OA12856A (en) * 2002-03-15 2006-09-15 Unimed Pharmaceuticals Inc Androgen pharmaceutical composition and method for treating depression.
WO2004043429A1 (en) * 2002-11-12 2004-05-27 Pharmacia & Upjohn Company Combination therapy for postmenopausal female sexual dysfunction comprising an androgen, and at least one agent selected from an estrogen and an anti-muscarinic
US20040259852A1 (en) * 2003-06-18 2004-12-23 White Hillary D. Trandsdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome
US8492369B2 (en) 2010-04-12 2013-07-23 Clarus Therapeutics Inc Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same
AU2006236564B2 (en) 2005-04-15 2011-02-17 Tolmar, Inc. Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same
WO2006127057A1 (en) * 2005-05-24 2006-11-30 Lyle Corporate Drvelopment, Inc. Non-systematic vaginal administration of estrogen and an androgen for the treatment of sexual dysfunction
US20130045958A1 (en) 2011-05-13 2013-02-21 Trimel Pharmaceuticals Corporation Intranasal 0.15% and 0.24% testosterone gel formulations and use thereof for treating anorgasmia or hypoactive sexual desire disorder
US20130040923A1 (en) 2011-05-13 2013-02-14 Trimel Pharmaceuticals Corporation Intranasal lower dosage strength testosterone gel formulations and use thereof for treating anorgasmia or hypoactive sexual desire disorder
US9757388B2 (en) 2011-05-13 2017-09-12 Acerus Pharmaceuticals Srl Intranasal methods of treating women for anorgasmia with 0.6% and 0.72% testosterone gels
US20140274985A1 (en) * 2013-03-15 2014-09-18 Raman Malhotra Systemic administration of androgen in treating dry eye syndrome
US11744838B2 (en) 2013-03-15 2023-09-05 Acerus Biopharma Inc. Methods of treating hypogonadism with transnasal testosterone bio-adhesive gel formulations in male with allergic rhinitis, and methods for preventing an allergic rhinitis event
US10258631B2 (en) 2014-08-28 2019-04-16 Board Of Regents, The University Of Texas System Formulations of testosterone and methods of treatment therewith
BR112018067554A2 (pt) * 2016-03-02 2019-03-06 Medcara Pharmaceuticals, Llc formulações de testosterona e métodos de tratamento com as mesmas
JP2022548314A (ja) * 2019-09-23 2022-11-17 ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー 妊娠を遷延させるためおよび月経または妊娠の合併症の処置の方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4496556A (en) * 1982-08-16 1985-01-29 Norman Orentreich Topical applications for preventing dry skin
US4863970A (en) * 1986-11-14 1989-09-05 Theratech, Inc. Penetration enhancement with binary system of oleic acid, oleins, and oleyl alcohol with lower alcohols

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9834621A1 *

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CA2280033A1 (en) 1998-08-13
AU6265998A (en) 1998-08-26
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