JP2008512425A - Testosterone gel with propylene glycol as a penetration enhancer - Google Patents

Abstract

Disclosed are pharmaceutical compositions and gels containing testosterone, and methods for using them, and more particularly, hydroalcohol / alcohol pharmaceutical compositions and gels containing testosterone.
The composition of the present invention is suitable for topical and transdermal applications and comprises propylene glycol. Propylene glycol has been shown to be a very powerful permeation enhancer in the compositions of the present invention and is used alone or in combination with other permeation enhancers such as isopropyl myristate. The
[Selection figure] None

Description

  The present invention relates to pharmaceutical compositions and gels containing testosterone and methods of use thereof.

(Testosterone in men)
Testosterone, the major circulating androgen in men, is synthesized from cholesterol. About 500 million Leydig cells in the testis secrete more than 95% of the testosterone produced 6-7 mg per day. Two hormones produced in the pituitary gland (Luteinizing Hormone (“LH”) and Follicle Stimulating Hormone (“FSH”)) are required for the development and maintenance of testicular function and also negatively regulate testosterone production. To do. Circulating testosterone is metabolized to various 17-ketosteroids by two different pathways. Testosterone is metabolized to dihydrotestosterone (“DHT”) by the enzyme 5-α-reductase or to estradiol (“E2”) by the aromatase enzyme complex. Testosterone circulates in the blood with 98% bound to protein. In men, approximately 40% of the binding is due to high affinity binding to sex hormone binding globulin (“SHBG”). The remaining 60% is weak binding to albumin. Here, since there are many clinical test results regarding the measured value of testosterone, it will be described below.

  The following table summarizes the normal adult male hormone concentrations at the UCLA-Harbor Medical Center.

Hormone concentration in males: normal hormone testosterone (total) 298-1043 ng / dL
Free testosterone 3.5-17.9 ng / dL
DHT 31-193ng / dL
DHT / T ratio 0.052-0.33
DHT + T 372-1349ng / dL
SHBG 10.8-46.6 nmol / L
FSH 1.0-6.9mLU / mL
LH 1.0-8.1 mLU / mL
E2 17.1-46.1 pg / mL

  In the above document, it is reported that the half-life of testosterone fluctuates within a considerable range (10 to 100 minutes). However, diurnal variation in circulating testosterone in normal adolescent men is known in the study. The maximum level is reached from about 6:00 am to 8:00 am, and then the level decreases throughout the day. The characteristic profile is to show testosterone levels up to 720 ng / dL and 430 ng / dL. However, the physiological significance of this circadian cycle, if present, has not been elucidated.

(Testosterone in women)
Androgen steroid excretion in the urine of adult women has been reported more than 50 years ago. Since then, physiologists and clinicians have analyzed the secretion source and biological function of human female testosterone and other endogenous androgen hormones. It is now known that androgens are secreted from female ovaries and adrenal glands. In women exhibiting a healthy “circulation”, about 50% (direct form and its precursor) of testosterone (300 μg) produced per day is produced from each secretory source. Although the side effects of excessive androgen production that occur in the case of polycystic ovary syndrome and tumors that produce certain androgens are often reported, there are very few reports on the normal physiological effects of female androgens. Estimated from animal experiments, male physiology and female symptoms of insufficient androgen production, the main physiological effects of androgens in normal women include effects on muscle, skin, hair and bone anabolism, red blood cell production. It includes, but is not limited to, stimulating effects, immune function modulating effects, and psychological effects on emotion, happiness and sexual function.

  In addition, endogenous androgens are important for pubic hair development and are thought to regulate the activity of estrogens and progestins in various target regenerating tissues. Androgens are also thought to play an important role in the regulation of lacrimal gland secretory function.

  50% of circulating testosterone is derived from direct secretion from ovarian follicular membrane cells under the control of luteinizing hormone. The other half comes from the conversion at the end of the adrenal androgen precursors dehydroepiandrosterone, androstenedione and dehydroepiandrosterone sulfate. Testosterone can also be converted to dihydrotestosterone or estradiol. That is, testosterone functions as both a hormone and a prohormone.

他のホルモンの不足と比較し、女性におけるテストステロンの不足は、診断対象としてはほとんど着目されていなかった。 98% of testosterone circulates in the blood in a protein bound state. In women, nearly 66% of the binding is due to high affinity with sex hormone binding globulins. The remaining 34% is weak binding to albumin. Here, since there are many clinical test results regarding the measured value of testosterone, it will be described below. The order of affinity of steroids binding to sex hormone-binding globulin is dihydrotestosterone>testosterone>androstenedione>estradiol> estrone in the strongest order. Sex hormone binding globulin binds weakly to dihydrotestosterone but not to dihydrotestosterone sulfate. The table below shows the approximate hormone concentrations of normal premenopausal women.

Compared to other hormone deficiencies, testosterone deficiency in women has received little attention as a diagnostic target.

  Nonetheless, cases in which androgen production is clearly inadequate and associated symptoms are described (eg, a woman who has been ovariectomized / extracted in the womb, undergoing estrogen replacement therapy) Including postmenopausal women, women taking oral contraceptives, women with adrenal insufficiency, women with adrenal suppression by corticosteroids, and women with human immunodeficiency virus).

  Since increasing testosterone levels are known to alter sexual behavior and urges, methods of administering testosterone to men and even women are being studied. These methods include intramuscular injection, oral administration, pellet implants and transdermal patches.

  However, these testosterone delivery methods have several drawbacks. For example, subcutaneous pellet implants and ester injections are painful and require surgical procedures and / or visits. Furthermore, male sexual dysfunction implant therapy involves a risk of leakage (8.5%), bleeding (2.3%) or infection (0.6%). Many of these methods (eg, oral / sublingual / buccal use) cause an abnormal value of testosterone concentration that results in an undesirable pharmacokinetic profile, followed by a return to baseline values. Transdermal patches are far from optimal pharmacokinetic characteristics, causing discomfort to many patients and prominent cortical irritation. In addition, patches lack the flexibility of medication and are not visually pleasing and can be peeled off, particularly during intense physical exercise. Oral administration produces abnormal values of testosterone concentration and unpredictable absorption patterns in patients. Furthermore, since the above preparation is metabolized in the liver, there is of course a risk of hepatotoxicity due to first-pass metabolism.

※無水エタノール６７ｇに相当。 In recent years, 1% testosterone gel has been approved for use in men, and it has become softer with less cortical irritation. This gel is available in the United States under the trademark “Androgel” ® from Unimed Pharmaceuticals, Inc. (Deerfield, Ill.), Solway Pharmaceuticals, Inc. (Marietta, GA 30062).

* Equivalent to 67 g of absolute ethanol.

  The present invention provides pharmaceutical compositions and gels containing testosterone and methods for their use. More particularly, the present invention provides hydroalcohol / alcohol pharmaceutical compositions and gels containing testosterone. It is suitable for topical and transdermal applications and includes propylene glycol. In addition to achieving highly effective testosterone delivery, the compositions of the present invention are also very attractive in aesthetic terms. Propylene glycol has been shown to be a very powerful permeation enhancer in the compositions of the present invention and is used alone or in combination with other permeation enhancers such as isopropyl myristate. The

  The present invention relates to a pharmaceutical composition comprising testosterone, at least one C2-C6 alcohol, at least one gelling agent, at least one permeation enhancer and water.

  The pharmaceutical composition can be prepared in various forms such as gels, solutions, creams, lotions, sprays, ointments, aerosols and the like. Preferably, the pharmaceutical composition is a gel.

  The term “testosterone” as used herein refers not only to testosterone itself but also its enantiomers, isomers, tautomers, salts, chelates, esters, amides, derivatives, prodrugs and precursors (eg DHT (dihydro Testosterone), 17-methyltestosterone, 17 [α] -methyl-testosterone 3-cyclopentyl enol ether, testosterone enanthate, testosterone cypionate, testosterone undecanoate, testosterone cyclodextrin, testosterone bucyclate). According to the present invention, testosterone may be naturally derived, or semi-synthetic or synthetically prepared.

  C2-C6 alcohols are known in the prior art. Such alcohols include ethanol, propanol, isopropanol (propan-2-ol), n-propanol (propan-1-ol), butanol, butan-1-ol, butan-2-ol, ter-butanol, pen Tanol and hexanol are included. Ethanol is preferred because it evaporates rapidly on contact with the skin, allowing testosterone to pass through efficiently.

  Gelling agents are known in the prior art. The term “gelling agent” generally refers to a compound that is polymeric and has the ability to gel upon contact with a particular solvent (eg, water). The gelling agent can increase the viscosity of the pharmaceutical composition of the present invention, but can also act as a solubilizing agent. Examples of gelling agents include anionic polymers such as acrylic acid-based polymers (including polyacrylic acid polymers such as Carbopol®, Goodrich Polymers and Chemicals Division of Cleveland, Ohio), cellulose derivatives Poloxamers and poloxamines. More specifically, carbomer or acrylic acid based polymers include, for example, Carbopol® 980 or 940, 981 or 941, 1382 or 1382, 5984, 2984, 934 or 934P (Carbopol® is allyl sucrose. Or a polymer of acrylic acid cross-linked by allylpentaerythritol), Pemulen TR1 (registered trademark) or TR2 (registered trademark), Ultrez, Synthalen CR, and the like. Examples of cellulose derivatives include ethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), etc., poloxamer or polyethylene-polypropylene copolymer, for example Lutrol ® grade 68 or 127, poloxamine, and other gelling agents include, for example, chitosan, dextran, pectin and natural rubber. All of these gelling agents can be used in the pharmaceutical composition of the present invention alone or in combination. The gelling agent can be selected in consideration of the pH and desired viscosity of the composition of the present invention.

  In particular, hydroxypropylcellulose, Carbopol® 980 and Lutrol® are suitable in the present invention.

  Permeation enhancers are also known in the prior art. “Permeation enhancers” are commonly known as mediators that accelerate the penetration of drugs or active ingredients into the skin. These mediators are also called penetration enhancers, adjuvants and permeation enhancers. This type of mediator includes those with various mechanisms of action, and those that have the function of improving the solubility and diffusibility of drugs, as well as changing the water retention capacity of the stratum corneum and softening the skin. These include those that improve skin permeability, act as penetration aids or hair follicle opening agents, or improve transdermal absorption by temporarily changing the state of the skin (eg, the boundary layer).

  Unless otherwise specified, percentages (%) refer to weight percent based on the total weight of the composition.

  In one embodiment, the pharmaceutical composition contains 0.5 to 5.0% (w / w) of testosterone, preferably 0.5 to 2.5% (w / w), more preferably 0.6 to 2. 0.0% (w / w), more preferably 0.7 to 1.5% (w / w), even more preferably 0.75 to 1.25% (w / w), still more preferably 0.0. It is contained in an amount of 8 to 1.2% (w / w), more preferably 0.9 to 1.1% (w / w), and most preferably about 1.0% (w / w).

  In another embodiment of the present invention, the pharmaceutical composition contains 0.5 to 5.0% (w / w) testosterone, preferably 0.5 to 2.5% (w / w), more preferably 0.75 to 2.25% (w / w), more preferably 0.9 to 2.0% (w / w), still more preferably 1.0 to 1.8% (w / w), Even more preferably 1.25 to 1.75% (w / w), still more preferably 1.3 to 1.6% (w / w), most preferably 1.5% (w / w) .

  In another embodiment, the pharmaceutical composition comprises 40.0-75.0% (w / w) of at least one C2-C6 alcohol, preferably 40.0-70.0% (w / w). More preferably, it is 45.0-65.0% (w / w), More preferably, it is 50.0-60.0% (w / w), More preferably, it is 52.0-58.0% (w / w) w), more preferably 53.0-57.0% (w / w), even more preferably 54.0-56.0% (w / w), most preferably about 56% (w / w) included.

  In another embodiment of the invention, the C2-C6 alcohol is selected from the group consisting of ethanol, propan-1-ol and propan-2-ol, and mixtures thereof. Preferably, the C2-C6 alcohol is ethanol.

  In another embodiment of the invention, the pharmaceutical composition contains at least one gelling agent in the range of 0.1-5.0% (w / w), preferably 0.15-4.5% (w / w). ), More preferably 0.2 to 4.0% (w / w), still more preferably 0.25 to 3.5% (w / w), still more preferably 0.3 to 3.0% ( w / w), more preferably 0.4-2.5% (w / w), even more preferably 0.5-2.0% (w / w), most preferably 0.5-1. 0% (w / w) is included.

  In another embodiment of the present invention, the gelling agent comprises an acrylic acid-based polymer (cellulose compounds (cellulose esters and derivatives (cellulose derivatives such as ethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC) carboxymethylcellulose). (Including CMC))), carbomers (Carbopol® polymers, such as Carbopol® 980 or 940, 981 or 941, 1382 or 1382, 5984, 2984, 934 or 934P, such as Pemulen TR1 (registered trademark) or TR2 (registered trademark), Ultrez, Synthalen CR), poloxamine, poloxamer or poly Selected from the group consisting of ethylene-polypropylene copolymers (eg Lutrol® grade 68 or 127, poloxamine or other gelling agents (such as chitosan, dextran, pectin and natural rubber)), and mixtures thereof Is done.

  In another embodiment of the invention, the pharmaceutical composition contains 0.1 to 5.0% (w / w) propylene glycol, preferably 0.15 to 4.5% (w / w), more preferably Is 0.2 to 4.0% (w / w), more preferably 0.3 to 3.5% (w / w), still more preferably 0.4 to 3.0% (w / w), More preferably 0.5 to 2.5% (w / w), most preferably 0.5 to 2.0% (w / w) is contained. Surprisingly in the present invention, it has been found that in the testosterone component and composition of the present invention, propylene glycol is a very effective and compatible permeation enhancer. Furthermore, the use of propylene glycol of the present invention provides a pharmaceutical composition that exhibits a very attractive appearance. The pharmaceutical composition of the present invention is more transparent, visually attractive and has a very favorable texture, which makes it better for patients. Furthermore, the pharmaceutical composition of the present invention needs to contain a lower alcohol. Furthermore, the compositions of the present invention are very stable and it has been found that propylene glycol is compatible with standard neutralizing agents (eg, triethanolamine). The composition of the present invention may contain several permeation enhancers.

In the present invention, the pharmaceutical composition may further optionally contain water.
In one embodiment, the present invention provides:
-Testosterone 0.5-5.0% (w / w)
At least one C2-C6 alcohol 40.0-75.0% (w / w)
-At least one gelling agent 0.1-5.0% (w / w)
-Propylene glycol 0.1-5.0% (w / w)
-Optionally water,
A pharmaceutical composition is provided.

In other embodiments, the present invention provides:
-Testosterone 0.75-1.25% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-4.0% (w / w)
-Propylene glycol 0.2-4.0% (w / w)
-Optionally water,
A pharmaceutical composition is provided.

In other embodiments, the present invention provides:
-Testosterone 0.8-1.2% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-3.0% (w / w)
-Propylene glycol 0.3-3.0% (w / w)
-Optionally water,
A pharmaceutical composition is provided.

In other embodiments, the present invention provides:
-Testosterone 0.9-1.1% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-2.5% (w / w)
-Propylene glycol 0.4-2.5% (w / w)
-Optionally water,
A pharmaceutical composition is provided.

In other embodiments, the present invention provides:
-Testosterone about 1.0% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-2.5% (w / w)
-Propylene glycol 0.4-2.5% (w / w)
-Optionally water,
A pharmaceutical composition is provided.

In other embodiments, the present invention provides:
-Testosterone 1.0-2.0% (w / w)
-At least one C2-C6 alcohol 50.0-75.0% (w / w)
-At least one gelling agent 0.1-5.0% (w / w)
-Propylene glycol 0.1-5.0% (w / w)
-Optionally water,
A pharmaceutical composition is provided.

In other embodiments, the present invention provides:
-Testosterone 1.25 to 1.75% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-4.0% (w / w)
-Propylene glycol 0.2-4.0% (w / w)
-Optionally water,
A pharmaceutical composition is provided.

In other embodiments, the present invention provides:
-Testosterone 1.4-1.6% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-3.0% (w / w)
-Propylene glycol 0.3-3.0% (w / w)
-Optionally water,
A pharmaceutical composition comprising is formed.

In other embodiments, the present invention provides:
-Testosterone about 1.5% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-2.5% (w / w)
-Propylene glycol 0.4-2.5% (w / w)
-Optionally water,
A pharmaceutical composition comprising

  The pharmaceutical composition is suitable for controlling the transdermal delivery of testosterone. That is, the pharmaceutical composition allows spontaneous administration by the patient himself and does not require the presence of a doctor during administration. In addition, the administration does not require surgery or injection.

  In the present invention, preferably propylene glycol functions as a very powerful permeation enhancer of testosterone, especially in combination with the testosterone dosage and the gelling agent of the composition of the present invention.

  In other embodiments, the pharmaceutical composition of the present invention further comprises a base. Preferably, the base is pharmaceutically acceptable and is preferably selected from the group consisting of triethanolamine, sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, aminomethylpropanol or tromethamine and mixtures thereof. The When the pH of the pharmaceutical composition is not optimal for transdermal administration (eg when the gelling agent comprises at least one acrylic acid-based polymer), the base can be used for topical administration on human skin. It plays a role in neutralizing. In addition, the base (neutralizing agent) provides optimal expansion of the polymer chain during charge neutralization and formation of polymer salts. In particular, when the gelling agent comprises an acrylic acid-based polymer, the base preferably includes triethanolamine. It also allows the pharmaceutical composition of the present invention to have an optimal viscosity. A person skilled in the art appropriately adjusts the appropriate amount of the base to be added to the composition according to the properties of the gelling agent contained and the alcohol content of the composition, in order to match the final pH of the composition. Can be adjusted. For example, in the case of carbomers and / or high alcohol content, tromethamine and / or NaOH can be used as a base and the amount required to adjust to the desired final pH of the composition can be adjusted. Alternatively, in one embodiment, the pharmaceutical composition of the invention contains 0.1 to 5.0% (w / w) of triethanolamine, preferably 0.15 to 4.5% (w / w), More preferably, it is 0.2-4.0% (w / w), More preferably, it is 0.25-3.5% (w / w), More preferably, it is 0.3-3.0% (w / w) w), more preferably 0.4-2.5% (w / w), even more preferably 0.5-2.0% (w / w), most preferably 0.5-1.0% (W / w) included.

  Preferably, the pH of the pharmaceutical composition according to the invention is 2-9, preferably 3-8, more preferably 3-7. In another embodiment of the invention, the pharmaceutical composition further comprises isopropyl myristate. Unexpectedly in the present invention, it has been found that the use of isopropyl myristate as a further permeation enhancer in combination with propylene glycol significantly increases the effect. Preferably, the pharmaceutical composition contains 0.05-5.0% (w / w) isopropyl myristate, preferably 0.1-4.0% (w / w), more preferably 0.15- 3.0% (w / w), more preferably 0.25 to 2.5% (w / w), even more preferably 0.25 to 2.0% (w / w), still more preferably 0 .25 to 1.5% (w / w), more preferably 0.25 to 1.0% (w / w), and most preferably 0.5 to 0.75% (w / w).

That is, in one embodiment, the present invention provides a pharmaceutical composition having the following composition.
-Testosterone 0.5-5.0% (w / w)
At least one C2-C6 alcohol 40.0-75.0% (w / w)
-At least one gelling agent 0.1-5.0% (w / w)
-Propylene glycol 0.1-5.0% (w / w)
-Isopropyl myristate 0.1-4.0% (w / w)
-Optionally water.

In another embodiment, the present invention provides a pharmaceutical composition having the following composition.
-Testosterone 0.75-1.25% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-4.0% (w / w)
-Propylene glycol 0.2-4.0% (w / w)
-Isopropyl myristate 0.15-2.0% (w / w)
-Optionally water.

In another embodiment, the present invention provides a pharmaceutical composition having the following composition.
-Testosterone 0.8-1.2% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-3.0% (w / w)
-Propylene glycol 0.3-3.0% (w / w)
-Isopropyl myristate 0.35-1.5% (w / w)
-Optionally water.

In another embodiment, the present invention provides a pharmaceutical composition having the following composition.
-Testosterone 0.9-1.1% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-2.5% (w / w)
-Propylene glycol 0.4-2.5% (w / w)
-Isopropyl myristate 0.4-1.0% (w / w)
-Optionally water.

In another embodiment, the present invention provides a pharmaceutical composition having the following composition.
-Testosterone about 1.0% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-2.5% (w / w)
-Propylene glycol 0.4-2.5% (w / w)
-About 0.5% isopropyl myristate (w / w)
-Optionally water.

In another embodiment, the present invention provides a pharmaceutical composition having the following composition.
-Testosterone 1.0-2.0% (w / w)
-At least one C2-C6 alcohol 50.0-75.0% (w / w)
-At least one gelling agent 0.1-5.0% (w / w)
-Propylene glycol 0.1-5.0% (w / w)
-Isopropyl myristate 0.1-4.0% (w / w)
-Optionally water.

In another embodiment, the present invention provides a pharmaceutical composition having the following composition.
-Testosterone 1.25 to 1.75% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-4.0% (w / w)
-Propylene glycol 0.2-4.0% (w / w)
-Isopropyl myristate 0.15-2.0% (w / w)
-Optionally water.

In another embodiment, the present invention provides a pharmaceutical composition having the following composition.
Testosterone 1.4-1.6% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-3.0% (w / w)
-Propylene glycol 0.3-3.0% (w / w)
-Isopropyl myristate 0.35-1.5% (w / w)
-Optionally water.

In another embodiment, the present invention provides a pharmaceutical composition having the following composition.
-Testosterone about 1.5% (w / w)
-At least one C2-C6 alcohol 50.0-70.0% (w / w)
-At least one gelling agent 0.1-2.5% (w / w)
-Propylene glycol 0.4-2.5% (w / w)
-Isopropyl myristate 0.4-1.0% (w / w)
-Optionally water.

  Furthermore, the pharmaceutical composition may contain usual pharmaceutical additives, salts, emollients, stabilizers, antibacterial substances, perfumes and / or sprays. The pharmaceutical composition may include at least one additional active ingredient (eg, other hormones).

  The present invention also provides a gel useful for transdermal or transcutaneous delivery comprising the pharmaceutical composition of the present invention. That is, the present invention also relates to a testosterone-containing hydroalcohol gel.

  In another embodiment, the present invention provides a dose packet, single dose packet or multiple dose packet comprising the pharmaceutical composition or the hydroalcohol gel. Preferably, this kind of device is applied to the pharmaceutical composition, which makes administration easier for the patient. That is, these packaging forms may reflect dosing schedules (eg daily or weekly dosing).

  In another embodiment, a dispenser, such as a manual pump or valve, is provided comprising the pharmaceutical composition or the hydroalcohol gel. Depending on the amount of composition applied, this type of dispenser can be flexibly adjusted.

  In one embodiment, the packet or dispenser may be accompanied by instructions on how to handle it.

  The pharmaceutical compositions, gels, packaging and containers according to the present invention are useful for the treatment of testosterone deficiency and the treatment and / or prevention of symptoms and / or disorders associated with testosterone deficiency. As used herein, the term “treat” or “treatment” refers to the treatment of any symptom, disorder or disease in a mammal with a depressive disorder, which may be considered as such symptom, disorder or disease. Preventing the occurrence of the symptom, disorder or disease in a patient who has not yet been diagnosed with the symptom, disorder or disease; stopping the onset of the symptom, disorder or disease (eg, inhibiting the symptom, disorder or disease) Alleviating symptoms, disorders or diseases (eg, reversing symptoms, disorders or diseases); or alleviating symptoms due to a disease or disorder (eg, stopping signs of a disease or disorder), Not limited to these

  The term “prevent” or “prevention” with respect to a symptom, disorder or disease does not cause the symptom, disorder or disease to occur if it does not exist, or further if the symptom, disorder or disease already exists It means not to progress a symptom, disorder or disease.

  “Deficiency of testosterone” in the present invention refers to a state in which the serum concentration of free testosterone in a patient is low compared to the standard serum concentration of healthy subjects of the same age. For example, in the normal female circulatory system, about 300 μg of testosterone is synthesized per day. The total serum testosterone concentration is usually about 20 ng / dL to about 80 ng / dL, with an average of about 40 ng / dL. In healthy young women, for example, the average free testosterone concentration is usually about 3.6 pg / mL. However, several factors can affect the total testosterone concentration and free serum concentration. For example, in women who ovulate regularly, blood testosterone concentrations are small but significantly increased at the middle third of the menstrual cycle. However, the mean testosterone concentration (1.2 nmol / L or 33 ng / dL) and free testosterone concentration (12.8 pmol / L or 3.6 pg / mL) are not significantly different in the luteal phase and follicular phase. Furthermore, testosterone production decreases continuously after age 30, and serum testosterone levels in women in their 60s are only 50% of those in young 30s. The percentage of free testosterone generally does not show a change with age, but a decrease in the absolute amount of free testosterone has been observed. This decline does not occur suddenly at menopause, but instead occurs in a stepwise and continuous manner as a result of an aging decrease in androgen production in the adrenal gland and ovary. In other words, women begin to realize symptoms associated with menopause in the years immediately before menopause. The decrease in testosterone following menopause results from a combination of ovarian failure, decreased renal secretion and peripheral conversion. Also, for example, after oophorectomy, testosterone levels are reduced by about 50%. The diagnosis of testosterone deficiency is known to the general physician in the relevant medical field.

The pharmaceutical compositions and gels of the present invention are useful for the treatment of many physiological and psychological parameters and / or symptoms associated with male or female testosterone deficiency. For example, the pharmaceutical composition and gel of the present invention are useful in the following cases.
-Increased sexual impulse, improved sexual function and / or treatment of sexual dysfunction; normalization of hypogonadism;
-Increased bone density and related indicators, increased lean body mass, decreased fat body weight; improved muscle mass and function;
-Normalization of blood glucose level; improvement of diabetic retinopathy and reduction of insulin requirement in diabetic patients; treatment, prevention or reduction of cataract development;
-Treatment, prevention or reduction of the development of cardiovascular diseases including normalization of hypertension and treatment of obesity; normalization of cholesterol levels; normalization of abnormal electrocardiograms of patients and treatment, prevention or reduction of vasomotor symptoms;
-Prevention of human immunodeficiency virus exhaustion syndrome;
-Prevention of osteoporosis, osteopenia, dryness of the vagina and reduction of vaginal wall thickness; alleviation of menopausal symptoms and transient warmth; treatment of premenstrual syndrome;
-Treatment, prevention or reduction of the onset of Alzheimer's disease and dementia;
-Improvement of cognition; restoration of emotion and self-esteem, treatment and / or prevention of depressive disorder, treatment, prevention or reduction of cognitive dysfunction;
-Treatment of autoimmune diseases.

  The pharmaceutical compositions and gels of the present invention can be used in “combination therapy” with other hormones or steroids, pharmaceuticals that increase a patient's testosterone level, estrogen hormones or other pharmaceuticals (eg, antidepressants).

  The invention also relates to a method for preparing a pharmaceutical composition, for example in the form of a gel or solution as described above.

  In one embodiment, the method comprises dissolving testosterone in a solvent comprising at least one C2-C6 alcohol and at least one permeation enhancer (eg, propylene glycol and / or isopropyl myristate) with stirring. Is included.

  In another embodiment, the method includes adding water to the resulting mixture with stirring.

  If gel preparation is required, at least one gelling agent (eg Carbopol®) is further added to the mixture with stirring.

  While stirring, a base / neutralizing agent such as triethanolamine may optionally be added to the mixture.

In another embodiment, the invention relates to a method for preparing a pharmaceutical composition or gel as described above, comprising the following steps.
-Preparing a mixture containing at least one C2-C6 alcohol, at least one permeation enhancer (eg propylene glycol and / or isopropyl myristate) and testosterone;
-Optionally adding water and mixing;
-Optionally adding a gelling agent to the mixture and mixing;
-Optionally add base and mix again.

  In another embodiment, the present invention also relates to the use of the gel or solution of the present invention in the preparation of a medicament for transdermal administration to treat physiological conditions associated with androgen / testosterone deficiency.

  In another embodiment, the invention relates to a method of treatment.

  In one embodiment, the method comprises administering testosterone to a patient in need thereof.

  In one embodiment, the pharmaceutical composition or gel of the invention is applied to healthy skin (eg, outside the shoulder, arm, thigh or leg).

  Serum testosterone levels may be measured by standard analytical techniques to measure and determine the amount of testosterone delivered to the patient.

  Using it, one skilled in the art will be able to determine how to measure the amount of composition administered based on the exact testosterone dose of the pharmaceutical composition.

  In general, the dosage of the pharmaceutical composition of the present invention in the form of gel or solution is usually 2.5 to 5 g (formulation) per day.

  The effects of the present invention will become apparent from the following examples, which are described below by way of illustration only and are not limited thereto. Those skilled in the art will recognize that the preferred features of the invention described above can be arbitrarily combined.

  All citations mentioned herein are hereby incorporated by reference in their entirety. Other embodiments of the present invention are not specifically shown, but are obvious to those skilled in the art and are therefore included in the technical scope and spirit of the present invention. The practice of the present invention uses conventional techniques of pharmacology and pharmacology, unless otherwise specified, which are within the skill of the artisan.

Tests for transdermal delivery of testosterone gel formulations were performed on animal and human skin using radiolabeled ( ¹⁴ C) testosterone and liquid scintillation titration. These tests were conducted on kinetic parameters (release amount and flow rate after 24 hours). Two aspects were analyzed.
-Physicochemical tests (testosterone solubility and gel viscosity)
-Transdermal delivery (effects of testosterone concentration, gelling agent properties, presence of permeation enhancers)

Materials and methods:
1. material
Drug Testosterone (Fluka)
¹⁴ C testosterone (Amersham)
Gelling agent Carbopol® 934P (Carb. 934P) (Polyplastic)
Carbopol (registered trademark) 980 (Carb. 980) (Lot 4419, Laboratories Besins Iscoves)
Klucel (registered trademark)
Neutralizing agent Triethanolamine (lot 4343, Laboratoires Beins Iscovesco)
Permeation enhancer Transcutanol (Gattefosse)
Oleic acid (OA) (Prolabo)
Propylene glycol (PG) (Gattefosse)
Propylene glycol dipelargonate (PGDP) (Gattefosse)
Animal skin model <br/> Naked rat, male, 5 weeks old
Human skin model Biopsy specimen taken during abdominal plastic surgery, Caucasian female, 35 years old

（Ｃａｒｂ．＝カルボポール（登録商標）） 2. Preparation of radiolabeled testosterone gel The gelling agent (polymer) was swollen overnight with as much water as necessary. Labeled and unlabeled testosterone dissolved in ethanol, presumably due to the presence of permeation enhancers. The aqueous phase and the alcohol phase were mixed and further neutralized with triethanolamine. Mix with a spatula until completely uniform. Seventeen reagents were evaluated for transdermal delivery. The composition is described in the following table (expressed in% by weight relative to the total amount of the preparation). Formulations 13 and 14 correspond to non-gelling solutions.

(Carb. = Carbopol (registered trademark))

3. Skin penetration kinetic protocol
3.1. Skin permeation cell A static flow cell with two deformed compartments was used (FIG. 1). From the upper cylindrical donor compartment 1 (cross section: 2.54 cm ² ), the formulation (solution or form of topical administration) can be administered onto the skin 2. The upper section 1 is connected to the lower section 4 by a metal ring. The lower receiving compartment 4 (average volume: 10 mL) likewise has an upper opening of 2.54 cm ² . Sampling is performed from a lateral shunt 5 with a needle and catheter system. The homogenization of the solvent in the lower compartment is performed by a magnetic stirrer 3 (see FIG. 1).

3.2. Biological membrane
Skin biopsy specimens of animal-derived male naked rat skin (IOPS rats, 5 weeks old) were sampled from the abdomen. Adipose tissue located on the inner surface was removed, and the skin was excised so as to be a sample with a region area larger than 2.54 cm ² . Each sample was placed in the lower compartment with the outer skin surface facing up.

The test was conducted using a sample of a 35-year-old white female abdomen excised by plastic surgery. Samples were used immediately after sampling and skin segmented to a thickness of about 250 μm.

3.3 Test Protocol The two compartments 1, 4 of the skin penetration cell were constituted by skin fragments 2. The receiving compartment 4 was filled with an accurately measured amount of 0.5% albumin solution. The cell was then shaken for 15 hours on a 37 ° C. agitation platform in a thermostatic bath to equilibrate the skin and the recipient solvent.

The preparation was administered onto the skin 2 to start the kinetics. The dose was about 20 mg per 2.54 cm ^{2 of} skin. Over a 24 hour period, 2 mL samples were sampled from the receiving compartment 4 at regular time intervals, and immediately thereafter 2 mL of fresh albumin solution was added to the compartment to keep the volume constant. Five permeation cells were used for each formulation. After refrigerated storage, samples were liquid scintillation titrated.

4). ^{The 14} C testosterone titration sample was divided into two 1 mL portions, 4 mL scintillation fluid (Pico Fluor 40 (registered trademark)) was added, and the measurement time was set to 5 minutes. Further samples were titrated by liquid scintillation using a β spectrophotometer (Beckman). In scintillation, since the detection efficiency is reduced by quenching, a calibration curve called a quenching curve was created to perform accurate measurement. For each sample, quenching measurements were calculated from the external standard source and actual radioactivity.

result
1. A known amount of testosterone solubility solvent (2 mL) was stirred at 37 ° C. in a sealed Erlenmeyer flask. Starting with a known amount of testosterone, fractions were added gradually. The amount in the Erlenmeyer flask was measured (by difference) and the remaining amount of testosterone was weighed. Testosterone solubility in various permeation enhancers such as a 37 ° C. water / ethanol mixture, propylene glycol (PG) oleic acid (OA) propylene glycol dipelargonate (PGDP), transcutol was measured by the increment method.
Testosterone solubility in various mediators

図２のグラフを参照。 Moreover, the solubility of testosterone corresponding to the ethanol content was analyzed.
Solubility of testosterone in water / ethanol mixture

See the graph in FIG.

2. The rheology of the gel's viscous gel was measured with a Carri-Med stress controlled rheometer (measuring geometry: plane / plane, diameter 2 cm, gap 1 mm, temperature 20 ° C.). The flow curve was plotted for fluidity according to the following defined shear cycle.
Ascending phase: stress increase from 0 to 300 N / m ^{2 for} 2 minutes;
Plateau: constant stress of 300 N / m ² for 1 minute;
Lowering phase: Stress reduction to 300-0 N / m ^{2 for} 2 minutes.
Without any hysteresis cycle, all the gels behaved softening (pseudoplastic).

Two rheological tests were performed.
-The effect of ethanol content on the viscosity of Carbopol (R) 934 gel-The effect of polymer content on the viscosity of Carbopol (R) 980 gel

エタノールが５５％以上では、粘度はエタノール含量増加に伴い大きく減少した。粘性は、エタノール５０％にて増加した。 2.1. The effect of the Carbopol® 934P hydroalcohol gel on the ethanol content of the viscous Carbopol® hydroalcohol gel was tested with the 95% ethanol content varied from 50% to 70%.

When ethanol was 55% or more, the viscosity decreased greatly with increasing ethanol content. The viscosity increased with 50% ethanol.

2.2. Carbopol® 980 gel was tested for the effect of polymer content in hydroalcohol gels containing 40% viscous ethanol by varying Carbopol® 980 from 0.3% to 0.7%. A plateau was applied at a stress of 300 N / m ² for 1 minute, and the viscosity was measured.

製剤１１〜２７では８ｍｇ／ｃｍ^２を投与した。 3. Skin penetration of testosterone preparation into rat skin The skin penetration of the preparation of Table 3 was analyzed in vitro using rat skin. Formulation 25 could not be evaluated for reasons of heterogeneity (phase separation). The results for the release amount at 24 hours and the release rate at 24 hours are shown in the table below.

In preparations 11 to 27, 8 mg / cm ² was administered.

4). The testosterone penetrating preparation 15 in human skin was used as a control, and human skin was evaluated using preparations 26 and 27. The results are shown below.

平均動態のプロット線を図３に示す。
平均流速：０．２６μｇ／ｃｍ^２．ｈ Formulation 26
Average penetration parameter values in 5 cells:

The plot line of average kinetics is shown in FIG.
Average flow rate: 0.26 μg / cm ² . h

平均動態のプロット線を図４に示す。
平均流速：０．３９μｇ／ｃｍ^２．ｈ Formulation 27
Average penetration parameter value in 5 cells

The plot line of average kinetics is shown in FIG.
Average flow rate: 0.39 μg / cm ² . h

平均動態のプロット線を図５に示す。
平均流速：０．１５μｇ／ｃｍ^２．ｈ Formulation 15 (control)
Average penetration parameter value in 5 cells

The plot plot of average kinetics is shown in FIG.
Average flow rate: 0.15 μg / cm ² . h

製剤を以下の通り調製した。 Materials and methods
1. Material [1,2,6,7- ³ H] testosterone (Amersham Laboratories): MW = 295 (1 mCi / mL (37 MBq / mL) in ethanol solution); 99 Ci / mmol (3.66 TBq / mmol) specific activity I.e. 336 mCi / mg (Lot 18).
Absolute ethanol (Carlo Erba, lot V4N051154N)
Material Carbopol (R) 980 lot 92010/4420 prepared by Laboratoires Beins
Carbopol® 934 lot / 3898
Testosterone lot92039 / 4461
Isopropyl myristate lot91169 / 5781
Triethanolamine (TEA) lot9304020 / 5721
Propylene glycol (PG)
Formulation administered dermally: (weight to 100 g of final formulation)

The formulation was prepared as follows.

Formulation 1:
1 g of radiolabeled gel was prepared as follows:
-100 μL (100 μCi) of radiolabeled ( ³ H) testosterone solution is dried,
595 mg of a solution of 2.5 g testosterone in 57 g absolute ethanol,
-391.5 mg of base gel (1 g Carbopol® 934 absorbed 38.15 g water, after complete expansion, homogenized with ultra-turax for 2-3 seconds before use) ), And -13.5 mg TEA.
Formulation radiation dose: 100 μCi / g gel. That is, 0.8 μCi and 200 μg of testosterone were administered at 8 mg (about 10 μL) per 1.77 cm ² cell.

Formulation 2:
1 g of radiolabeled gel was prepared according to the following protocol:
-100 μL (100 μCi) of radiolabeled ( ³ H) testosterone solution is dried,
595 mg of a solution of 1 g testosterone and 0.5 g PG in -58 g absolute ethanol,
-393 mg base gel (0.6 g Carbopol® 980 absorbed 38.7 g water, after complete expansion, homogenized with ultra-turax for 2-3 seconds before use) ) And -resuspended in 12 mg TEA diluted 2-fold with water.
Formulation radiation dose: 100 μCi / g gel. That is, 0.8 μCi and 80 μg of testosterone were administered at 8 mg (about 10 μL) per cell.

Formulation 3:
1 g of radiolabeled gel was prepared according to the following protocol:
-100 μL (100 μCi) of radiolabeled ( ³ H) testosterone solution is dried,
595 mg of a solution of 1 g testosterone and 0.5 g PG in -58 g absolute ethanol,
-389 mg base gel (0.8 g Carbopol® 980 absorbed 38.1 g water, after complete expansion, homogenized with ultra-turax for 2-3 seconds before use) ) And -resuspended in 16 mg TEA diluted 2-fold with water.
Formulation radiation dose: 100 μCi / g gel. That is, 0.8 μCi and 80 μg of testosterone were administered at 8 mg (about 10 μL) per cell.

Formulation 4:
1 g of radiolabeled gel was prepared according to the following protocol:
-100 μL (100 μCi) of radiolabeled ( ³ H) testosterone solution is dried,
-685 mg of a solution of 1 g testosterone and 0.5 g isopropyl myristate dissolved in -67 g absolute ethanol,
-267.75 mg of base gel (0.9 g Carbopol® 980 absorbs 25.875 g of water and after complete expansion, the mucilage is homogenized with ultra-turax for a few seconds before use. And 47.25 mg of -NaOH (0.1 M) solution.
Formulation radiation dose: 100 μCi / g gel. That is, 0.8 μCi and 80 μg of testosterone were administered at 8 mg (about 10 μL) per cell.

Formulation 5:
1 g of radiolabeled gel was prepared according to the following protocol:
-100 μL (100 μCi) of radiolabeled ( ³ H) testosterone solution is dried,
-685 mg of a solution of 1 g testosterone and 0.5 g isopropyl myristate dissolved in -67 g absolute ethanol,
-305 mg of base gel (0.5 g Carbopol® 980 absorbed 30 g of water, and after complete expansion, the mucilage was homogenized with ultra-turax for a few seconds) And resuspended in 10 mg of TEA diluted -2 times.
Formulation radiation dose: 100 μCi / g gel. That is, 0.8 μCi and 80 μg of testosterone were administered at 8 mg (about 10 μL) per cell.

2. Method
In vitro transdermal absorption:
Principle Using a human abdominal skin segmented biopsy specimen placed in a stationary diffusion cell (Frantz cell) (the living fluid (receptor fluid) through which percutaneous absorption is performed and the dermis are in contact) Quantitative tests of in vitro transdermal absorption were performed.

A cell skin biopsy specimen is placed horizontally between the two parts of the cell and separates the two compartments:
One compartment on the epidermis side is a glass cylinder (with an exact 1.77 cm ² area and placed on the upper side of the skin);
The other is the dermis side and is located on the lower face of the outer skin and contains a constant volume storage port with a lateral collection port.

  The above two elements were configured via clamps.

  The lower compartment (dermis side) was filled with a viable solution composed of 9 g / L sodium chloride solution supplemented with bovine serum albumin at 15 g / L. At each time point, the entire amount of viable fluid was sampled from the lateral collection port and replaced with fresh fluid.

  The lower cell was maintained at 37 ° C. The mixture was stirred with a magnetic stirrer to keep the temperature and composition of the receiving liquid constant.

  Since the upper part (epidermal side section) is open to the outside, the surface of the epidermis is exposed to laboratory air.

Skin segment of a biopsy specimen of human abdominal skin:
Human abdominal skin samples taken in plastic surgery for white donors were used. The skin was stored at −20 ° C. before use. Adipocytes adhering under the dermis were surgically removed with a scalpel and the skin was segmented to a thickness of about 0.5 mm. In each analysis, different skin samples were used equally from lot to lot.

General protocol Franz cells are usually installed the day before the day of administration of the formulation to be tested. With the epidermis compartment in contact with the test room air, the skin was contacted with physiological saline containing albumin for approximately 17 hours while maintaining the dermis compartment at a constant temperature of 37 ° C. Under these conditions, the skin is very hydrated.

  10 μL of the solution (about 8 μL, about 8 μCi) was applied with a micropipette over the entire surface of the epidermis delimited by a glass cylinder. The fluid contained in the dermal compartment was sampled from the lateral collection port at 2 hours, 4 hours, 6 hours, 8 hours and 24 hours. At each time point, the whole amount of the viable liquid was sampled outside and replaced with fresh liquid.

At the end of the analysis, the treated dermis side surface was washed with 200 μL of various solvents according to the following protocol.
First wash: Setablon® / water (1/9 (v / v));
-2nd wash: water;
-3rd wash: Setablon® / water (1/9 (v / v));
-4th wash: water;
-5th wash: water.

  Further, the administered area was wiped with Q-tips (registered trademark). In addition, the epidermis and dermis were mechanically separated with a scalpel and digested in 1 mL and 3 mL Solene (R) (Packard), respectively.

Radioactivity measurement Liquid scintillation was measured using a Packard-tricarb 4530 particle counter.

Preparation of radioactive samples:
The viable fluid sampled from the lower compartment of the diffusion cell was added directly to 15 mL of liquid scintillation cocktail (Picofluor 4OR, Packard) and measured with a radioactivity measuring device. Wash solution and Q-tips® were added to approximately 30 mL of 95% ethanol vial and weighed accurately. After overnight incubation at 4 ° C., the radioactivity of this accurately weighed dilution was measured according to the same procedure as the viable solution. The epidermis and dermis must first be dissolved with a strong organic base. They were contacted and dissolved (1 mL per 100 mg tissue) at 37 ° C. for 24 hours using a Soluene 350® Packard, and further 15 mL liquid scintillation cocktail (Honic Fluor 30®, Packard) was added, Furthermore, it measured with the meter.

Radioactivity measurement:
When quenching was involved, the count rate was corrected by a calibration curve generated from an external standard and the decay rate (dpm) per minute representing the true activity of each sample was measured. The background value was subtracted from the cpm of each sample. A quenching curve was created for each scintillation fluid.

  The result calculated from the count rate from the optimal dilution calibration curve is expressed as the weight or percentage of the substance present in the sample at each dose.

Transdermal absorption:
The degree of transdermal absorption was evaluated by calculating the absorption percentage (%) of the addition amount (Qi) over time:
% = (Qt / Qi) × 100
(Where Qt is the amount of absorption at time t).

The average flow rate and absorption amount at each time interval were measured and expressed in units of ng / cm ² / h and ng, respectively.

  The average of 6 to 8 experimental results was taken as the result, and the standard deviation (SD) was taken.

  Analysis of variance was performed and the above results averaged were compared.

3. Results Expressed as the weight percent concentration of the material present in 100 g of the final formulation.

＠：対照との差異（分散分析、フィッシャー検定（ｐ＜５％））
※：対照との差異（ａｎｏｖａ、フィッシャー検定及びシェッフェＦ検定（ｐ＜５％））
回収値（蓄積値）

Ｅ：表皮、Ｄ：真皮、Ｃ：セル、Ｗ：洗浄、Ｔ：全量
＠：対照との差異（分散分析、フィッシャー検定（ｐ＜５％））
°：製剤２、３及び４との差異（ａｎｏｖａ、フィッシャー検定（ｐ＜５％））
＊：対照との差異（ａｎｏｖａ、フィッシャー検定及びシェッフェＦ検定（ｐ＜５％））
フランツセル中へのインビトロにおけるテストステロン浸透（非蓄積値） In vitro testosterone penetration into Franz cells (accumulated value)
The average value +/− Sd is expressed for each hour.

@: Difference from control (ANOVA, Fisher test (p <5%))
*: Difference from control (anova, Fisher test and Scheffe F test (p <5%))
Collected value (accumulated value)

E: epidermis, D: dermis, C: cell, W: wash, T: total amount @: difference from control (ANOVA, Fisher test (p <5%))
°: Difference from Formulations 2, 3 and 4 (anova, Fisher test (p <5%))
*: Difference from control (anova, Fisher test and Scheffe F test (p <5%))
In vitro testosterone penetration into Franz cells (non-accumulated value)

＠：対照との差異（分散分析、フィッシャー検定（ｐ＜５％））
※：対照との差異（分散分析、フィッシャー検定及びシェッフェＦ検定（ｐ＜５％）） The average value +/− Sd is expressed for each hour.

@: Difference from control (ANOVA, Fisher test (p <5%))
*: Difference from control (ANOVA, Fisher test and Scheffe F test (p <5%))

FIG. 2 is a schematic diagram showing a static flow cell having two deformed compartments. The graph which shows the solubility to the water / ethanol mixed liquid of testosterone. A plot line of the average kinetics of formulation 26 is shown. A plot line of the average kinetics of formulation 27 is shown. A plot of the mean kinetics of formulation 15 (control) is shown.

Explanation of symbols

1 Upper compartment 1
2 Skin 3 Magnetic stirrer 4 Lower compartment 5 Shunt

Claims (10)

A pharmaceutical composition comprising:
-Testosterone 0.5-5.0% (w / w)
-40.0-75.0% (w / w) of at least one C2-C6 alcohol
-0.1 to 5.0% (w / w) of at least one gelling agent
-Propylene glycol 0.1-5.0% (w / w)
-Optionally water.   The pharmaceutical composition according to claim 1, wherein the C2-C6 alcohol is selected from the group consisting of ethanol, propan-1-ol and propan-2-ol, and mixtures thereof.   The pharmaceutical composition according to any one of claims 1 or 2, wherein the gelling agent is selected from the group consisting of acrylic acid-based polymers, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, cellulose compounds and mixtures thereof. object.   The gelling agent is selected from the group consisting of carbomers, such as Carbopol® 980, Carbopol® 934P, Carbopol® 1342, Carbopol® 1382, and mixtures thereof. The pharmaceutical composition according to any one of claims 1 to 3, comprising at least one gelling agent.   The base further comprises a base preferably selected from the group consisting of triethanolamine, sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, aminomethylpropanol, tromethamine and mixtures thereof. The pharmaceutical composition according to any one of the above.   The pharmaceutical composition according to any one of claims 1 to 5, further comprising isopropyl myristate.   A gel useful for transdermal delivery or transepidermal delivery, comprising the pharmaceutical composition according to any one of claims 1 to 6.   A unit dose packet, a single dose packet or a multiple dose packet comprising the pharmaceutical composition according to any one of claims 1 to 6 or the gel according to claim 7.   A dispenser, such as a hand pump, comprising the pharmaceutical composition according to any one of claims 1 to 6 or the gel according to claim 7. Providing a mixture comprising at least one C2-C6 alcohol, at least one permeation enhancer and testosterone;
Optionally adding and mixing water;
Optionally adding and mixing a gelling agent to the mixture;
A method for preparing a pharmaceutical composition according to any one of claims 1 to 6 or a gel according to claim 7, comprising the step of optionally adding a base and mixing again.

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