EP1175204A1 - Aerosolformulierung und artikel zur steigerung der libido bei frauen durch momentane testosteronverabreichung - Google Patents
Aerosolformulierung und artikel zur steigerung der libido bei frauen durch momentane testosteronverabreichungInfo
- Publication number
- EP1175204A1 EP1175204A1 EP00932051A EP00932051A EP1175204A1 EP 1175204 A1 EP1175204 A1 EP 1175204A1 EP 00932051 A EP00932051 A EP 00932051A EP 00932051 A EP00932051 A EP 00932051A EP 1175204 A1 EP1175204 A1 EP 1175204A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- testosterone
- formulation
- patient
- aerosolized
- aerosol
- 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- Withdrawn
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Definitions
- This invention relates generally to aerosol formulations and devices for treating women with a decreased libido. More specifically, the invention relates to acute non- invasive administration of testosterone by inhalation to enhance libido over a discrete period of time.
- libido defined as the urge to engage in sexual activity
- the primary naturally occurring hormone responsible for libido is testosterone.
- the baseline testosterone level is a relatively constant throughout life, decreasing slowly in old age.
- Each maturing follicle produces testosterone at the mid-point of the menstrual cycle, consistent with observations that female libido peaks with ovulation.
- the number of maturing follicles per month decreases, and there is a decreasing total amount of testosterone produced.
- Testosterone is available as an oral preparation and can be given, for instance, in combination with estrogen to restore testosterone levels.
- the replacement of the once pulsatile endogenous delivery of testosterone with the sustained blood level of the hormone produces unwanted side effects.
- Women taking testosterone for a few weeks typically begin to complain of the emergence of secondary sexual characteristics such as unwanted body hair, oily hair, and, with prolonged a use. deepening voice. For this reason, oral testosterone replacement therapy is not a practical solution for most patients with decreased libido.
- testosterone replacement therapy for women are being explored.
- a transdermal patch capable of delivering a steady rate of testosterone is being tested for use in women.
- the study state blood levels of testosterone produced via transdermal delivery are likely to be associated with the same side effect profile issues.
- Formulations for aerosolized delivery are disclosed.
- the formulations are preferably present in a container which can be easily loaded into an aerosol drug delivery device.
- the formulation is comprised of a testosterone and a suitable carrier which are combined to provide a formulation suitable for aerosol administration to a patient - preferably a human adult female.
- kits which are comprised of a device for creating an aerosol and a plurality of containers adapted for being loaded into the device.
- the container holds a formulation comprised of testosterone and a carrier and is aerosolized to create particles having a diameter in a range of from about 1 micron to about 3 microns in diameter.
- Containers may hold a single dose or multiple doses and the active ingredient is present in a therapeutically effective amount.
- the ingredient is a testosterone and/or a vasodilator, e.g. sildenafil citrate.
- a method of increasing the libido of a woman over a discrete period of time (e.g. 30- 240 minutes) by the administration of testosterone is disclosed.
- a formulation comprised of testosterone is aerosolized preferably producing particles which have a size in a range of from about 1 to 3 microns which can be inhaled into areas of the lung where they can readily enter the blood stream.
- the aerosol is inhaled into the lungs of a patient.
- the patient's normal baseline serum testosterone level is preferably increased 25% or more and more preferably 100% or more Because delivery is by inhalation the patient's serum testosterone level is quickly raised to a desired level e g in thirty minutes or less, more preferably fifteen minutes or less When the patient's testosterone level is raised to a desired level the patient's libido is increased The increased testosterone level gradually subsides (as the testosterone is metabolized and cleared) thereby avoiding the adverse side effects generated by maintaining enhanced testosterone levels over long pe ⁇ ods
- An aspect of the invention is a method of treatment whereby testosterone or de ⁇ vative thereof is aerosolized, inhaled and provided to the circulatory system of the patient at levels sufficient to increase libido (over a short period of time) and propensity for orgasm
- An advantage of the invention is that the testosterone levels are raised within minutes of administration and return to normal levels within hours — preferably in less than four hours
- Another advantage is that the administered testosterone is quickly metabolized allowing the patient's testosterone levels to return to normal thereby avoiding the adverse effects of long term administration
- a feature of the invention is that aerosolized particles of testosterone having a diameter of about 0 5 to 8 microns (preferably 1-3 microns) are created and inhaled deeply into the lungs thereby enhancing the speed and efficiency of administration
- the delivery of testosterone by inhalation provides, for the first time, the means for non-invasively delivering clinically relevant amounts of testosterone on demand near the time of planned intercourse. It is an object of the invention to provide a method of treatment of erectile dysfunction in a patient comprising the steps of aerosolizing a formulation comprising sildenafil citrate, inhaling the aerosolized formulation into the lungs of a patient, and allowing the particles of sildenafil citrate to deposit on lung tissue and enter the patient's circulatory system.
- kits comprising an aerosol delivery device and a formulation comprising a testosterone, sildenafil citrate, or a combination thereof. It is an object of the invention to provide a kit comprising two aerosol delivery devices and two formulations, a first formulation comprising a testosterone for use by a women, and a second formulation comprising a testosterone, sildenafil citrate, or a combination thereof, for use by a man.
- testosterone a testosterone
- testosterone a testosterone
- testosterone USP is a white or creamy- white crystalline powder having a molecular weight of 288.43.
- testosterone derivative refers to any androgen hormone for pharmaceutical use.
- the term includes testosterone esters, i.e. compounds where the "H” of the "OH” group is replaced with an alkyl group, e.g. propionate, cypionate and enanthate.
- Other pharmaceutically acceptable derivatives include methyltestosterone, methandrostenolone, fluovymesterone and danazol.
- a number of useful derivatives of testosterone are disclosed within the Physician's Desk Reference (most recent edition) as well as Harrison's Principles of Internal Medicine. In addition, applicants refer to U.S.
- the terms “diameter”, “particle diameter” and the like are used interchangeably herein to refer to particle size as given in the "aerodynamic" size of the particle.
- the aerodynamic diameter is a measurement of a particle of unit density that has the same terminal sedimentation velocity in air under normal atmospheric conditions as the particle in question. This is pointed out in that it is difficult to accurately measure the diameter of small particles using current technology and the shape of such small particles may be continually changing.
- the diameter of one particle of material of a given density will be said to have the same diameter as another particle of the same material if the two particles have the same terminal sedimentation velocity in air under the same conditions.
- An acceptable range for particle diameter is in the range of 0.5 to 12 microns, preferably 0.5 to 8 microns and more preferably 1 to 3 microns.
- testosterone replacement therapy to modulate libido could be of value to women still of child bearing age.
- Disappearance of or reduction of the libido has been described in women who are continuing to ovulate.
- the reduction in libido may be due to therapy including the use of birth control pills which contain hormones. Therefore, acute administration of testosterone to significantly raise blood levels for discrete periods has potentially widespread application in women across a wide range of ages.
- the baseline serum testosterone level of a normal adult human female is generally below about 1 ng/ml with modest changes through the menstrual cycle (Geobelmann et al., Am J. Obstet. Gynecol. 1 19:445 (1974)) with general fluctuation between about 0.3 to 0.5 ng/ml.
- adult human females with polycystic ovarian disease have ovarian vein testosterone levels of 20 to 65 ng/ml and peripheral venous levels of about 7.5 ng/ml (Dupon et al., Am. J. Obstet. Gynecol. 115:478 (1973)).
- Abnormally high levels of testosterone over long periods are associated with acne and hirsutism.
- an adult human female will produce about 0.25 mg of testosterone per day as compared to about 5-6 mg/day produced by a normal adult male to maintain a normal adult male testosterone level of 3 to 10 ng/ml. Because women produce such small amounts of testosterone the administration of very small amounts will dramatically increase the patient's normal levels.
- 0.05 mg to 5 mg, preferably 0.25 to 2 mg and more preferably about 1 mg of testosterone is administered to the circulatory system of the patient. Administration of such amounts to the circulatory system may require aerosolizing larger amounts due to inefficiencies in the aerosol delivery system.
- Testosterone can be administered orally. However, after oral administration it is absorbed from the gut into the portal blood and degraded promptly by the liver.
- Testosterone can also be administered parenterally. However, when so administered it is rapidly absorbed and metabolized making it difficult to sustain effective levels in plasma over time. In view of such, effective therapy has been carried out using means of delivery where testosterone is slowly absorbed (e.g. dermal patches) or when the testosterone is chemically modified to retard absorption and/or catabolism.
- the present invention uses intrapulmonary delivery to avoid first pass liver metabolism and to obtain quick infusion into the patient's systemic circulatory system. Further, the method of the present invention does not require maintaining increased testosterone levels over long periods. Accordingly, chemical modification to retard absorption and/or catabolism are not required or desired.
- the present invention administers sufficient testosterone by inhalation to tempora ⁇ ly raise the patient's libido, increase the patient's propensity for orgasm, and thereafter allow the patient's testosterone level to return to a level normally expe ⁇ enced by the patient
- intrapulmonary administration is not 100% efficient the amount of drug aerosolized will be greater than the amount which actually reaches the patient's circulation
- the inhalation system used is only 50% efficient then the patient will aerosolize a dose which is twice that needed to raise the patient's testosterone level to the extent needed to obtain the desired results
- the patient will aerosolize an amount of formulation containing about 2 mg of testosterone
- Testosterone therapy as desc ⁇ bed herein can be used in construction with other therapies intended to increase or enhance libido
- Such therapies include but are not limited to herbal preparations and vitamin supplements
- the method of the invention has broad applicability to both the male and female populations However, its use is specifically indicated in four catego ⁇ es
- men having a decreased level of serum testosterone in the first three catego ⁇ es it is not desirable to administer sufficient amounts of a testosterone so as to raise the patient's testosterone level continually over long pe ⁇ ods of time For example, it is not desirable to administer testosterone several times per day for several days. Such will raise testosterone levels over long periods and result in adverse side effects including acne, and increased growth of body hair.
- the amount of a testosterone administered will vary based on a factor such as the age, weight and baseline testosterone level of the patient. Initially, small doses, e.g. about 0.25 mg, is administered. If the desired result is obtained no further dosing is provided. If the desired effect is not obtained additional 0.25 mg doses can be administered up to 2.0 mg. If the patient finds that larger doses are needed then for further treatment the patient may be provided with doses of 0.5 mg, 1.0 mg or 2.0 mg. The amount aerosolized may be substantially greater than the amount administered if the interpulmonary delivery device is inefficient. Thus, the device and method efficiencies must be taken into consideration when calculating the doses.
- the present invention includes the administration of 5 ⁇ -dihydroxytestosterone which is the active molecule.
- the invention also includes the administration of testosterone derivatives provided such derivatives increase libido and do not result in unacceptable adverse effects.
- Obtaining a result such as increased libido may be difficult to ascertain. Some placebo effect will be experienced by some patients and others may continuously administer doses in an attempt to obtain a more enhanced effect.
- the delivery device may be controlled by a suitable lockout system such as taught in U.S. Patents 5,507,277; 5,694,919; and 5,735,263.
- a suitable lockout system such as taught in U.S. Patents 5,507,277; 5,694,919; and 5,735,263.
- Such a system can prevent release of more than a given amount of drug at a single dosing event and/or restrict the number of dosing events within a given period of time. The restrictions are designed to prevent the patient from experiencing adverse secondary effects.
- compositions can be produced as a white or creamy white powder.
- the pure powder is aerosolized and inhaled by itself or with the use of a dry powder inhaler (DPI) device.
- DPI dry powder inhaler
- the particles preferably have a diameter in a range of from about 1 to 10 microns more preferably 1 to 5 microns and still more preferably about 1 to about 3 microns.
- Methods of formulating dry powders and dry powder inhaler devices are disclosed in U.S. Patents 5,826,633; 5,814,607; 5,785,049; 5,780,014; 5,775,320; 5,740,794; and Des. 390,651 all of which are incorporated by reference to describe and disclose such.
- Testosterone is relatively insoluble in water. Accordingly, to create a solution of testosterone a solubilizer (e.g., one of several cyclodextrines or phospholipids) or an organic solvent such as ethanol is used. Alternatively, a microsuspension of testosterone in water with or without ethanol can also be produced.
- the testosterone solution is aerosolized and inhaled.
- the testosterone solution can be placed in a low boiling point propellant in a pressurized canister and released using a conventional metered dose inhaler (MDI) device.
- MDI metered dose inhaler
- the MDI device is modified so that the aerosolized dose is released each time at the same inspiratory flow rate and inspiratory volume. When this is done the patient is more likely to receive the same dose each time.
- a device for obtaining repeatable dosing with an MDI canister is taught in U.S. Patent 5,404,871 issued April 11, 1995.
- the testosterone solution it is preferable to load the testosterone solution into a container which opens to a porous membrane.
- a container which opens to a porous membrane.
- aerosolized Such containers are taught in U.S. Patent 5,497,763 issued March 12, 1996.
- the container is loaded into a device and delivered via a method as taught in U.S. Patent 5,823,178 issued October 10, 1998 both of which patents are incorporated herein by reference to describe and disclose containers, devices and methods of drug delivery by inhalation.
- Aerosol drug delivery devices vary but generally are comprised of (1) a container for the drug e.g. testosterone; (2) a means for aerosolizing the drug; and (3) a mouthpiece from which the aerosol is inhaled.
- the aerosol can be any small particles dispersed in air, e.g. a cloud of a dry powder or a fine spray of liquid formulation.
- Nebulizers, metered dose inhalers (MDIs) and dry powder inhalers (DPIs) are the most well known devices for creating an aerosol. Less conventional devices known as electrohydrodynamic aerosol devices as taught in U.S. Patent 4,358,059; PCT WO 99/07478; and 98/03267 can also be used to create an aerosol in the method of the invention.
- Nasal or buccal formulations could be used for nasal or buccal delivery.
- agents such as sildenafil citrate (U.S. 5,426,107 and U.S. 5,250,534) can also be administered to women or men by the methods of the instant invention, alone or in combination with testosterone.
- Sildenafil citrate also termed VIAGRATM, is typically administered in tablet form to men experiencing erectile dysfunctions resulting from peripheral vascular disease.
- the tablet is taken orally about thirty (30) minutes to four (4) hours before sexual activity.
- the typical oral dose of sildenafil is 25-100mg per day. As described above, such doses can be administered to the lungs through the use of aerosolized aqueous solutions or as a dry powder.
- the sildenafil citrate can be formulated alone or as an admixture with a testosterone for simultaneous delivery.
- men in need of supplemental testosterone and experiencing erectile dysfunction due to peripheral vascular diseases can administer the drugs either simultaneously or sequentially.
- the dosage of testosterone will typically be sufficient to raise the serum testosterone level of the man to a normal range, that being about 200 - 1000 ng/dL.
- the formulation of sildenafil citrate can be administered to male or female patients and may be administered alone or in combination with an aerosolized dose of testosterone.
- the sildenafil citrate is administered orally and the testosterone is administered by aerosol about 30 - 60 minutes after the oral administration of sildenafil citrate.
- the oral administration of sildenafil citrate is an administration in advance of a sexual event and after allowing time to achieve a therapeutic effect on increasing blood flow the patient is dosed with testosterone via aerosol.
- the testosterone enhances the libido and the sildenafil citrate enhances the patient's ability to perform and/or achieve orgasm.
- the aerosolized administration of testosterone could also be in combination with other drugs used in the treatment of various sexual dysfunctions e.g. administered in combination with the topical application of alprostadil.
- Other oral, injectable and topical drugs are and will become available for the treatment of sexual dysfunctions and such drugs (e.g. vasodilators) can be used in combination with aerosolized delivery of testosterone to obtain enhanced results.
- drugs e.g. vasodilators
- a kit for use by a healthcare provider, more preferably a patient.
- An exemplary kit will provide a hand-held aerosol delivery device and at least one dose, preferably one to about one hundred, more preferably one to thirty doses of a testosterone for use by a women.
- the kit will comprise a hand-held aerosol delivery device and at least one dose, preferably one to about one hundred, more preferably one to thirty doses of a testosterone for use by a man.
- the kit will provide a hand-held aerosol delivery device and at least on dose, preferably one to about one hundred, more preferably one to thirty doses of an admixture of testosterone and sildenafil citrate for use by a man.
- the kit will contain a hand-held aerosol delivery device and at least one dose, preferably one to about one hundred, more preferably about one to thirty doses of sildenafil citrate for use by a man.
- a kit is provide with comprises two hand-held delivery devices, wherein a first delivery device comprises at least one dose, preferably one to one hundred doses, of a testosterone for use by a woman.
- the second delivery device comprises at least one dose, preferably one to one hundred doses, of a testosterone, sildenafil citrate, or a combination thereof for use by a man.
- a kit is intended for use by a couple in need of such treatment.
- the kit of the invention can be comprised of various combinations of drugs and drug delivery devices.
- the kit will preferably be comprised of an aerosol drug delivery device which comprises a container which holds one or a plurality of doses of testosterone, a means for aerosolizing the testosterone and a mouthpiece from which the aerosolized testosterone may be inhaled.
- This device is present in the kit with another drug.
- the kit may comprise a container of sildenafil citrate or related drug which obtains a response similar to sildenafil citrate.
- the other drug may be administered orally or topically but is preferably in a container which can be loaded into the device used to deliver the testosterone by inhalation.
- a preferred kit will comprise a drug delivery device which can generate an aerosol for inhalation and a plurality of containers of testosterone which can be loaded into the device and a plurality of containers of a vasodilator such as sildenafil citrate which can be loaded into the device.
- a drug delivery device which can generate an aerosol for inhalation and a plurality of containers of testosterone which can be loaded into the device and a plurality of containers of a vasodilator such as sildenafil citrate which can be loaded into the device.
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Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US56377399A | 1999-05-04 | 1999-05-04 | |
US13247299P | 1999-05-04 | 1999-05-04 | |
US132472P | 1999-05-04 | ||
PCT/US2000/012092 WO2000066084A1 (en) | 1999-05-04 | 2000-05-03 | Aerosol formulations and devices for increasing libido in women via acute testosterone administration |
Publications (2)
Publication Number | Publication Date |
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EP1175204A1 true EP1175204A1 (de) | 2002-01-30 |
EP1175204A4 EP1175204A4 (de) | 2006-05-31 |
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Application Number | Title | Priority Date | Filing Date |
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EP00932051A Withdrawn EP1175204A4 (de) | 1999-05-04 | 2000-05-03 | Aerosolformulierung und artikel zur steigerung der libido bei frauen durch momentane testosteronverabreichung |
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Citations (7)
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WO1997029735A1 (en) * | 1996-02-19 | 1997-08-21 | Monash University | Dermal penetration enhancers and drug delivery systems involving same |
US5756071A (en) * | 1992-06-03 | 1998-05-26 | Arrowdean Limited | Method for nasally administering aerosols of therapeutic agents to enhance penetration of the blood brain barrier |
WO1998029096A1 (en) * | 1996-12-31 | 1998-07-09 | Inhale Therapeutic Systems | Aerosolized hydrophobic drug |
WO1998031346A1 (en) * | 1997-01-16 | 1998-07-23 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
WO1998034595A1 (de) * | 1997-02-05 | 1998-08-13 | Jago Research Ag | Medizinische aerosolformulierungen |
WO2000040226A2 (en) * | 1999-01-06 | 2000-07-13 | Pharmacia & Upjohn Company | Method of treating sexual disturbances |
EP1097711A2 (de) * | 1999-11-02 | 2001-05-09 | Pfizer Limited | Behandlung der pulmonalen Hypertension |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06211675A (ja) * | 1993-01-11 | 1994-08-02 | Shiro Tezuka | 山椒入り局部塗付液 |
-
2000
- 2000-05-03 EP EP00932051A patent/EP1175204A4/de not_active Withdrawn
Patent Citations (7)
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---|---|---|---|---|
US5756071A (en) * | 1992-06-03 | 1998-05-26 | Arrowdean Limited | Method for nasally administering aerosols of therapeutic agents to enhance penetration of the blood brain barrier |
WO1997029735A1 (en) * | 1996-02-19 | 1997-08-21 | Monash University | Dermal penetration enhancers and drug delivery systems involving same |
WO1998029096A1 (en) * | 1996-12-31 | 1998-07-09 | Inhale Therapeutic Systems | Aerosolized hydrophobic drug |
WO1998031346A1 (en) * | 1997-01-16 | 1998-07-23 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
WO1998034595A1 (de) * | 1997-02-05 | 1998-08-13 | Jago Research Ag | Medizinische aerosolformulierungen |
WO2000040226A2 (en) * | 1999-01-06 | 2000-07-13 | Pharmacia & Upjohn Company | Method of treating sexual disturbances |
EP1097711A2 (de) * | 1999-11-02 | 2001-05-09 | Pfizer Limited | Behandlung der pulmonalen Hypertension |
Non-Patent Citations (6)
Title |
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DATABASE WPI Section Ch, Week 199435 Derwent Publications Ltd., London, GB; Class B04, AN 1994-283265 XP002374718 & JP 06 211675 A (TEZUKA G) 2 August 1994 (1994-08-02) * |
EDWARDS D A ET AL: "LARGE POROUS PARTICLES FOR PULMONARY DRUG DELIVERY" SCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE,, US, vol. 276, no. 5320, 20 June 1997 (1997-06-20), pages 1868-1871, XP000857276 ISSN: 0036-8075 * |
FAVA MAURIZIO ET AL: "An open trial of oral sildenafil in antidepressant-induced sexual dysfunction" PSYCHOTHERAPY AND PSYCHOSOMATICS, vol. 67, no. 6, November 1998 (1998-11), pages 328-331, XP009064518 ISSN: 0033-3190 * |
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KO K-T M NBEEDHAM T E ET AL: "EMULSION FORMULATIONS OF TESTOSTERONE FOR NASAL ADMINISTRATION" JOURNAL OF MICROENCAPSULATION, TAYLOR AND FRANCIS, BASINGSTOKE, GB, vol. 15, no. 2, March 1998 (1998-03), pages 197-205, XP000732871 ISSN: 0265-2048 * |
See also references of WO0066084A1 * |
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