RU2642244C2 - Oral pharmaceutical compositions of testosterone esters and method for testosterone shortage treatment with their use - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention concerns an oral pharmaceutical composition for testosterone shortage treatment for men, containing testosterone undecanoate dissolved in a medium containing at least one lipophilic surfactant and at least one hydrophilic surfactant with a ratio of the total number of lipophilic surfactants to the total number of hydrophilic surfactants (in/out), being in an approximate range from 6:1 to 3.5:1, while the dissolved testosterone undecanoate ranges from 18 to 22 wt % of the composition. The invention also relates to composition application for production of a drug for treatment of testosterone shortage or its symptoms in men and a treatment method, which includes oral intake of an effective amount of the pharmaceutical composition.

EFFECT: application of the invention provides an opportunity to achieve a higher bioavailability, providing an effective therapeutic product based on testosterone for oral introduction, which can increase the levels of testosterone in the blood serum to clinically effective values, efficient oral testosterone therapy.

23 cl, 10 tbl, 5 ex, 5 dwg

Description

FIELD OF TECHNOLOGY

The present invention generally relates to oral testosterone ester formulations for treating testosterone deficiency. In particular, the present invention relates to a pharmaceutical composition with improved and enhanced absorption and pharmacokinetics, including testosterone undecanoate (TU).

BACKGROUND

Testosterone (T) is the main androgen hormone produced in the interstitial cells of the testicles and is responsible for the normal growth, development and functioning of the male genital organs, as well as for secondary sexual characteristics (e.g., decreased voice timbre, muscular development, facial hair, and etc.). During adulthood, testosterone is necessary to ensure the proper functioning of the testicles and their supporting structures, prostate and seminal vesicle; to ensure well-being; as well as to support libido and erectile potency.

A lack of testosterone, that is, insufficient secretion of testosterone, characterized by its low serum concentrations, can lead to the development of certain diseases in men (for example, hypogonadism). Symptoms associated with male hypogonadism include impotence and decreased sex drive, fatigue and loss of energy, depression, regression of secondary sexual characteristics, decreased muscle mass, and increased fat mass. In addition, male hypogonadism is a risk factor for osteoporosis, metabolic syndrome, type 2 diabetes, and cardiovascular disease.

For the treatment of male hypogonadism, various commercially available types of testosterone replacement therapy are used. Medications include testosterone and its derivatives in the form of intramuscular injections, implants, oral tablets of alkylated testosterone (e.g. methyltestosterone), topical gels or patches. All existing testosterone treatments, however, cannot properly provide an easy and clinically effective way to deliver testosterone. For example, intramuscular injections cause pain and are accompanied by significant changes in serum testosterone levels between doses; testosterone patches usually provide testosterone levels in the lower normal range (i.e., are clinically ineffective) and often cause significant skin irritation; and testosterone gels are associated with unsafe transfer of testosterone from the patient to women and children. And also the only "approved" drug for oral testosterone therapy - methyltestosterone, shows significant toxicity to the liver. Therefore, for a long time, existing methods of treating testosterone deficiency did not meet the goal and, therefore, did not provide satisfactory treatment for men with low testosterone levels.

Testosterone and its esters are biologically poorly accessible - due to exposure to large primary intestinal and hepatic metabolism, or ineffective - due to the body's inability to release testosterone from its prodrug. For example, testosterone and testosterone esters with carbon chains of less than 10 groups in length are mainly absorbed through portal circulation, which leads to their significant, if not complete, primary metabolism. Fatty acid esters with long carbon chains (i.e., with 14 or more carbon atoms) can be absorbed by the intestinal lymphatic system, however, as the chain length of the fatty acid esters increases, the rate and degree of hydrolysis of the ester with esterases slows down when testosterone is released, which leads to to obtain poor (i.e., clinically ineffective) pharmacological activity.

The proposed testosterone ester composition, which differs from the testosterone ester selected, presents unique advantages. The gastrointestinal environment is definitely water in nature, which requires the solubility of drugs to absorb them. However, testosterone and especially its esters are extremely insoluble in an aqueous or water-containing medium, and even if testosterone or its ester is initially dissolved in this therapeutic composition, it must be able to maintain this therapeutic agent in dissolved or dispersed form without precipitation, or, otherwise, maintain the solution in vivo (although this property can be tested in vitro, for example, by mixing the contents of the composition with simulated intestinal fluid). In addition, the oral composition of testosterone should effectively release testosterone or its ester in accordance with the desired profile of its release. Therefore, the effective composition of testosterone or its ester should combine good solubility with optimal release and achievement of a given concentration profile in plasma or serum.

For these reasons, among others, so far no oral testosterone or testosterone ester formulations have been approved by the US Food and Drug Administration (FDA). In fact, currently the only FDA-approved oral testosterone product is methyltestosterone (in which the methyl group is covalently linked to the C-17 position of the testosterone nucleus to inhibit hepatic metabolism; we also note that methyltestosterone is not a prodrug of testosterone), and its approval took place several decades ago. Unfortunately, the use of methyltestosterone is associated with significant manifestations of liver intoxication, and it is rarely prescribed for the treatment of men with low testosterone levels.

As noted above, testosterone fatty acid esters provide another mode of potential testosterone delivery in the body (that is, they serve as a “prodrug”). After absorption, testosterone can be released from its ester due to the action of esterases of non-specific tissues and plasma. In addition, such prodrugs can be absorbed by increasing the relative hydrophobicity of their testosterone part and the lipophilicity of the resulting molecule, determined by the values of their distribution coefficients of n-octanol-water (log P), and they can be absorbed, at least in part, by the intestinal lymphatic system, decreasing thus the effect of primary liver metabolism. Typically, lipophilic compounds with a log P value of at least 5 and with an oil solubility of at least 50 mg / ml are transported through the lymphatic system.

Despite promises, testosterone prodrugs, including testosterone esters, were not formulated to provide effective and stable levels of serum testosterone when they reached their ergonomic levels (i.e., average serum testosterone concentration was in the range of about 300-1100 ng / dl ) In fact, an orally administered testosterone prodrug pharmaceutical preparation including testosterone esters is still not approved by the FDA.

Consequently, there remains a need for an oral composition of testosterone ester that provides an optimal level of serum testosterone that is clinically effective for treating men with hypogonadism (i.e., with a serum concentration of testosterone ≤300 ng / dl) for a long period of time.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides an oral pharmaceutical composition comprising testosterone undecanoate dissolved in a carrier containing at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio of total lipophilic surfactant to the total amount of hydrophilic surfactants (w / w), ranging from about 6: 1 to 3.5: 1, which when administered orally once or twice a day provides a stable average level of serum hydrochloric testosterone concentrations in the range from about 300 to 1100 ng / dL. The pharmaceutical composition provides a C _max value which, when taken with food, does not exceed 2500 ng / dl, preferably does not exceed 1800 ng / dl, and most preferably does not exceed 1500 ng / dl.

In accordance with a preferred embodiment of the present invention, at least one hydrophilic surfactant comprises Cremophor RH 40 (polyoxyethylene glycerol trihydroxystearate); at least one lipophilic surfactant contains oleic acid. Pharmaceutical compositions according to the present invention may include 18-22 mass. % soluble testosterone undecanoate and may essentially not contain monohydric alcohols such as ethanol.

In another embodiment, the present invention provides a dosage form of testosterone undecanoate, including testosterone undecanoate, dissolved in a carrier containing at least one lipophilic surfactant and at least one hydrophilic surfactant, which when administered orally once or twice a day by a patient suffering from hypogonadism or its symptoms, provides a stable average serum testosterone concentration in the range of about 300 to 1100 ng / dl, without allowing a Cmax value of more than 2500 ng / dl, before ochtitelno preventing a Cmax value of 1800 ng / dl, more preferably not allowing Cmax values over 1500 ng / dl.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising testosterone undecanoate, dissolved in a carrier containing at least one lipophilic surfactant and at least one hydrophilic surfactant, which when administered orally with food containing fat in the range from 20 mass. % to 50 mass. %, provides an average level of serum concentration of testosterone, statistically slightly different from the observed level when taken orally with food containing about 30 wt. % fat.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising testosterone undecanoate dissolved in a carrier containing at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio of the total amount of lipophilic surfactants to the total amount of hydrophilic surfactants (in / c), ranging from about 6: 1 to 3.5: 1, which, when taken orally once or twice a day, provides a half-life of the fast phase of serum testosterone of about 5 hours c, and the total lifetime of serum testosterone is approximately 29 hours.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising testosterone undecanoate dissolved in a carrier containing at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio of the total amount of lipophilic surfactants to the total amount of hydrophilic surfactants (in / c), ranging from about 6: 1 to 3.5: 1, which, when taken orally once or twice a day by a patient suffering from a lack of testosterone or its symptoms, provides an average serum concentrations of testosterone for 30 days with a daily intake which practically corresponds to the observed on day 7. In accordance with the present invention, the average serum concentration of testosterone on day 30 with a daily intake may practically correspond to that observed on day 60.

In another embodiment, the present invention provides a method for treating a testosterone deficiency or its symptoms, comprising oral administration to a patient suffering from a lack of testosterone or its symptoms, an effective amount of a pharmaceutical composition comprising testosterone undecanoate, dissolved in a carrier containing at least one lipophilic surfactant and at least one hydrophilic surfactant with a ratio of the total amount of lipophilic surfactants to the total amount of hydrophilic surfactants (w / w) I in the range from about 6: 1 to 3.5: 1, to ensure the stable average serum testosterone concentration in the range from about 300 to 1100 ng / dL. The composition can be taken once or twice a day and get an increase in C _max to a value in the range of about 900 to 1100 ng / dl.

In accordance with this method, the composition can be taken with food containing at least 20 mass. % fat. This method can provide an increase in testosterone to almost complete absence of its daily pharmacokinetic change with an average value of T _max in serum that is in the specified range after about 3-7 hours after oral administration, and there is an almost insignificant decrease in the steady state for serum concentration of testosterone repeated reception.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising:

but. 15-25 mass. % soluble testosterone undecanoate;

b. 12-18 mass. % of at least one hydrophilic surfactant;

at. 50-65 mass. % of at least one lipophilic surfactant;

g. 10-15 mass. % of a mixture of borage oil and peppermint oil, and this composition may be completely free of monohydric alcohols, namely ethanol, and after oral administration by the corresponding patient, the half-life of serum testosterone (T _1/2 ) increases, falling in the range of about 10 hours up to 18 hours. The preferred hydrophilic surfactant is Cremophor RH40, and the preferred lipophilic surfactant is oleic acid. Borage oil and peppermint oil are considered lipophilic surfactants.

In a particularly preferred embodiment of the present invention, the composition comprises:

but. 18-22 mass. % soluble testosterone undecanoate;

b. 15-17 mass. % of at least one hydrophilic surfactant;

at. 50-55 mass. % of at least one lipophilic surfactant; and;

g. 10-15 mass. % mixture of borage oil and peppermint oil.

The ratio between borage oil and peppermint oil can be in the range from 8: 1 to 3: 1; a preferred value of from 6: 1 to 5: 1; the most preferred value is from 5: 1 to 4: 1. In addition, Cremophor RH40, Solutol HS-15, Tween 80 and TPGS are considered preferred hydrophilic surfactants, and glycerol monooleate, propylene glycol laurate and Capmul MCM are considered preferred lipophilic surfactants, in addition to oleic acid. The use of combinations of two or more lipophilic surfactants with two or more hydrophilic surfactants is also considered.

In another embodiment, the present invention provides a method of treating a testosterone deficiency, comprising orally administering to a patient suffering from hypogonadism an effective amount of a pharmaceutical composition, comprising:

but. 15-25 mass. % soluble testosterone undecanoate;

b. 12-18 mass. % of one or more hydrophilic surfactants;

at. 50-65 mass. % of one or more lipophilic surfactants;

g. 10-15 mass. % of a mixture of borage oil and peppermint oil, the composition not containing ethanol, and after oral administration once or twice a day, the patient has an increase in the patient's average (or averaged) stable level of serum concentration of testosterone, C _ave , in the range of about 300 and up to about 1100 ng / dl. This composition can optionally be taken with food containing from about 15 mass. % to 25 mass. % fat or even more. In accordance with this method, one or all of the following pharmacokinetic parameters can be obtained from a patient:

but. the C _max value of serum testosterone in a patient in the range of 900-1100 ng / dl;

b. the practical lack of daily pharmacokinetic changes in testosterone content;

at. serum T _max value 3-7 hours after administration of the composition; and

G. there is an almost insignificant decrease in the steady state for serum concentration of testosterone with its repeated use.

In this regard, before a detailed explanation of at least one embodiment of the present invention, it should be understood that the present invention is not limited to the use of the construction details and arrangement of elements shown in the following description or illustrated in the drawings. The present invention may have implementations in addition to those described, and may be used and practiced in various ways. In addition, it should be understood that the phraseology and terminology used here, as well as the abstract, are for description only and should not be considered limiting.

Professionals should be aware that the concept on which the present description is based can easily be used as the basis for the development of other substances, methods and systems to achieve some of the objectives of the present invention. For example, some embodiments of the present invention may include combining testosterone undecanoate (TU) with other active drugs, including other hormones, in an oral delivery system that, in particular, will prevent or alleviate symptoms associated with a lack of testosterone. Therefore, it is important that the points of the application be considered as including such equivalent designs that do not go beyond the scope and direction of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

In FIG. Table 1 summarizes serum testosterone levels over a 24-hour period when taken orally once or twice a day with the testosterone undecanoate (TU) composition of the present invention.

In FIG. Figure 2 shows the reaction of serum testosterone in time for men with hypogonadism when taking the composition of the present invention, depending on the usual oral composition of testosterone undecanoate (TU), which contains TU in oleic acid (Restandol).

In FIG. 3 shows serum testosterone levels T _max in patients eating foods with a variable fat content (in mass%) before oral administration of the testosterone undecanoate (TU) composition of the present invention.

In FIG. 4 shows serum testosterone levels C _max in patients eating foods with a variable fat content (in mass%) before oral administration of the testosterone undecanoate (TU) composition of the present invention.

In FIG. 5 shows the values of total exposure (area under the curve) (AUC) for serum testosterone levels in patients eating a variable fat content (in mass%) before oral administration of the testosterone undecanoate (TU) composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an oral pharmaceutical composition comprising testosterone undecanoate (TU), which, when taken no more than twice a day by men suffering from hypogonadism, provides moderate steady-state levels (concentrations) of serum testosterone in those men who fall into the required “normal” or self-controlled a range (i.e., about 300-1100 ng / dl) while preventing high C _max values considered undesirable or unacceptable by the IPA US Food and Drug Administration (FDA). For example, FDA-approved guidelines indicate that less than 85% of treated patients may have a C _max value of about 1500 ng / dl or more, and no one should have a C _max value greater than 2500 ng / dl. Less than 5% of treated patients may have a C _max value in the range of 1800-2500 ng / dl. In addition, the compositions of the present invention are designed to create self-emulsifiable drug delivery systems (SEDDS), wherein the TU-containing emulsion (or dispersion) is formed by mixing intestinal fluids in the gastrointestinal tract.

In one embodiment of the present invention, testosterone and / or esters at the C-17 position of the testosterone molecule, alone or in combination with other active ingredients, can be delivered orally using the composition of the present invention. For example, in some embodiments, a combination of testosterone undecanoate with orally active Type I or Type II 5α-reductase inhibitors, or a combination of testosterone undecanoate with synthetic progestin may be preferred.

Although many embodiments of the present invention will be described and illustrated with testosterone undecanoate acid ester examples (i.e., TU), other esters of hydrophobic compounds, including testosterone (T), may be selected based on a study of specifications for oral delivery. In fact, it should be clear to those skilled in the art that the invented drug delivery systems and compositions may be suitable for oral delivery of other testosterone esters as well, such as short chain fatty acid esters (C ₂ -C ₆ ), medium chain ( C ₇ -C ₁₃ ) and a long chain (C ₁₄ -C ₂₄ ), preferably medium chain testosterone fatty acid esters.

The compositions of the present invention include a testosterone ester dissolved in a mixture containing one or more lipophilic surfactants and one or more hydrophilic surfactants. As defined here, a lipophilic surfactant has a hydrophilic lipophilic balance (HLB) value of less than 10, and preferably less than 5. As defined here, a hydrophilic surfactant has an HLB value of more than 10. (HLB is an empirical expression for the ratio of hydrophilic and hydrophobic surface-active groups amphiphilic molecule, such as that of surfactants. It is used to index surfactants, and its value varies from 1 to 45 and includes both non-ionic and ionic surfactants. The higher the HLB value, the better it dissolves in water / disperses surfactants).

In accordance with one embodiment of the present invention, each component of the delivery system (i.e., lipophilic and hydrophilic surfactants) has a separate solubility profile and partially contributes to the dissolution of the active ingredient. Those lipophilic surfactants that make a significant contribution to drug dissolution are here defined as the “main” solvent (s). However, it should be noted that the temperature of the solvent / composition may affect solubility. The compositions of the present invention, including, for example, about 20% testosterone undecanoate, remain soluble at a temperature of 30 ° C or higher, including a range from 30 to 40 ° C.

To achieve the required dispersion of the composition in the gastrointestinal tract (GIT) and release of the drug, a component from a hydrophilic surfactant may be needed. That is, a hydrophilic surfactant in addition to being used as an auxiliary solvent may be required to release the drug from the matrix of the lipid carrier, or as the main solvent. High HLB surfactants such as Cremophor RH40 can usually help in this regard. Levels (values) of surfactants with high HLB can be selected to ensure optimal drug release without compromising the solubility of the active ingredient.

Lipophilic surfactants suitable for use in the drug delivery systems of the present invention include:

Fatty acids (C ₆ -C ₂₄ , preferably C ₁₀ -C ₂₄ , more preferably C ₁₄ -C ₂₄ ), for example, octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid , linoleic acid and linolenic acid. It is preferable to use oleic acid.

Fatty acid mono- and / or di-glycerides, such as Imwitor 988 (glyceryl mono / di-caprylate), Imwitor 742 (glyceryl mono / di-caprylate), Imwitor 308 (glyceryl mono-caprylate), Imwitor 191 (glyceryl mono-stearate), Softigen 701 (glyceryl mono- / di-ricinoleate), Capmul MCM (glyceryl mono / di-caprylate / caprine), Capmul MCM (L) (liquid form Capmul MCM), Capmul GMO (glyceryl mono oleate), Capmul GDL (glyceryl dilaurate), Maisine (glyceryl mono-linoleate), Peceol (glyceryl mono-oleate), Myverol 18-92 (distilled monoglycerides from sunflower oil) and Myverol 18-06 (distilled monoglycerides from hydrogen of oia oil), Precirol ATO 5 (glyceryl palmitostearate) and Gelucire 39/01 (semi-synthetic glycerides, i.e., C _12-18 mono-, di- and tri-glycerides). Preferred members of this class of lipophilic surfactants are such partial glycerides as oleic, palmitic and stearic acids, as well as mixtures thereof.

Acetic, succinic, dairy, citric and / or tartaric esters of mono- and / or di-glycerides of fatty acids, e.g. Myvacet 9-45 (distilled acetylated monoglycerides), Miglyol 829 (caprylic / capric diglyceryl succinate), Myverol SMG (mono / monoglyceride di-succinates), Imwitor 370 (glyceryl stearate citrate), Imwitor 375 (glyceryl monostearate / citrate / lactate) and Crodatem T22 (diacetyl wine monoglyceride esters).

Propylene glycol mono- and / or di-esters of fatty acids, for example, Lauroglycol (propylene glycol monolaurate), Mirpyl (propylene glycol monomyristate), Captex 200 (propylene glycol dicaprylate / dicaprate), Miglyol 840 (propylene glycol dicaprylate / dicaphenol-20 and Necapenicol 20 dicaprilat / dicaprate).

Polyglycerol fatty acid esters such as Plurol oleique (polyglyceryl oleate), Caprol ET (mixed polyglyceryl fatty acids) and Drewpol 10.10.10 (polyglyceryl oleate).

Low ethoxylate castor oil ethoxylates (HLB <10) such as Etocas 5 (5 moles of ethylene oxide reacted with 1 mole of castor oil) and Sandoxylate 5 (5 moles of ethylene oxide reacted with 1 mole of castor oil).

Acid and ester ethoxylates formed by the reaction of ethylene oxide with fatty acids or glycerol fatty acid esters (HLB <10), such as Crodet 04 (polyoxyethylene (4) lauric acid), Cithrol 2MS (polyoxyethylene (2) stearic acid), Marlosol 183 (polyoxyethylene (3) stearic acid) and Marlowet G12DO (glyceryl 12 EO dioleate).

Sorbitan fatty acid esters, for example, Span 20 (sorbitan monolaurate), Crill 1 (sorbitan monolaurate) and Crill 4 (sorbitan mono-oleate).

Transesterification products of natural or hydrogenated triglyceride of vegetable oil and polyalkylene polyol (HLB <10), for example Labrafil M1944CS (polyoxyethylene apricot kernel oil), Labrafil M2125CS (polyoxyethylene corn oil) and Gelucire 37/06 (polyoxyethylenated hydrogenated). Labrafil M1944CS is preferred.

Alcohol ethoxylates (HLB <10), e.g. Volpo N3 (polyoxyethylated (3) oleyl ether), Brij 93 (polyoxyethylated (2) oleyl ether), Marlowet LA4 (polyoxyethylated (4) lauryl ether).

Pluronic surfactants, for example, polyoxyethylene-polyoxypropylene copolymers and block copolymers (HLB <10), for example, Synperonic PE L42 (HLB = 8) and Synperonic PE L61 (HLB = 3).

If desired, mixtures of appropriate lipophilic surfactants, such as those listed above, may be used, and in some cases this may be useful.

Any pharmaceutically acceptable hydrophilic surfactant (i.e., having an HLB value greater than 10) can be used in the present invention. Some non-limiting examples include:

Castor oil ethoxylates or hydrogenated castor oil (HLB> 10), e.g. Cremophor EL (polyoxyethylene (35) castor oil), Cremophor RH40 (polyoxyethylene (40) hydrogenated castor oil), Etocas 40 (polyoxyethylene (40) castor oil), Nikkol HCO-60 (polyoxyethylene (60) hydrogenated castor oil), Solutol HS-15 (polyethylene glycol 660 hydroxystearate), Labrasol (caprylocaproyl macrogol-8 glycerides), α-tocopherol-polyethylene glycol-1000-succinate (TPGS) and ascorbyl-6. It is preferable to use Cremophor RH40.

Polyoxyethylene sorbitan derivatives of fatty acids, for example, Tween 20 (polyoxyethylene (20) monolaurate), Tween 80 (polyoxyethylene (20) monooleate), Crillet 4 (polyoxyethylene (20) monooleate) and Montanox 40 (polyoxyethylene (20) monopalmitate). Tween 80 (Polysorbate 80) is preferred.

Gelucire surfactants, preferably Gelucire 50/13 (polyethylene glycol mono- and diesters of palmitic and stearic acids. (In the designation of Gelucire surfactants, the first number (i.e., 50) corresponds to the melting point of the material, and the second (i.e., 13) to HLB).

Fatty acid ethoxylates (HLB> 10), e.g. Myrj 45 (polyoxyethylene (8) stearate), Tagat L (polyoxyethylene (30) monolaurate), Marlosol 1820 (polyoxyethylene (20) stearate) and Marlosol OL15 (polyoxyethylene (15) oleate) . Myrj 45 is preferred.

Alcohol ethoxylates (HLB> 10), e.g. Brij 96 (polyoxyethylene (10) oleyl ether), Volpo 015 (polyoxyethylene (15) oleyl ether), Marlowet OA30 (polyoxyethylene (30) oleyl ether) and Marlowet LMA20 (polyoxyethylene (20) C ₁₂ -C ₁₄ fatty acid ester).

Polyoxyethylene-polyoxypropylene copolymers and block copolymers (HLB> 10), available on the market under the trade name Pluronics or Poloxamers, such as Poloxamers 188 and 407, also known as Syperonic PE L44 (HLB = 16) and Syperonic FI27 (HLB = 22), respectively.

Anionic surfactants, for example, sodium lauryl sulfate, sodium oleate and sodium dioctisulfosuccinate.

Alkylphenolic surfactants (HLB> 10), for example, Triton N-101 (polyoxyethylene (9-10) nonylphenol) and Synperonic NP9 (polyoxyethylene (9) nonylphenol).

As already mentioned in one embodiment of the present invention, each of the components of the delivery system (i.e., lipophilic and hydrophilic surfactants) has a separate solubility profile and partially contributes to the dissolution of the active ingredient. Thus, without reference or limitation by theory, the present invention does not require the use of additional solvents, such as cosolvents, however, they can be further included in the systems and compositions of the present invention.

Additional cosolvents that may be used in the present invention are, for example, water, mono-, di-, and short chain polyhydric alcohols such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, polyethylene glycol with an average molecular weight of from about 200 to 10000, diethylene glycol monoethyl ether (e.g. Transcutol HP), and combinations thereof. Preferably, the use of, in particular, cosolvents such as ethanol or other monoethanol should be avoided altogether.

Additional oils that may be incorporated into embodiments of the present invention include full glycerol triesters with medium chains (C ₇ -C ₁₃ ) or long chains (C ₁₄ -C ₂₂ ) of low molecular weight (up to C ₆ ) mono-, di- or polyhydric alcohols. Thus, some examples of oils suitable for use in the present invention include: vegetable oils (e.g., soybean oil, safflower vegetable oil, corn oil, olive oil, castor oil, cottonseed oil, peanut oil, sunflower oil, coconut oil, palm oil oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond, borage, peppermint and apricot kernel oil) and animal oils (for example , Fish liver oil, shark oil and mink oil).

Other embodiments of the present invention provide methods and compositions for modulating (i.e., maintaining) the rate of delivery of serum testosterone by incorporating a component (s) capable of biochemically modulating (1) the absorption of testosterone undecanoate (TU), (2) the conversion of TU to testosterone ( T) and / or (3) the conversion of T to dihydrotestosterone (DHT). For example, administration of a long chain fatty acid ester medium can improve TU absorption. Thus, more TU may not undergo hydrolysis in the intestinal tract and will enter the bloodstream. In other words, a fatty acid ester can effectively inhibit esterases that could otherwise metabolize (process) TU. Examples of other esters or combinations thereof include plant extracts or weak esters used as food additives (e.g., propyl paraben, octyl acetate and ethyl acetate).

Other components capable of modulating TU absorption include “natural” and synthetic inhibitors of 5α-reductase, present as an enzyme in red blood cells and other tissues, and serving as a catalyst for the conversion of T to DHT. Complete or partial inhibition of this conversion can increase and inhibit the increase in serum testosterone levels after oral administration of TU with a concomitant decrease in serum levels of DHT. Borage oil, which contains a significant amount of a 5α-reductase inhibitor, gamma-linolenic acid (GLA), is an example of a “natural” TU metabolism modulator. Unlike borage oil, of course, GLA can be directly incorporated as a separate component into the testosterone undecanoate (TU) of the present invention. Many natural 5α-reductase inhibitors are known (for example, epigallocatechin gallate, in which catechin is extracted mainly from green tea, and Serenoa repens palm extract from plants) and all of them can be used in the present invention. Non-limiting examples of synthetic 5α-reductase inhibitors suitable for use in the present invention include compounds such as finasteride, dutasteride and the like.

In addition to 5α-reductase inhibitors, the present invention proposes to use testosterone metabolism inhibitors in other ways. One such inhibition method may be to use the isoenzyme CYP3A4 of cytochrome P450, which is present in red blood cells and liver cells, and is capable of metabolizing testosterone. Accordingly, in selected embodiments of the present invention, peppermint oil is introduced, which is known to contain components capable of inhibiting CYP3A4 activity.

However, other additional ingredients that are traditionally used in oil-based drug delivery systems, for example, antioxidants such as tocopherol, tocopherol acetate, ascorbic acid, butylhydroxytoluene (BHT), ascorbyl palmitate, butylhydroxyanisole and propyl gallate, may be included in the compositions of the present invention; pH stabilizers such as citric acid, tartaric acid, fumaric acid, acetic acid, glycine, arginine, lysine and dipotassium phosphate; thickeners / suspending agents such as hydrogenated vegetable oils, beeswax, colloidal silicon dioxide, mannitol, resins, cellulose, silicates, bentonite; flavors such as cherry, lemon and anise flavors; sweeteners such as aspartame, acesulfan K, sucralose, saccharin and cyclamates; etc.

The inventors of the present invention have found that the relative proportions of one or more lipophilic surfactants and one or more hydrophilic surfactants can be critical to achieve the desired pharmacokinetics of the present invention. More precisely, the inventors found a ratio of the total amount of lipophilic surfactants to the total amount of hydrophilic surfactants, which not only allows the dissolution of a relatively large amount of testosterone ester (for example, more than 15%, 18%, 20%, 22% or 25%), but also allows optimal release of testosterone ester from the corresponding composition. It is preferable that the ratio of the total amount of oil (for example, oleic acid + borage oil + peppermint oil, which are all considered lipophilic surfactants) to the number of hydrophilic surfactants (w / w) fall in the range from about 6: 1 to 1: 1, from 6 : 1 to 3: 1, from 6: 1 to 3.5: 1 or from 6: 1 to 4: 1; and more preferably, from about 5: 1 to 3: 1, and most preferably, from about 4: 1 to 3: 1.

The following relative concentrations by weight (percent of total composition weight) are preferred:

Hydrophilic surfactant: 10-20%, more preferably 12-18%, and most preferably 15-17%;

Lipophilic surfactant: 50-70%, more preferably 50-65%, and most preferably 50-55%;

Other oils: 5-15%, more preferably 7-15%, and most preferably 10-13%;

Drug: 10-30%, more preferably 15-25%, and most preferably 18-22%.

The compositions of the present invention have the properties of self-emulsification, forming a thin emulsion when diluted in a medium containing water or in intestinal fluids in vivo. In other words, the compositions may contain a large number of surfactants and lipids, designed to ensure optimal dispersion when mixed with an aqueous medium. A qualitative description of the self-emulsification property of the compositions of the present invention can be visually observed during their dissolution in vitro. Alternatively, quantitative measurements of particle size in emulsified droplets can be made using laser light scattering and / or solution turbidity measurements using a UV and visible spectrophotometer. Any of these methods is available and known to those skilled in the art.

The pharmaceutical compositions of the present invention should preferably be liquid or semi-solid at appropriate ambient temperatures. In addition, these pharmaceutical compositions can be converted into solid dosage forms by their absorption by solid particles of carriers such as silicon dioxide, calcium silicate or magnesium aluminum metasilicate, in order to obtain free-moving powders, which can then be filled into hard capsules, or which can be compressed into tablets. See, for example, US patent US 2003/0072798, the description of which is incorporated in its entirety by reference. Therefore, the term “dissolved” as used herein should be interpreted as describing an active pharmaceutical ingredient (API), dissolved in a liquid solution, which is then uniformly dispersed in a solid carrier. Batch (sachet) type dosage forms can also be formed and used.

The present invention preferably includes an active pharmaceutical ingredient (API) dissolved in the presence of lipid filler surfactants (for example, any combination of lipophilic and hydrophilic surfactants mentioned above). Thus, the melting point of the surfactant used is the only factor that can determine whether the resulting composition will be liquid or semi-solid at ambient temperature. Particularly preferred compositions of the present invention are liquid oral dosage forms, more preferably filled in hard or soft capsules, for example, as gelatin or non-gelatin capsules made of cellulose, carrageenan or polulan. The technology for encapsulating lipid drugs is well known to those skilled in the art. Since the drug delivery systems and compositions of the present invention described herein are not limited to any one encapsulation method, certain encapsulation methods are not discussed hereinafter.

Drug delivery systems and drugs in accordance with the present invention can be prepared by conventional methods for a lipid-based drug delivery system. In a typical procedure for preparing the preferred delivery system of the present invention, the lipophilic surfactant component is weighed in an appropriate stainless steel vessel, and then the hydrophilic surfactant component is weighed and added to the container along with any additional components. In a preferred method, a hydrophobic drug may be added to the lipophilic surfactant component (e.g., oleic acid) and completely dissolved before the hydrophilic surfactant component is added. In any case, the mixing of the components may be affected by the use of a high shear homogenizing mixer or other device, as well as the high temperature - especially when using a high melting point surfactant - in order to ensure a homogeneous liquid state of all components before or after drug addition.

In a situation where the hydrophobic drug is weighed and added to the combined lipid mixture, mixing continues, preferably at high temperature, until a homogeneous solution is obtained. The composition may be deaerated before encapsulation in a soft or hard capsule. In some cases, filling with the composition can be carried out at elevated temperature using an appropriate vessel with a shell to support processing. Also, in some cases, a homogeneous solution can be filtered (for example, through a 5 micron filter) before filling into capsules.

Returning now to the delivery of testosterone, the pharmaceutical compositions of the present invention may be suitable for the treatment of testosterone. Testosterone is the main endogenous androgen in men. Leydig cells in the testes produce about 7 mg of testosterone daily, which leads to its serum concentration in the range from about 300 to 1100 ng / dl. Women also synthesize testosterone in the ovaries and adrenal glands, but its amount is about one tenth of that observed in full-fledged men. Most (≥98%) of circulating testosterone is associated with the sex hormone that binds globulin and albumin, and it is biologically active only when released in free form. The term "free" in this case is defined as unbound or not limited within, for example, biological molecules, cells and / or lipid matrices of the inventive compositions described herein. In the general case, the “free” drugs described herein refer to drugs available for circulating metabolic enzymes in serum.

Although the present invention is not limited to the delivery of testosterone or any single ester, it has been found that TU offers unique chemical and physical characteristics so that in some embodiments its use is preferred. The inventors of the present invention have found that testosterone undecanoic acid ester, in particular, can exhibit biological activity far superior to that found with other equivalent esters (e.g. testosterone enanthate (TE)).

Moreover, the use of TU in the formulations of the present invention results in a significantly lower ratio of serum dihydrotestosterone (DHT) to testosterone (T) than has been reported for other forms of testosterone replacement - including oral formulations of TU (Table 1). Testosterone interacts with androgen receptors directly or after conversion to DHT through the action of 5α-reductase. DHT is a more potent androgen than testosterone, and its increased levels are believed by some scientists to increase the risk of prostate cancer. Thus, the present invention provides yet another unexpected advantage over known testosterone delivery vehicles.

Now, non-limiting examples will describe individual embodiments of the present invention. Table 2 provides details on the composition of the various pharmacological forms of TU in accordance with the ideas of the present invention. For calculation purposes, 1 mg of testosterone is equivalent to 1.58 mg of T-undecanoate.

Details regarding the composition shown in Table 2 (mg / capsule and mass%) are based on an approximate filled weight of 800 mg for the filled weight of a hard gelatin capsule of size '00'. However, when the amounts of testosterone ester are less than about 100 mg / capsule, the compositions can be proportionally adjusted to obtain a lower total filled weight, which allows the use of reduced hard gelatin capsules (for example, size '0' or even smaller if necessary).

It should also be apparent to those skilled in the art that many, if not all, surfactants in their category (e.g. lipophilic, hydrophilic, etc.) can be replaced by other surfactants from the same category. Thus, although Table 1 lists the compositions comprising oleic acid, those skilled in the art should understand that other lipophilic surfactants (e.g., those listed above) can also be used. Similarly, although Table 1 lists the formulations including Cremophor RH40 (HLB = 13), those skilled in the art should understand that other hydrophilic surfactants (such as those listed above) may also be used. Borage oil, peppermint oil, BHT, and ascorbyl palmitate can be replaced with similar chemicals or removed.

Preferred compositions of TU filled into capsules of size "00" in accordance with the present invention:

Composition A

Composition B

Hereinafter, in vivo and in vitro parameters of the compositions made in accordance with the present invention will be described. However, the scope of the present invention is not limited to the examples given below, nor to the individual compositions studied in these examples.

Example 1 - One-Day Study

Composition B was studied relative to its one-day pharmacokinetic profile when taken once or twice a day by men suffering from hypogonadism. The study was organized as a one-day, dosed, open-label, sequential, cross-sectional, pharmacokinetic study. It was attended by twelve (12) hypogonadal men after they gave written informed consent, and all 12 patients completed this study. Each patient received a daily dose of Compound B as follows:

1.200 mg T (as TU) QD, i.e., 2 capsules / dose

2.200 mg T (as TU) BID (100 mg / dose), i.e., 1 capsule / dose

3.400 mg T (as TU) BID (200 mg / dose)

Doses were taken by patients in capsules five minutes after eating (breakfast for QD, breakfast and lunch for BID).

Table 3 presents the corresponding pharmacokinetic parameters obtained in the study:

The average serum testosterone concentration over the 24-hour period after taking the dose (C _avg ) shows a positive increase in serum testosterone levels for all the studied regimens, with the best response in the case of Scheme 3 (C _avg 385 ng / dl). The average peak serum testosterone concentration observed in response to the oral administration of testosterone ester formulations studied in this study never exceeded the upper normal limit (i.e., 1100 ng / dl). Although C _max values for testosterone were observed in some individual patients above the upper normal limit, the vast majority of these peak values were in the range from 1200 to 1400 ng / dl. None of the patients in any group had a C _max value in excess of 1500 ng / dl.

The average half-life of serum testosterone (T _1/2 ) was approximately 15 hours for Schemes 1 and 2; for Scheme 3, the T _1/2 value was 8 hours. In each regimen, serum concentrations of DHT consistently increased along with an increase in serum testosterone levels. The average DHT: T (R _avg ) ratio over all periods was moderately above normal ranges as determined using liquid chromatography - mass spectroscopy (LC / MS / MS) (i.e., 0.03-0.1), however, this is clinically inconsequential.

TUs were taken in doses of 200 mg of equivalent testosterone, BID, with food, and showed the most promising results with 75% of patients who achieved serum testosterone C _avg values above 300 ng / dl (lower normal ergonomic limit value). Similarly, 75% of patients achieved average serum testosterone in the normal range (i.e., 0.03-0.1 ng / dl). Those patients who did not reach a C _avg value of at least 300 ng / dl all had a value above 200 ng / dl, indicating that a moderate increase in TU dose would be effective oral testosterone replacement therapy for these patients.

Serum testosterone and DHT concentrations consistently increased in most patients, regardless of the dose of testosterone ester, with an excellent linear dose response for oral TU when data were adjusted at baseline for serum testosterone. Although DHT: T ratios were slightly increased, this increase should be considered clinically insignificant. Smaller changes between patients were observed specifically for this composition than with equivalent compositions of other testosterone esters (e.g. TE). In addition, for the BID Dosing Scheme, there was no difference in average peak serum testosterone concentrations or in 12-hour AUC between morning and evening doses.

Regarding the safety of administration, although a headache was noted as an undesirable effect, more than one patient did not report an undesirable effect in each treatment regimen. There were no serious events or deaths during this study, and there were no patients who prematurely discontinued participation in the study due to adverse events. Therefore, it should be considered that all undesirable events are of low intensity.

Example 2 - Seven-Day Study

Composition B was studied for tolerance and stability of the state of the serum pharmacokinetic profile for two doses that were taken twice a day by men suffering from hypogonadism. The study was organized as a pharmacokinetic study with an open label, a repeated dose, a cross (with a check of the effect of food in one group).

Twenty-nine (29) hypogonadal men took part in it after they gave written informed consent, and 24 of them completed this study. Each patient who completed this study received Composition In the following Scheme:

1. 7 daily doses of 600 mg T in the form of TU BID (300 mg / dose), that is, 3 capsules / dose

2. 8 daily doses of 400 mg T in the form of TU BID (200 mg / dose)

Doses were taken by patients in capsules 30 minutes after the start of a meal (breakfast and lunch), with the exception of 8 days when the morning dose was taken on an empty stomach.

The peak effect (C _max ) on testosterone and the total effect (AUC) on testosterone was proportional to the dose after correction for the endogenous baseline testosterone level. The time to peak testosterone concentrations (T _max ) was approximately 4 hours after dosing for each course of treatment. Also, serum concentrations of TU and DHTU increased and decreased in the dose range at concentrations at the beginning and end of the dose interval of less than 20% of the peak concentration for TU, and less than 25% of the peak concentration for DHTU. Base levels of testosterone concentrations due to its endogenous production progressively decreased for each course of treatment. This observation is consistent with the progressive and sustained suppression of gonadotropins by exogenous testosterone, which leads to a decrease in the production of endogenous testosterone. At least partial suppression was maintained during the 14-day wash period.

Again, the pharmacokinetics of serum testosterone did not demonstrate a daily change in serum testosterone concentrations. The night dose (taken at about 8 o’clock in the evening) provided a concentration-time profile similar to the morning dose (taken at about 8 o’clock in the morning) (Fig. 1). Given the similarity of concentrations after the morning and evening doses (evaluated in Scheme 1), the 12-hour pharmacokinetic data for Scheme 2 (nutrition) were used to accurately predict the complete 24-hour pharmacokinetic response profile at 200 mg T (as TU), BID dosing. Simulation results show that (a) 77% of patients achieved serum testosterone C _avg values in the 24-hour period based on AUC accounting, thus meeting the FDA's current requirement for 75% efficacy for a testosterone replacement product; and (b) no patient had a C _max value greater than 1500 ng / dl, which exceeds the current FDA criterion, according to which less than 85% of patients can have a C _max value of more than 1500 ng / dl when using a testosterone replacement product. Therefore, this also corresponds to the current FDA-established efficacy endpoints, no patient had a C _max value in excess of 2500 ng / dl, and less than 5% of patients had a C _max value in the range of 1800-2500 ng / dl. It should be noted that these results were obtained in the absence of any dose selection.

Table 4 presents a comparison of the steady state morning and evening pharmacokinetics of testosterone with BID dosing:

The intake of TU foods with a high fat content resulted in the same concentration-time profile for serum testosterone, as with a standard meal. In contrast, fasting TU resulted in a more than 50% reduction in serum testosterone (C _max and AUC). Table 5. In all cases, a strong correlation was observed between the observed value of C _max and the calculated value of C _avg , and it is assumed that reaching a certain value of C _avg by oral administration of the testosterone ester composition can lead to the expected peak testosterone levels after a dose.

DHT concentrations follow testosterone concentrations, although DHT concentrations were only 11-34% of testosterone concentrations. The conversion of T to DHT showed slight non-linearity, showing an increase less than a proportional increase in testosterone concentration. The DHT / T ratio was the smallest at the highest concentrations of testosterone, and the DHT / T ratio before starting TU treatment was approximately 0.1, while during steady-state treatment, the average value of this ratio was 0.24, and it was in the range from about 0.1 to 0.35 depending on the time of sampling after oral administration of TU.

The average concentration of estradiol before the start of oral TU therapy was approximately 11 pg / ml, and it was in the range from 19 pg / ml to 33 pg / ml on the 7th day of various treatment (pre-dose concentrations). Estradiol steady-state concentrations prior to dosing were approximately 20-30 pg / ml.

Example 3 - Four-week study

Composition B was also studied to determine the time required to achieve a steady state in the case of treatment of men suffering from hypogonadism within 28 days when taking a twice-daily dose of 200 mg of testosterone (in the form of TU) (that is, 2 capsules / dose. The study was organized as an open-label, repeat dose pharmacokinetic study.

Fifteen (15) hypogonadal men took part in it after they gave written informed consent and they all completed this study. Each patient received twice daily doses of 200 mg of testosterone as TU for 28 days.

For each patient, a “28 day” pharmacokinetic sampling sequence was scheduled for 32 days of the study. Therefore, each patient taking the dose received only 31 daily doses of 400 mg of testosterone in the form of TU (i.e., 200 mg of T, BID), and the final morning dose of 200 mg of testosterone in the form of TU. Doses were taken in capsules by patients who had been instructed on taking doses 30 minutes after the start of a meal (breakfast and lunch).

Table 6 presents the corresponding pharmacokinetic parameters obtained in the study:

86.7% of patients achieved serum testosterone C _avg in the normal range in the absence of patients with C _max concentrations of more than 1800 ng / dl, and only 13.3% of patients with C _max concentrations of more than 1500 ng / dl. (Note: During this study, no dosage selection was made to ensure that patients were in the target ranges for efficacy and safety). The half-life of testosterone in response to TU in the test composition was significantly longer than that reported for testosterone itself or for TU taken orally in previous formulations. For example, in clinical trials of the oral composition of the TU described in the present invention, a half-life (α phase) of about 5 hours was observed, compared with a (roughly) half lower value (i.e., from 2 to 3 hours) obtained based on published serum testosterone profiles after oral administration of doses of the prior TU formulation. A large (i.e., final) half-life of about 29 hours was also observed in the oral composition of the TU of the present invention. The endogenous production of testosterone was suppressed, however, by taking exogenous testosterone, and during the first 3 days only limited suppression was observed, and it took 5-7 days of continuous treatment to achieve maximum suppression.

The concentrations of T and DHT reached steady state on day 7 of treatment. The concentrations of T and DHT were greater on day 3 than day 5, which indicates that it took some time for exogenously taken testosterone to suppress endogenously produced testosterone, thus allowing a steady state to be achieved in response to oral TU. Of course, the addition of exogenous testosterone suppresses endogenous testosterone levels from 276 ng / dl before starting treatment to 108 ng / dl after 28 days of testosterone replacement therapy.

However, it is significant that after reaching a steady state for serum testosterone in response to oral administration of twice a day TU, there was a slight or no decrease in the reaction of serum testosterone over time (that is, there was no tendency to decrease serum testosterone levels with continued doses of TU) . For example, the C _avg value on day 15 was completely similar to the C _avg value observed on day 28 (Fig. 2). In contrast, the previously mentioned TU oral formulations tended to decrease the average testosterone over time (Cantrill, JA Clinical Endocrinol (1984) 21: 97-107). In hypogonadal men with oral therapy with a known TU compound, the serum testosterone response observed 4 weeks after the start of treatment was reported to be approximately 30% less than that observed on the first day of treatment of hypogonadism in men - most of which took the form of primary hypogonadism and therefore, low baseline serum testosterone levels (for example, <100 ng / dl), and therefore a decrease in testosterone could not be explained by the suppression of endogenous testosterone alone.

Serum DHT concentrations accurately tracked testosterone concentrations with an increase in DHT and DHT / T values from 4 to 7 times during treatment. The average DHT / T ratio over the 12-hour dose interval was 0.245, although the values in the dose interval deviated from the average maximum ratio of 0.380 to the average minimum ratio of 0.131. DHT concentrations returned to pre-treatment levels within 36 hours after discontinuing treatment with oral TU. However, testosterone concentrations did not return to levels before starting treatment so quickly, because suppressing the production / release of endogenous testosterone does not reverse so quickly.

Estradiol (E2) concentrations showed a monotonous proportional increase to steady state, which was also achieved on day 7 of treatment. E2 concentrations also showed systematic changes in the dose interval that track changes in testosterone concentration. The average values of C _max , C _avg , and C _min for E2 were 30.6 pg / ml, 22.0 pg / ml and 15.5 pg / ml, respectively. Concentrations of E2 returned to the levels that existed before the start of treatment, within 36 hours after interruption of treatment with oral administration of TU.

The steady-state average concentrations of C _max , C _avg , and C _min (morning dose on day 28) for testosterone were 995 ng / dl, 516 ng / dl and 199 ng / dl, respectively. The average T _max for testosterone was reached 5.0 hours after the dose. The average value of C _min was 23.5% of C _max , which leads to a deviation index (FI) of 156%. The half-life of testosterone could be estimated in only about half of the patients, and its average (median) value in these patients was 18.4 hours (average T1 / 2 was 29 hours).

Example 4 - Study the impact of write

The effect of dietary fat on the pharmacokinetics of Composition B in hypogonadal men was studied in a five-sided open-label, cross-sectional, two-center study. After a washout period of 4–10 days for sixteen hypogonadal men with a baseline serum testosterone level of 205.5 + 25.3 ng / dl (mean ± standard deviation (SE), range 23–334.1 ng / dl) a single dose was suggested a dose of 300 mg of testosterone (475 mg TU, 3 capsules of Composition B). Patients were randomized to take the drug in a fasting state or 30 minutes after a meal containing approximately 800 calories with a specific fat content (wt.%): Very little fat (6-10%); low fat (20%); “Normal” dietary fat content (30%); or high fat content (50%). A “normal” diet was a priori established as a basic (that is, a reference diet) in order to perform statistical comparisons. During all 24 hours after taking the drug, consecutive blood samples were taken to determine the levels of serum testosterone and dihydrotestosterone (DHT) using liquid chromatography - mass spectroscopy (LC / MS / MS).

It was found that the pharmacokinetic parameters (Table 7, Figs. 3-5) observed for serum testosterone in response to a single oral administration of a large dose of TU, are similar to low-fat and normal fat diets - in fact, so much so that they are bioequivalent (i.e., 90% confidence interval was 85-125%). Similar pharmacokinetic parameters of serum testosterone were also observed when comparing normal and fatty foods. Although fatty foods showed an increased serum testosterone response (although not statistically different), the average least squares ratio fell in the range of 70-143% when compared to normal foods with a fat content - the clinically insignificant difference is <30%.

The scatter in the pharmacokinetic reaction is greatest after taking the first dose or the first few doses with oral administration of TU, and it decreases with continued treatment. Therefore, any effect of a low-fat-high fat diet on the pharmacokinetic parameters of serum testosterone is likely to be negligible with continued doses. This position coincides with the pharmacokinetic findings of a 7-day treatment (Example 2) and a 30-day treatment (Example 3), in which repeated oral doses of TU were studied, and in which the pharmacokinetics under different nutritional conditions showed similar results for the distributions of C _max and C _avg [200 mg of testosterone (as TU), BID] was taken in both studies.

Statistical comparisons of the serum testosterone response observed after oral administration of TU were made without food, for a very low fat, low fat, or high fat diet compared to a normal fat diet (i.e., a reference diet), and they showed no statistically significant difference at p <0.05 between diets high or low in fat compared to a normal diet. On the contrary, oral administration of TU as an SEDDS (self-emulsifying) composition on an empty stomach or after breakfast with a very low fat content gives significantly different pharmacokinetic parameters of serum testosterone (i.e., lower) than a normal diet. Thus, the fat content of food taken with the formulations of the present invention may differ significantly from “normal” without a clinically important effect on testosterone levels obtained. Thus, the patient is allowed to be flexible in terms of eating habits when moving from one meal to another and from one day to another, which until now has been impossible with other known oral TU formulations. Previously known oral formulations of TU were not able to ensure the achievement of any significant levels of serum testosterone in a fasted state.

Example 5 - in vitro solubility tests

A study of the solubility of the formulations of the present invention was performed in vitro to evaluate correlation with pharmacokinetic profiles observed in vivo. In a first study, the solubility of Composition B. Andriol Testocaps® (40 mg TU on a soft gel, dissolved in a mixture of castor oil and propylene glycol laurate) was included for comparison. The study was carried out with equivalent doses of TU, that is, 1 capsule of Composition B (158.3 mg TU) and 4 soft gels Testocaps (4 × 40 mg = 160 mg TU). Dissolution (i.e., the release of TU from the corresponding formulations) was studied in a Simulated Intestinal Fluid After-Meal (FeSSIF) environment, which simulated the intestinal fluid after it was stimulated with food. FeSSIF contained sodium hydroxide, crystallized acetic acid, potassium chloride, lecithin and sodium taurocholate. The resulting emulsion was adjusted to pH 5.0.

The data presented in Tables 8 and 9 demonstrate that the composition of the present invention releases about 40% TU in the first 30 minutes, and about 60% of the entire capsule after 4 hours. Testocaps®, however, releases little or no drug at all (1%) for a full 4 hours. The observed large difference in the solubility of TU from the two compositions can be explained, at least in part, by the presence of a hydrophilic surfactant, for example. Cremophor RH40, part B. In contrast, Andriol Testocaps® includes only oil (castor oil) and lipophilic surfactant (propylene glycol laurate).

In a second study, Composition A was subjected to a similar analysis, but when using 5% Triton XI00 potassium phosphate buffer (pH 6.8) as the solvent medium. The results are presented below in Table 10. In this study, 98% TU from the composition of the present invention was released within the first 15 minutes of dissolution, and again the presence of the Cremophor RH40 hydrophilic surfactant definitely contributed to the rapid dissolution and release of TU.

In yet another embodiment of the present invention, the pharmaceutical compositions disclosed herein may also be useful in improving certain side effects of certain male contraceptive strategies. For example, progestin-based male contraception strongly inhibits luteinizing hormone (LH) and follicle stimulating hormone (FSH), and therefore inhibits spermatogenesis, resulting in clinical azoospermia (defined as having less than about 1 million sperm / ml of seminal fluid during 2 consecutive months). However, taking progestins also has an undesirable side effect of significantly reducing steady-state serum testosterone levels.

In such situations, for example, it may be preferable to take progestin agents together with testosterone or its derivatives (for example, TU). It is more preferable to propose a pharmaceutical agent of the present invention with the inclusion of progestin - in an amount sufficient to substantially inhibit the production of LH and FSH - in combination with testosterone. In some embodiments, the pharmaceutical preparation may be intended for single oral administration.

The compositions of the present invention can provide increased release, allowing the delivery of testosterone to serum within a few hours. Indeed, the half-life of serum testosterone in accordance with the present invention is between 3 and 7 hours, preferably more than 4, 5 or 6 hours. The half-life of serum testosterone in men, in contrast, is considered to be in the range of 10 to 100 minutes.

Without reference or limitation on the part of theory, it is believed that the compositions of the present invention achieve such results, on the one hand, by improving the absorption of the corresponding medication by the intestinal lymphatic system, and not by portal blood circulation. On the other hand, again, without reference or restriction from the theory, it is believed that when using testosterone ester, the time required for deesterification contributes to the increase in the half-life of testosterone.

Oral doses of the present invention may be administered to patients in need of testosterone treatment approximately every 12 hours to maintain desired serum testosterone levels. In more preferred embodiments of the present invention, oral doses may be administered to patients in need of testosterone treatment approximately every 24 hours. Typically, “desirable” testosterone levels are those found in people characterized as having no testosterone deficiency.

Although the present invention has been described using its individual embodiments, it should be understood that further modifications can be made, and the present application is intended to cover any variations, uses or changes of the present invention. In general, the principles of the present invention, including those deviating from the present disclosure that arise from known or common practice in the industry to which the invention relates, and which may be applied to the essential features, are formulated and presented in the following list of patent claims formulas.

Claims (33)

1. An oral pharmaceutical composition for treating a testosterone deficiency in men, containing testosterone undecanoate, dissolved in a carrier containing at least one lipophilic surfactant and at least one hydrophilic surfactant with a ratio of the total amount of lipophilic surfactants to the total amount of hydrophilic surfactants ( in / in), ranging from about 6: 1 to 3.5: 1, with dissolved testosterone undecanoate is from 18 to 22 wt.% composition. 2. The oral pharmaceutical composition according to claim 1, characterized in that at least one hydrophilic surfactant contains Cremophor RH 40 (polyoxyethylene glycerol trihydroxystearate). 3. The oral pharmaceutical composition according to claim 1, characterized in that at least one lipophilic surfactant contains oleic acid. 4. An oral pharmaceutical composition according to claim 1, characterized in that the testosterone undecanoate is dissolved in a carrier substantially free of ethanol. 5. The oral pharmaceutical composition according to claim 1, characterized in that it contains from 15 to 17 wt.% At least one hydrophilic surfactant. 6. The oral pharmaceutical composition according to claim 1, characterized in that it contains from 50 to 55 wt.% At least one lipophilic surfactant. 7. A method of treating a testosterone deficiency or its symptoms in men, comprising oral administration to a patient suffering from a lack of testosterone or its symptoms, an effective amount of a pharmaceutical composition according to any one of claims. 1-6. 8. The use of an oral pharmaceutical composition according to any one of paragraphs. 1-6 for the manufacture of a medicament for the treatment of testosterone deficiency or its symptoms in men. 9. A method of treating a testosterone deficiency or its symptoms in men, comprising oral administration to a patient suffering from a lack of testosterone or its symptoms, an effective amount of a pharmaceutical composition containing testosterone undecanoate, dissolved in a carrier containing at least one lipophilic surfactant and, according to at least one hydrophilic surfactant with a ratio of the total amount of lipophilic surfactants to the total amount of hydrophilic surfactants (w / w) in the range from about 6: 1 to 3.5: 1, while tosterona undecanoate ranges from 18 to 22 wt.% of the composition, for average serum testosterone concentration in a stationary state in the range from about 300 to 1100 ng / dL. 10. The method according to p. 9, characterized in that the composition is taken once a day. 11. The method according to p. 9, characterized in that the composition is taken twice a day. 12. The use of a pharmaceutical composition containing testosterone undecanoate, dissolved in a carrier containing at least one lipophilic surfactant and at least one hydrophilic surfactant in the ratio of the total number of lipophilic surfactants to the total amount of hydrophilic surfactants (w / w) in the range of from about 6: 1 to 3.5: 1, wherein dissolved testosterone undecanoate is from 18 to 22 wt.% of the composition, to provide an average serum concentration of testosterone in steady state in the range of from about 300 up to 1100 ng / dl, for the treatment of testosterone deficiency or its symptoms in men. 13. The use according to p. 12, characterized in that the composition is taken once a day. 14. The use according to p. 12, characterized in that the composition is taken twice a day. 15. An oral pharmaceutical composition for treating testosterone deficiency in men, comprising: but. 18-22 wt.% Soluble testosterone undecanoate; b. 50-55 wt.% At least one lipophilic surfactant, and; at. 15-17 wt.% At least one hydrophilic surfactant; d. 10-15 wt.% a mixture of borage oil and peppermint oil. 16. The composition according to p. 15, characterized in that the hydrophilic surfactant is Cremophor RH40. 17. The composition according to p. 15, wherein the lipophilic surfactant is oleic acid. 18. The composition according to p. 15, characterized in that the ratio of lipophilic surfactants to hydrophilic surfactants is 4: 1. 19. A method of treating a testosterone deficiency or its symptoms in men, comprising oral administration to a patient suffering from a lack of testosterone or its symptoms, an effective amount of a pharmaceutical composition according to any one of claims. 15-18. 20. The use of an oral pharmaceutical composition according to any one of paragraphs. 15-18 for the manufacture of a medicament for the treatment of testosterone deficiency or its symptoms in men. 21. An oral pharmaceutical composition for treating testosterone deficiency in men, comprising: but. 19.8 wt.% Soluble testosterone undecanoate; b. 51.6 wt.% Oleic acid; at. 16.07 wt.% Cremophor RH40; g. 10 wt.% borage oil; D. 2.5 wt.% peppermint oil; e. 0.03 wt.% of butylhydroxytoluene (BHT). 22. A method of treating a testosterone deficiency or its symptoms in men, comprising oral administration to a patient suffering from a lack of testosterone or its symptoms, an effective amount of a pharmaceutical composition according to claim 21. 23. The use of an oral pharmaceutical composition according to claim 21 for the manufacture of a medicament for the treatment of testosterone deficiency or its symptoms in men.

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