HK1196765B - Oral testosterone ester formulations and methods of treating testoterone deficiency comprising same - Google Patents

Abstract

An oral pharmaceutical composition is provided comprising testosterone undecanote solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a total lipohilic surfactant to total hydrophilic surfactant ratio (w/w) falling in the range of about 6:1 to 3.5:1, wherein the solubilized testosterone undecanoate comprises 18 to 22 percent by weight of the composition. A dosage form of testosterone undecanoate is further provided. A method of treating testosterone deficiency or its symptoms by using the pharmaceutical composition of the invention is further provided. The treating method comprising the oral pharmaceutical composition of the invention provides optimum serum testosterone levels; therefore it is clinically effective to treat hypogonadal men over an extended period of time.

Description

Oral testosterone ester preparation and method for treating testosterone deficiency comprising same

The application is a divisional application of an application with the application date of 12/04/2010, international application number of PCT/US2010/030788, national application number of 201080066142.8, entitled "oral testosterone ester formulation and method for treating testosterone deficiency comprising the same".

Technical Field

The present invention relates generally to oral formulations of testosterone esters for the treatment of testosterone deficiency. More specifically, the present invention relates to pharmaceutical compositions comprising Testosterone Undecanoate (TU) with enhanced and prolonged absorption and pharmacokinetics.

Background

Testosterone (T) is a major androgen produced in leydig cells and is responsible for the normal growth, development and maintenance of male sexual organs and secondary sexual characteristics (e.g., hypo-vocal, muscle development, facial hair, etc.). In adulthood, testosterone is essential for the normal function, well-being and the maintenance of libido and erectile ability of the testes and their accessory structures (prostate and seminal vesicles).

Testosterone deficiency, T hyposecretion characterized by low serum T concentrations, can cause male medical conditions (e.g., hypogonadism). Symptoms associated with male hypogonadism include impotence and decreased libido, fatigue and lack of energy, depressed mood, deterioration of secondary sexual characteristics, loss of muscle mass and increased fat mass. Moreover, male hypogonadism is a risk factor for osteoporosis, metabolic syndrome, type II diabetes and cardiovascular disease.

Various testosterone replacement therapies are commercially available to treat male hypogonadism. Pharmaceutical formulations include testosterone and testosterone derivatives in the form of intramuscular injections, implants, oral tablets of alkylated T (e.g., methyltestosterone), topical gels, or topical patches. However, all current T therapies fail to adequately provide an easy way to deliver TAnd isA clinically effective method. For example, intramuscular injection is painful in humans and is associated with significant fluctuations in serum T levels between doses; t-patches are commonly associated with T levels below normal (i.e., clinically ineffective) and often cause substantial skin irritation; while Tgels have been associated with unsafe transfer of T from users to women and children. Likewise, the only "approved" oral T therapy, methyltestosterone, is associated with the occurrence of significant hepatotoxicity. Thus, over time, current methods of treating testosterone deficiency suffer from poor compliance and thus result in unsatisfactory low T male treatment.

The bioavailability of testosterone and its esters is poor-because first pass intestinal and liver metabolism is significant-or ineffective-because the body is unable to release testosterone from its testosterone prodrug. For example, testosterone and testosterone esters with side chains less than 10 carbons in length are primarily absorbed through the portal circulation, resulting in a large, if not total, first-pass metabolism. Long carbon chain (i.e., 14 or more carbons) fatty acid esters can be absorbed by intestinal lymph, but the longer the fatty acid chain length, the lower the rate and extent at which esterases hydrolyze esters to release testosterone, and thus the less pharmacologically active (i.e., clinically ineffective).

In addition to the choice of testosterone esters, the formulation of testosterone esters presents unique challenges. The gastrointestinal environment is clearly aqueous in nature, which requires that the drug must be dissolved for absorption. However, testosterone (and particularly its esters) is extremely insoluble in water and aqueous media, and even if the T or T ester is initially dissolved in the formulation, the formulation must be capable of maintaining the drug in a soluble or dispersed form without precipitating or otherwise precipitating out of solution in vivo (although this property can be tested in vitro, for example, by mixing the contents of the formulation in simulated intestinal fluid). Furthermore, oral T formulations must effectively release the T or T ester according to the desired release profile. Thus, an effective formulation of the T or T ester must balance good solubility with optimal release and meet the target plasma or serum concentration profile.

For these and other reasons, the U.S. Food and Drug Administration (FDA) has not heretofore approved oral formulations of testosterone or testosterone esters. Indeed, the only oral testosterone product approved by the FDA to date is methyltestosterone (where methyl is covalently bound to the C-17 position of the testosterone "nucleus" to inhibit hepatic metabolism; note also that methyltestosterone is not a prodrug of testosterone) and that approval has occurred decades ago. Unfortunately, the use of methyltestosterone is significantly associated with the incidence of hepatotoxicity, and therefore, this drug is rarely prescribed to treat men with low testosterone.

As noted above, fatty acid esters of testosterone provide the body with another form of latent testosterone delivery (i.e., in a "prodrug" form). Upon absorption, testosterone may be released from its ester by the action of non-specific tissues and plasma esterases. Moreover, by increasing the relative hydrophobicity of the testosterone moiety and the lipophilicity of the resulting molecule, the prodrug can be absorbed at least in part by intestinal lymph, as determined by its n-octanol-water partition coefficient (log P) value, thereby reducing hepatic first pass metabolism. In general, lipophilic compounds having log P values of at least 5 and oil solubility of at least 50mg/mL are predominantly delivered through the lymphatic system.

Although promising, testosterone prodrugs, including testosterone esters, are not formulated in a manner that achieves effective and sustained serum testosterone levels (i.e., average serum T concentrations in the range of about 300-1100 ng/dL) at normal gonadal levels. Indeed, pharmaceutical formulations for oral administration of testosterone prodrugs (including testosterone esters) remain unapproved by the FDA.

Thus, there remains a need for an oral formulation of testosterone esters that provides optimal serum testosterone levels that are clinically effective in treating hypogonadal men (i.e., those with serum T concentrations ≦ 300 ng/dL) over an extended period of time.

Summary of The Invention

In one embodiment of the invention, an oral pharmaceutical composition is provided comprising testosterone undecanoate dissolved in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio (w/w) of total lipophilic surfactant to total hydrophilic surfactant in the range of about 6:1 to 3.5:1, the composition providing a steady state average serum testosterone concentration in the range of about 300 to about 1100ng/dL after once daily or twice daily oral administration. When administered with a meal, the pharmaceutical composition provides a C of no more than 2500ng/dL, preferably no more than 1800ng/dL, and most preferably no more than 1500ng/dL_max。

According to a preferred embodiment, the at least one hydrophilic surfactant comprises Cremophor RH40 (polyoxyethylene glycerol trihydroxystearate); the at least one lipophilic surfactant comprises oleic acid. The pharmaceutical compositions of the present invention may comprise from 18 to 22% by weight dissolved testosterone undecanoate and may also be substantially free of monohydric alcohols (e.g., ethanol).

In another embodiment of the invention, a dosage form of testosterone undecanoate is provided comprising testosterone undecanoate dissolved in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant, which upon once or twice daily administration of the dosage form to a subject suffering from hypogonadism or symptoms thereof, provides a steady state average serum testosterone concentration in the range of from about 300 to about 1100ng/dL while avoiding a C above 2500ng/dL_maxOccurrence of a value, more preferably, avoiding a C exceeding 1800ng/dL_maxOccurrence of a value, most preferably, avoiding C exceeding 1500ng/dL_maxThe occurrence of a value.

In yet another embodiment of the present invention, a pharmaceutical composition is provided comprising testosterone undecanoate dissolved in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant, which composition, upon oral administration with a meal having a fat content of from as low as 20% by weight to as high as 50% by weight, provides an average serum testosterone concentration that is statistically insignificant relative to that observed upon oral administration with a meal having a fat content of about 30% by weight.

In yet another embodiment of the present invention, a pharmaceutical composition is provided comprising testosterone undecanoate dissolved in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio (w/w) of total lipophilic surfactant to total hydrophilic surfactant in the range of about 6:1 to 3.5:1, the composition providing a rapid phase half-life of serum testosterone of about 5 hours and a terminal half-life of serum testosterone of about 29 hours after once daily or twice daily oral administration.

In yet another embodiment of the present invention, a pharmaceutical composition is provided comprising testosterone undecanoate dissolved in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio (w/w) of total lipophilic surfactant to total hydrophilic surfactant in the range of about 6:1 to 3.5:1, said composition upon once daily or twice daily oral administration to a subject suffering from testosterone deficiency or a symptom thereof, providing an average serum testosterone concentration on day 30 of a daily treatment regimen that is substantially the same as that observed on day 7. The mean serum testosterone concentration obtained on day 30 of the daily treatment regimen according to the present invention was also essentially the same as observed on day 60.

In another embodiment of the invention, a method of treating testosterone deficiency or a symptom thereof is provided comprising orally administering to a subject suffering from testosterone deficiency or a symptom thereof an effective amount of a pharmaceutical composition comprising testosterone undecanoate dissolved in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio (w/w) of total lipophilic surfactant to total hydrophilic surfactant of about 6:1 to 3.5:1 to provide a steady state average serum testosterone concentration in the range of about 300 to about 1100 ng/dL. The composition may be administered once daily or twice daily and may result in a C in the range of about 900 and 1100ng/dL_maxThe value is obtained.

According to the present method, the composition may be administered with a meal comprising at least 20 wt.% fat. The method causes substantially no daily change in testosterone pharmacokinetics, mean serum T_maxValues ranged from about 3 to 7 hours after oral administration, and substantially no significant decrease in steady state serum testosterone response was observed after repeated dosing.

In a preferred embodiment of the present invention, there is provided a pharmaceutical composition comprising:

(a) 15-25% by weight dissolved testosterone undecanoate;

(b)12-18 wt% of at least one hydrophilic surfactant;

(c) 50-65% by weight of at least one lipophilic surfactant;

(d) 10-15% by weight of a mixture of borage oil and peppermint oil,

the compositions may be generally free of monohydric alcohols, particularly ethanol, and, upon oral administration to a subject in need thereof, result in a serum testosterone half-life (T) in the range of about 10 hours to about 18 hours_1/2). Cremophor RH40 is a preferred hydrophilic surfactant and the preferred lipophilic surfactant is oleic acid. Both borage oil and peppermint oil are considered lipophilic surfactants.

In a particularly preferred embodiment, the composition comprises:

(a) 18-22% by weight dissolved testosterone undecanoate;

(b)15-17 wt% of at least one hydrophilic surfactant;

(c) 50-55% by weight of at least one lipophilic surfactant; and

(d) 10-15% by weight of a mixture of borage oil and peppermint oil.

The ratio of borage oil to peppermint oil can be in the range of 8: 1 to 3:1, preferably, 6:1 to 5:1, more preferably, 5:1 to 4: 1. in addition to Cremophor RH40, Solutol HS-15, Tween80 and TPGS are also preferred hydrophilic surfactants; in addition to oleic acid, glycerol monooleate, propylene glycol laurate and Capmul MCM are also preferred lipophilic surfactants. Combinations of two or more lipophilic surfactants with two or more hydrophilic surfactants are also contemplated.

In another embodiment of the present invention, there is provided a method of treating testosterone deficiency comprising orally administering to a hypogonadal subject an effective amount of a pharmaceutical composition comprising:

(a) 15-25% by weight dissolved testosterone undecanoate;

(b)12-18 wt% of one or more hydrophilic surfactants;

(c) 50-65% by weight of one or more lipophilic surfactants;

(d) 10-15% by weight of a mixture of borage oil and peppermint oil,

and without ethanol, once-daily or twice-daily oral administration of the pharmaceutical composition results in a mean serum testosterone concentration at steady state, C, in the range of about 300 to about 1100ng/dL for the subject_ave. The composition may optionally be administered with a meal having a fat content of about 15% by weight and about 25% by weight or higher. According to the present method, the subject may achieve any or all of the following pharmacokinetic parameters:

(a) subject serum testosterone C_maxIn the range of 900 to 1100 ng/dL;

(b) substantially free of testosterone pharmacokinetic diurnal variation;

(c) serum T after administration of the composition_maxIs 3 to 7 hours; and

(d) substantially no steady state serum testosterone response was observed after repeated administration.

In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of embodiments in addition to those described and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein, as well as the abstract, are for the purpose of description and should not be regarded as limiting.

Those skilled in the art will appreciate, therefore, that the conception upon which this disclosure is based may readily be utilized as a basis for the designing of other parts, methods and systems for carrying out the several purposes of the present invention. For example, some embodiments of the invention may combine TUs with other active drugs (including other hormones) in an oral delivery system that partially prevents or alleviates symptoms associated with testosterone deficiency. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the scope and spirit of the present invention.

Brief Description of Drawings

Figure 1 provides serum T levels over 24 hours of once daily or twice daily oral administration of a TU formulation of the invention.

Figure 2 shows the serum T response over time in hypogonadal men following administration of a formulation of the invention versus a conventional oral TU formulation (Restandol) comprising TU in oleic acid.

FIG. 3 provides the T of serum T levels of subjects eating diets of different fat content (expressed as weight percent) prior to oral administration of TU formulations of the invention_maxThe value is obtained.

FIG. 4 provides C for serum T levels in subjects fed diets of different fat content (expressed as weight percent) prior to oral administration of TU formulations of the invention_maxThe value is obtained.

Figure 5 provides area under the curve (AUC) values for serum T levels for subjects eating diets of different fat content (expressed as weight percent) prior to oral administration of a TU formulation of the invention.

Detailed Description

The present invention provides an oral pharmaceutical composition comprising TU which, when administered no more than twice daily to a hypogonadal male, provides a mean steady state serum level (concentration) of testosterone that is within the desired "normal" or eugonadal range (i.e., about 300 ng/dL) in such male, while avoiding high C that is considered undesirable, even unacceptable, by the U.S. food and drug administration_maxThe value is obtained. For example, FDA approval guidelines state that less than 85% of treated subjects may have a C of 1500ng/dL or greater_maxValues, and no one has a C in excess of 2500ng/dL_maxThe value is obtained. Less than 5% of treated subjects have a C in the range 1800 + 2500ng/dL_maxThe value is obtained. Furthermore, the formulations of the present invention are designed as self-emulsifying drug delivery systems(SEDDS) to form a TU-containing emulsion (or dispersion) upon mixing with intestinal fluid of the gastrointestinal tract.

In one embodiment of the invention, the formulations of the invention are employed to deliver testosterone and/or an ester at the C17 position of the testosterone molecule orally, alone or in combination with other active ingredients. For example, in some embodiments it may be preferred to combine testosterone undecanoate with an orally active inhibitor of type i or type ii 5 α -reductase or testosterone undecanoate with synthetic progesterone.

While various embodiments of the present invention are described and exemplified by undecanoate esters of testosterone (i.e., TU), other esters of hydrophobic compounds (including T) can be employed for oral delivery in accordance with the teachings of the specification. Indeed, it will be apparent to those skilled in the art from the teachings herein that the drug delivery systems of the present invention, and compositions therefrom, can be adapted for oral delivery of other testosterone esters, such as short chain (C)₂-C₆) Medium chain (C)₇-C₁₃) And long chains (C)₁₄-C₂₄) Fatty acid esters, preferably medium chain fatty acid esters of testosterone.

The formulations of the present invention comprise T-esters dissolved in a mixture comprising one or more lipophilic surfactants and one or more hydrophilic surfactants. The lipophilic surfactant as defined herein has a hydrophilic-lipophilic balance (HLB) value of less than 10 and preferably less than 5. The hydrophilic surfactant as defined herein has an HLB value of greater than 10. (HLB is an empirical expression of the relationship of the hydrophilic to hydrophobic groups of a surface-active amphiphilic molecule (e.g., surfactant.) it is used to denote surfactants and its values vary from about 1 to about 45 and includes both nonionic and ionic surfactants.

According to an aspect of the invention, each component (i.e., the lipophilic and hydrophilic surfactants) in the delivery system has its own solubilizing properties and contributes in part to the dissolution of the active ingredient. Those lipophilic surfactants that substantially aid in the dissolution of the drug are defined herein as "primary" solvents. However, it will be appreciated that solubility may be affected by the temperature of the solvent/formulation. For example, formulations of the present invention comprising about 20% testosterone undecanoate remain soluble at temperatures of 30 ℃ or above, including in the range of 30 to about 40 ℃.

The hydrophilic surfactant component is required to achieve the desired dispersibility and drug release of the formulation in the gastrointestinal tract. That is, the hydrophilic surfactant, in addition to acting as a co-solvent, also needs to be used to release the drug from the lipid carrier matrix or primary solvent. In this regard, high HLB surfactants, such as Cremophor RH40, are generally satisfactory. The level (amount) of high HLB surfactant can be adjusted to provide optimal drug release without compromising dissolution of the active ingredient.

Lipophilic surfactants suitable for the drug delivery system of the present invention include:

fatty acid (C)₆-C₂₄Preferably, C₁₀-C₂₄More preferably, C₁₄-C₂₄) For example, caprylic acid, capric acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid. Oleic acid is preferred.

Mono-and/or di-glycerides of fatty acids, for example Imwitor988 (glycerol mono-/di-octanoate), Imwitor742 (glycerol mono-/di-octanoate/decanoate), Imwitor308 (glycerol mono-octanoate), Imwitor191 (glycerol mono-stearate), Softigen701 (glycerol mono-/di-ricinoleate), Capmul MCM (glycerol mono-/di-octanoate/decanoate), Capmul MCM (L) (liquid form of Capmul MCM), Capmul GMO (glycerol mono-oleate), Capmul GDL (glycerol dilaurate), Maisine (glycerol mono-linoleate), Peceol (glycerol mono-oleate), Myverol18-92 (distilled monoglycerides from sunflower oil) and Myverol18-06 (distilled monoglycerides from hydrogenated soybean oil), preferrol ATO5 (glycerol palmitate stearate) and Gelucire39/01 (glycerol esters, i.e. C_12-18Mono-, di-and tri-glycerolsEsters). Preferred ingredients of such lipophilic surfactants are partial glycerides of oleic acid, palmitic acid and stearic acid and mixtures thereof.

Acetates, succinates, lactates, citrates and/or tartrates of mono-and/or di-glycerides of fatty acids, for example, Myvacet9-45 (distilled acetylated monoglycerides), Miglyol829 (caprylic/capric diglycerol succinate), Myverol SMG (mono/di-succinylated monoglycerides), Imwitor370 (glycerol stearate citrate), Imwitor375 (glycerol monostearate/citrate/lactate) and crodat 22 (diacetyl tartaric acid ester of monoglycerides).

Propylene glycol mono-and/or di-esters of fatty acids, for example, Lauroglycol (propylene glycol monolaurate), mircyl (propylene glycol monomyristate), Captex200 (propylene glycol dicaprylate/dicaprate), Miglyol840 (propylene glycol dicaprylate/dicaprate) and Neobee M-20 (propylene glycol dicaprylate/dicaprate).

Polyglycerol esters of fatty acids, such as Plurol oleique (polyglycerol oleate), Caprol ET (polyglycerol mixed fatty acids) and drewpol10.10.10 (polyglycerol oleate).

Castor oil ethoxylates with low levels of ethoxylates (HLB < 10) such as Etocas5 (5 moles of ethylene oxide reacted with 1 mole of castor oil) and sandoxlate 5 (5 moles of ethylene oxide reacted with 1 mole of castor oil).

Acids and ester ethoxylates (HLB < 10) formed by reacting ethylene oxide with fatty acids or glycerides of fatty acids, such as Crodet04 (polyoxyethylene (4) lauric acid), Cithrol2MS (polyoxyethylene (2) stearic acid), Marlosol183 (polyoxyethylene (3) stearic acid) and Marlowet G12DO (glyceryl 12EO dioleate).

Sorbitan esters of fatty acids, for example, Span20 (sorbitan monolaurate), Crill1 (sorbitan monolaurate) and Crill4 (sorbitan monooleate).

Transesterification products of natural or hydrogenated vegetable oil triglycerides with polyalkylene polyols (HLB < 10), for example Labrafil M1944CS (polyoxyethylated almond oil), Labrafil M2125CS (polyoxyethylated corn oil) and Gelucire37/06 (polyoxyethylated hydrogenated coconut). Preferably Labrafil M1944 CS.

Alcohol ethoxylates (HLB < 10), e.g., Volpo N3 (polyoxyethylated (3) oleyl ether), Brij93 (polyoxyethylated (2) oleyl ether), Marlowet LA4 (polyoxyethylated (4) lauryl ether).

Pluronics, e.g., polyoxyethylene-polypropylene oxide copolymers and block copolymers (HLB < 10), e.g., Synperonic PE L42(HLB =8) and Synperonic PE L61(HLB = 3).

Mixtures of suitable lipophilic surfactants (e.g., those listed above) can be used if desired, and in some instances, such mixtures have been found to be beneficial.

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

castor oil or hydrogenated castor oil ethoxylates (HLB > 10), for example Cremophor EL (polyoxyethylene (35) castor oil), Cremophor RH40 (polyoxyethylene (40) hydrogenated castor oil), Etocas40 (polyoxyethylene (40) castor oil), Nikkol HCO-60 (polyoxyethylene (60) hydrogenated castor oil), Solutol HS-15 (polyethylene glycol 660 hydroxystearate), Labrasol (caprylocaproyl polyethylene glycol-8 glyceride), α -tocopherol-polyethylene glycol-1000-succinate (TPGS) and ascorbic acid-6 palmitate. Cremophor RH40 is preferred.

Polyoxyethylene sorbitan fatty acid derivatives, for example, Tween20 (polyoxyethylene (20) monolaurate), Tween80 (polyoxyethylene (20) monooleate), Crillet4 (polyoxyethylene (20) monooleate) and Montanox40 (polyoxyethylene (20) monopalmitate). Tween80 (polysorbate 80) is preferred.

Gelucires, preferably Gelucire50/13 (PEG mono-and diesters of palmitic and stearic acids). (for Gelucires, the first number (i.e., 50) corresponds to the melting point of the material and the second number (i.e., 13) corresponds to the HLB number).

Fatty acid ethoxylates (HLB > 10), for example Myrj45 (polyoxyethylene (8) stearate), Tagat L (polyoxyethylene (30) monolaurate), Marlosol1820 (polyoxyethylene (20) stearate) and Marlosol OL15 (polyoxyethylene (15) oleate). Preferably Myrj 45.

Alcohol ethoxylates (HLB)>10) For example, Brij96 (polyoxyethylene (10) oil ether), Volpo015 (polyoxyethylene (15) oil ether), Marlowet OA30 (polyoxyethylene (30) oil ether) and Marlowet LMA20 (polyoxyethylene (20) C)₁₂–C₁₄Fatty ethers).

Polyoxyethylene-polypropylene oxide copolymers and block copolymers (HLB > 10) are available under the trade names Pluronics or Poloxamers, such as Poloxamers188 and 407, also known as Syperonic PE L44 (HLB = 16) and Syperonic F127 (HLB = 22), respectively.

Anionic surfactants, for example, sodium lauryl sulfate, sodium oleate, and sodium dioctyl sulfosuccinate.

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

As noted, in one aspect of the invention, each component (i.e., the lipophilic and hydrophilic surfactants) in the delivery system individually has solvent properties and partially contributes to the dissolution of the active ingredient. In this manner, without being bound by or limited to theory, the present invention does not require other solvents, e.g., co-solvents, but these may optionally be included in the present systems and formulations.

Optional co-solvents suitable for the present invention are, for example, water, short chain monohydric alcohols, glycols and polyols, such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, polyethylene glycol having an average molecular weight of about 200 to about 10,000, diethylene glycol monoethyl ether (e.g., Transcutol HP), and combinations thereof. Preferably, the co-solvent is not included, especially ethanol or other mono-ethanol.

Other oils that may be incorporated into embodiments of the present invention include medium chain (C)₇–C₁₃) Or long chain (C)₁₄–C₂₂) Fatty acids and low molecular weight (up to C)₆) Complete triglycerides of mono-, di-or polyhydric alcohols. Thus, some examples of oils useful in the present invention include: vegetable oils (e.g., soybean oil, safflower oil, corn oil, olive oil, castor oil, cottonseed oil, peanut oil, sunflower oil, coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond, borage, mint, and almond oil) and animal oils (e.g., cod liver oil, shark oil, and mink oil).

In other embodiments of the invention, the methods and compositions modulate (i.e., maintain) serum testosterone availability by incorporating components that biochemically modulate (1) TU absorption, (2) TU metabolism to T, and/or (3) T metabolism to Dihydrotestosterone (DHT). For example, inclusion of a mediator in a long chain fatty acid ester may improve TU absorption. In this way, more TU evades hydrolysis in the intestine and enters the bloodstream. In other words, the fatty acid ester can competitively inhibit the esterase, which would otherwise metabolize TU. Examples of other esters or combinations thereof include botanical extracts or benign esters (e.g., propyl paraben, octyl acetate, and ethyl acetate) used as food additives.

Other components that may modulate TU absorption include "natural" and synthetic inhibitors of 5 α -reductase, an enzyme that catalyzes the conversion of T to DHT that is present in intestinal cells and other tissues. Complete or partial inhibition of this conversion can increase and maintain an increase in serum levels of T following oral administration of TU, with concomitant reduction in serum DHT levels. Borage oil, which contains significant amounts of the 5 α -reductase inhibitor gamma-linolenic acid (GLA), is an example of a "natural" regulator of TU metabolism. Of course, GLA may be added directly as a separate component of the TU formulation of the present invention, except in borage oil. Various natural inhibitors of 5 α -reductase are known in the art (e.g., epigallocatechin gallate, which is a catechin derived primarily from green tea and saw palm extract from berries of the species Serenoa repens), all of which may be suitable for the present invention. Non-limiting examples of synthetic 5 α -reductase inhibitors suitable for use in the present invention include compounds such as finasteride (finasteride), dutasteride (dutasteride), and the like.

In addition to5 α -reductase inhibitors, the present invention encompasses inhibitors of T metabolism by other mechanisms. One such inhibition site may be the cytochrome P450 isoenzyme CYP3a4, which is present in intestinal and hepatic cells and is therefore capable of metabolizing testosterone. Accordingly, selected embodiments of the present invention include peppermint oil, which is known to contain components capable of inhibiting CYP3a4 activity.

Other optional ingredients that may be included in the compositions of the present invention are those commonly used in oil-based drug delivery systems, for example, antioxidants, such as, tocopherol acetate, ascorbic acid, Butylated Hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole, and propyl gallate; pH stabilizers such as citric acid, tartaric acid, fumaric acid, acetic acid, glycine, arginine, lysine and dipotassium hydrogen phosphate; thickeners/suspending agents, such as hydrogenated vegetable oils, beeswax, colloidal silica, mannitol, gums, cellulose, silicates, bentonite; flavoring agents, such as cherry, lemon, and anise flavors; sweeteners such as aspartame (asparatame), potassium acesulfame, sucralose, saccharin and cyclamate; and the like.

The inventors have recognized that the relative proportions of the lipophilic surfactant(s) and the hydrophilic surfactant(s) are critical to achieving the desired pharmacokinetics of the present invention. More specifically, the inventors have discovered a ratio of total lipophilic surfactant to total hydrophilic surfactant that is not only capable of dissolving relatively large amounts of T-esters (e.g., greater than 15%, 18%, 20%, 22%, or 25%) but also capable of providing optimal release of the T-esters from the formulation. Preferably, the ratio (w/w) of total oil (e.g., oleic acid + borage oil + peppermint oil, all of which are considered lipophilic surfactants) to hydrophilic surfactant is in the range of about 6:1 to 1:1, 6:1 to 3.1, 6:1 to 3.5:1, or 6:1 to 4:1, and more preferably, in the range of about 5:1 to 3:1, and most preferably, in the range of about 4:1 to 3: 1.

The following relative concentrations by weight (percentages are based on the total weight of the formulation) 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%.

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

The preparation of the invention has self-emulsifying property, and forms a fine emulsifying agent after being diluted by aqueous medium or intestinal fluid in vivo. In other words, the formulation can have a high surfactant and lipid content designed to form a desirable dispersion upon mixing with an aqueous medium. A qualitative description of the self-emulsifying properties of the formulations of the invention can be observed during their in vitro dissolution. On the other hand, quantitative measurement of the particle size of the emulsified droplets can be carried out by means of laser light scattering and/or turbidity measurement in the dissolution medium by means of a UV/VIS spectrophotometer. Any of these methods may be utilized and understood by one of ordinary skill in the art.

The pharmaceutical composition according to the invention is preferably liquid or semi-solid at ambient temperature. Moreover, pharmaceutical compositions can be converted into solid dosage forms by adsorbing them onto solid carrier particles (e.g., silicon dioxide, calcium silicate, or magnesium aluminum silicate) to give a non-flowing powder, which can be filled into hard capsules or compressed into tablets. See, for example, US2003/0072798, the disclosure of which is incorporated by reference in its entirety. Thus, the term "dissolved" herein is understood to describe an Active Pharmaceutical Ingredient (API) that is dissolved in a liquid solution or uniformly dispersed in a solid carrier. Dosage forms in encapsulated form can be formed and used.

The present invention preferably includes an API that is solubilized in the presence of a lipid surfactant excipient (e.g., any combination of lipophilic and hydrophilic surfactants described above). Thus, the melting point of the surfactant used is one factor that can determine whether the resulting composition will be a liquid or semi-solid at ambient temperature. Particularly preferred compositions of the invention are liquid oral unit dosage forms, more preferably filled into hard or soft capsules, e.g., gelatin or non-gelatin capsules, such as those made of cellulose, carrageenan or pullulan (pollulan). Encapsulation techniques for lipid-based pharmaceutical formulations are well known to those of ordinary skill in the art. Since the delivery systems and formulations of the present invention described herein are not limited to any one encapsulation method, no further discussion of specific encapsulation techniques is necessary.

The pharmaceutical carrier systems and pharmaceutical formulations according to the present invention may be prepared by conventional techniques for lipid-based pharmaceutical carrier systems. In a typical method for the preparation of the preferred carrier system of the present invention, the lipophilic surfactant component is weighed out and added to a suitable stainless steel container, and then the hydrophilic surfactant component is weighed out and added to the container along with the other components. In a preferred method, the hydrophobic drug may be added first to the lipophilic surfactant component (e.g., oleic acid) and the hydrophilic surfactant component added after complete dissolution. In any event, mixing of the components can be accomplished by using a homomixer or other high shear device and elevated temperatures (especially where high melting surfactants are used) to ensure that all components are in a homogeneous liquid state before or after addition of the drug.

Where the hydrophobic drug is weighed out and added to the combined lipid mixture, mixing is preferably continued at elevated temperature until a homogeneous solution is obtained. The formulation may be degassed and then encapsulated in soft or hard gelatin capsules. In some cases, the filled formulation may be maintained at an elevated temperature using a suitable jacketed vessel to facilitate processing. Also, in some cases, the homogeneous solution may be filtered (e.g., through a 5 micron filter) prior to encapsulation.

Returning now to testosterone delivery, the pharmaceutical compositions of the present invention may be suitable for testosterone therapy. Testosterone is the major endogenous androgen of men. The mesenchymal cells in the testis (Leydig cells) produce about 7mg of testosterone per day, resulting in serum concentrations in the range of about 300 to about 1100 ng/dL. The ovaries and adrenals of women also synthesize testosterone, but in about one-tenth the amount observed in males with normal gonadal function. Most (. gtoreq.98%) of the circulating testosterone is biologically active when bound to sex hormone-binding globulin and albumin and only released in free form. Thus, the term "free" is defined as not bound to, or confined within, a biomolecule, cell, and/or lipid matrix of, for example, the formulations of the invention described herein. Generally, as used herein, a "free" drug refers to a drug that is accessible to metabolic enzymes circulating in the serum.

Although the present invention should not be limited to the delivery of testosterone or any particular ester thereof, TU was found to provide unique chemical and physical properties that make its preferred use in some embodiments. The present inventors have recognized that undecanoate esters of testosterone, in particular, can result in superior bioavailability than is observed with other equivalent esters (e.g., Testosterone Enanthate (TE)).

Furthermore, the use of TU in the formulations of the invention correlates with a significantly lower ratio of serum DHT to T compared to the reported values for other forms of T-substitutes, including oral formulations of TU (table 1). Testosterone or testosterone is converted to DHT by the action of 5 α -reductase and then interacts with the androgen receptor. DHT is a more potent androgen than testosterone, and some scientists believe that elevated levels of DHT increase the risk of prostate cancer. In this manner, the present invention provides yet another unexpected advantage over other known testosterone delivery vehicles.

Table 1: observed serum DHT and DHT response to T-surrogate by various routes of administration: comparison of T ratios

¹Atkinson, LE, Chang, Y-L and Synder, PJ. (1998) Long-term experiment with a Testosterone reproduction through sodium skin. in Testosterone: Action, discovery and stabilization (Nieschlag, E and Behre, HM, eds.) Springer-Verlag, Berlin, page 365-

²Swerdloff, RS, et al (2000). Long-term pharmacological kinetics of transdermaltosterone gel in hypogonadal men.J.Clin.Endocrinol.Metab.85: 4500-.

³Wang, C et al (2004). Long-term testosterone geltreatmentmaintains beneficial effects on sexual function and mood,lean and fat massand bone mineral density in hypogonadal men.J.Clin.Endocrinol.Metab.89:2085-2098.

⁴Houwing, NS et al (2003), pharmaceutical students in the world of new formulations of organic testosterone monocarbonate, andriolTestocaps. Pharmotherapy: 23:1257-1265.

⁵Gooren,LJG(1994).A ten-year safety study of the oral androgentestosterone undecanoate.J.Androl.15:212-215.

Specific embodiments of the present invention will be illustrated in the non-limiting examples. Table 2 provides compositional details of various formulations of TU in accordance with the teachings of the present invention. For the calculation, 1mg of T corresponds to 1.58mg of T-undecanoate.

The compositional details (mg/capsule and wt%) of table 2 are about 800mg fill weight per '00' hard gelatin capsule. However, at testosterone ester amounts less than about 100 mg/capsule, the formulation can be scaled for a smaller total fill weight that allows for the use of smaller hard gelatin capsules (e.g., '0' or smaller size, if desired).

Also, it should be apparent to one of ordinary skill in the art that many, if not all, surfactants in one species (e.g., lipophilic, hydrophilic, etc.) may be exchanged with another surfactant from the same species. Thus, while table 1 lists formulations comprising oleic acid, one of ordinary skill in the art will recognize that other lipophilic surfactants (e.g., those listed above) may also be suitable. Likewise, while table 1 lists formulations comprising Cremophor RH40 (HLB = 13), one of ordinary skill in the art will recognize that other hydrophilic surfactants (e.g., those listed above) may be suitable. Borage oil, peppermint oil, BHT and ascorbyl palmitate may be replaced or removed with chemically similar substances.

TABLE 2

¹Rounding to the nearest whole number in milligrams of weight; 800 (+/-10%)

²±8mg

Preferred formulations of TU filled into "00" size capsules according to the invention are:

preparation A

Preparation B

In the following, in vivo and in vitro performance data of the formulations according to the invention will be described. However, the scope of the present invention should not be limited to the following examples or the particular formulations studied in the examples.

Example 1 Single day study

Study of the single-day pharmacokinetic profile of formulation B following once-daily or twice-daily administration to hypogonadal men. The study was designed as an open label, single day dosing, continuous, crossover pharmacokinetic study. After written informed consent was given, 12 hypogonadal men were enrolled and all 12 subjects completed the study. Each subject received a daily dose of formulation B as follows:

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

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

3.400mg T (in TU form) BID (200 mg/dose)

After eating for 5 minutes, the dose was administered to the subject in the form of capsules (breakfast QD, and breakfast and supper BID).

Table 3 provides the relevant PK parameters studied:

^athe indicated values for half-life and time to peak are median and range.

^bThe dose is expressed as T-equivalent. Each TU capsule contains 158.3mg TU, which corresponds to an equivalent amount of 100mg T.

Mean serum T concentration (C) over a 24 hour period after administration_avg) Indicating a positive increase in serum T levels for all protocols studied, with protocol 3 giving the best response (C)_avg385 ng/dL). The mean serum T peak concentrations observed in response to oral T-ester formulations evaluated in this study never exceeded the upper normal limit (i.e., 1100 ng/dL). Although some individual subjects' C_maxThe T values exceeded the upper normal limit, but the vast majority of these peaks were in the range of 1200 to 1400 ng/dL. Subject C of any treatment group_maxNone exceeded 1500 ng/dL.

Serum T half-life (T) of schemes 1 and 2_1/2) Median of about 15 hours, and T for scheme 3_1/2Was 8 hours. In each protocol, serum DHT concentrations increased with serum T levels. Average DHT to T ratio (R) over all periods as determined by liquid chromatography-mass spectrometry (LC/MS/MS)_avg) Slightly outside the normal range (i.e., 0.03-0.1), but not clinically significant.

TU administered with BID and food in 200mgT equivalents yields the bestSatisfactory results, wherein 75% of subjects reached serum T C_avgAbove 300ng/dL (below the normal gonadal normality limit). Likewise, the mean serum T achieved in 75% of subjects was within the normal range (i.e., 0.03-0.1 ng/dL). Not reach C_avgThose subjects who were at least 300ng/dL were all above 200ng/dL, indicating that a slight increase in the TU dose would be effective oral T-replacement therapy for these subjects.

When the data for serum T were corrected at baseline, a consistent increase in serum T and DHT concentrations was observed in the majority of subjects regardless of T-ester dose, with the dose for oral TU being excellent linearly. Although the DHT to T ratio was slightly elevated, any elevation was considered clinically insignificant. No inter-subject variability of this formulation was observed relative to equivalent formulations of other T esters (e.g., TE). Furthermore, in the "BID" dosing regimen, there was no difference in mean serum T peak concentration or 12 hour AUC during AM versus PM dosing.

With respect to safety, although headache is reported as a side effect, no side effect was reported in one subject in each treatment regimen. No serious adverse events or deaths occurred during the study, and none of the subjects prematurely discontinued the study due to adverse events. Therefore, all adverse events were considered to be moderate intensity events.

Example 2 seven day study

Study of acute tolerability and steady state serum pharmacokinetic profiles of formulation B after twice daily dosing in hypogonadal men. The study was designed as an open label, repeat dosing, cross pharmacokinetic study (examining food effect in one group).

After written informed consent was given, 29 hypogonadal men were recruited, 24 of which completed the study. The protocol for each subject completing the study to receive formulation B was as follows:

1.7 daily doses of 600mg T (in TU), BID (300 mg/dose), i.e., 3 capsules/dose

2.8 daily doses of 400mgT (in TU), BID (200 mg/dose)

The dose was administered to the subject in capsule form 30 minutes after the start of the meal (breakfast and dinner), but on day 8, the AM dose was administered on an empty stomach.

Peak of T exposure (C)_max) And total exposure to T (AUC) is dose-proportional after T-correction for endogenous baseline. Peak concentration of T (T)_max) Occurs about 4 hours after each treatment administration. Likewise, the serum concentrations of TU and DHTU rise and fall within the dosing interval, where the initial and end concentrations of the dosing interval are less than 20% of the peak concentration of TU and less than 25% of the peak concentration of DHTU. For each treatment, baseline T concentrations gradually decreased due to endogenous T production. This observation is consistent with the gradual and sustained suppression of gonadotropins by exogenous T, thus resulting in reduced endogenous T production. At least partially inhibited for a 14 day washout period.

Again, serum T pharmacokinetics did not show daily changes in serum T concentration. PM administration (approximately at 8PM administration) resulted in a similar concentration-time curve as AM administration (approximately at 8AM administration) (fig. 1). Because of the concentration similarity between AM and PM dosing (evaluated in regimen 1), the 12-hour PK data from regimen 2 (satiation) was used to accurately predict a 24-hour PK profile throughout the day in response to 200mg T (as TU) administered in BID. Simulation results showed that (a) based on AUC, 77% of subjects were in a 24 hour time period_{Blood circulation}Qing T C_avgWithin the normal range of gonadal function, thus meeting the 75% potency requirements of the current FDA for T-substitute products; and (b) C without subject_maxOver 1500ng/dL, which is beyond the current FDA standards, i.e., less than 85% of subjects have C for T-substitute products_maxIs more than 1500 ng/dL. Thus, also consistent with the current FAD-prescribed potency endpoint, no subject C_maxC over 2500ng/dL and less than 5% of subjects studied_maxIn the range of 1800 and 2500 ng/dL. Notably, these results were obtained without any dose adjustment.

Table 4 provides a comparison of steady state AM and PM pharmacokinetics of T upon dosing with BID:

administration of TU with a high fat diet resulted in similar serum T-concentration-time curves and administration with a standard diet. In contrast, administration of TU in fasting condition resulted in serum T exposure (C)_maxAnd AUC) by more than 50% (table 5). In all cases, observed C was found_maxAnd C calculated_avgA strong correlation between the two, indicating targeting of specific C with oral T-ester formulations_avgMay result in the expected peak T level after administration.

The DHT concentration tracks the T concentration, although DHT concentrations are only 11-34% of T concentration. The conversion of T to DHT showed slight non-linearity, increasing at a smaller concentration-proportional rate than T. DHT/T ratio was minimal when T concentration was highest and was about 0.1 before starting TU treatment, while during treatment the average ratio was 0.24 and ranged from about 0.1 to 0.35 at steady state, depending on the sampling time after oral administration of TU.

The mean estradiol concentration was approximately 11pg/mL before starting oral TU treatment, while the range of 7 days for each treatment ranged from 19pg/mL to 33pg/mL (pre-dose concentration). The steady state estradiol concentration prior to administration is about 20-30 pg/mL.

Example 3 four weeks study

Formulation B was also studied to determine the time required to reach steady state when treated with 200mg T (in TU) at a twice daily dose (i.e., 2 capsules/dose) for 28 days in hypogonadal men. The study was designed as an open label, repeated dose pharmacokinetic study.

After written informed consent was given, 15 hypogonadal men were enrolled, and all completed the study. Each subject received a twice daily dose of 200mg T (in TU) for 28 days.

For each subject, the study on day 32 was scheduled for "day 28" consecutive PK sampling days. Thus, each dose-compliant subject received a total of 31 daily doses of 400mg T (in TU) (i.e., 200mg T, BID), and the last AM administration of 200mg T (in TU). The dose was administered in capsule form, where subjects were instructed to take the dose 30 minutes after the start of the meal (breakfast and dinner).

Table 6 provides the relevant PK data for the study:

86.7% of subjects in the normal range achieved serum T C_avgC of none of the subjects_maxC at concentrations greater than 1800ng/dL in only 13.3% of subjects_maxConcentrations greater than 1500ng/dL (note: no dose adjustments were made during the study to bring the subject within the targeted efficacy and safety range.) in the formulations tested the T half-life in response to TU was significantly longer than reported for TU administered orally to either T alone or prior art formulationsWhile endogenous T production is inhibited by administration of exogenous T, only limited inhibition occurs during the first 3 days and requires 5-7 days of continued treatment to achieve maximum inhibition.

By day 7 of treatment, T and DHT concentrations reached steady state. The concentrations of T and DHT at day 3 were greater than day 5, indicating that for exogenously administered T, a period of time was required to suppress endogenous T production, thus achieving homeostasis in response to oral TU. Indeed, the addition of exogenous T suppressed endogenous T levels from 276ng/dL prior to treatment to 108ng/dL after 28 days of T-supplemented treatment.

However, it is evident that once serum T reaches steady state in response to twice daily oral TU, a slight decrease in serum T response to no decrease over time is observed (i.e., no trend towards lower after continuous TU administration_{Blood circulation}Trend in clear T levels). For example, day 15C_avgSubstantially similar to C observed on day 28_avg(FIG. 2). In contrast, oral TU formulations in the art are reported to move towards lower T-means over time (Cantrill, j.a. clinical Endocrinol (1984)21: 97-107). In hypogonadal men treated with oral TU formulations known in the art, it has been reported that the observed serum T response after 4 weeks of treatment is about 30% less than the observed value on the first day of treatment for hypogonadal men-most of which have a primary hypogonadal form and thus low baseline levels of serum T (e.g.,<100 ng/dL), therefore, T reduction cannot be explained by inhibition of endogenous T alone.

Serum DHT concentrations closely track T concentrations, with DHT and DHT/T values increasing 4 to 7 fold during treatment. The average DHT/T ratio during the 12 hour dosing interval is 0.245, although values during the dosing interval may range from an average maximum ratio of 0.380 to an average minimum ratio of 0.131. Within 36 hours of discontinuation of treatment with oral TU, DHT concentrations returned to pre-treatment levels. However, T concentrations do not return to pre-treatment levels quickly, apparently because the inhibition of endogenous T production/release cannot be reversed quickly.

Estradiol (E2)The concentrations of (a) and (b) showed a single gradual increase to steady state, which was also reached on day 7 of treatment. The E2 concentration also shows a systematic change that tracks the change in T during the dosing interval. Average C of E2_max、C_avgAnd C_min30.6pg/mL, 22.0pg/mL, and 15.5pg/mL, respectively. Within 36 hours of discontinuation of treatment with oral TU, the E2 concentration returned to the pre-treatment level.

Mean C at T Steady State (day 28 AM administration)_max、C_avgAnd C_minThe concentrations were 995ng/dL, 516ng/dL and 199ng/dL, respectively. Median value T of T_maxOccurs 5.0 hours after administration. C_minAverage is C_max23.5% of (A), a fluctuation index of 156% was obtained. Elimination half-life of T was evaluated for only about half of the subjects, and the median for those subjects was 18.4 hours (mean T_1/2Is 29 hours).

Example 4 food Effect study

The study of any effect of dietary fat in hypogonadal men on the pharmacokinetics of formulation B was an open label, two-center, five-way crossover study. After a 4-10 day washout period, a single dose of 300mg T (475 mg TU, 3 formulation B capsules) was administered to 16 hypogonadal men with a serum baseline T level of 205.5 + -25.3 ng/dL (mean + SE, 23-334.1 ng/dL). Subjects were randomized to receive medication on empty stomach or after eating for 30 minutes, diet containing-800 calories with a specific amount of fat (% by weight): very low fat (6-10%); low fat (20%); "normal" dietary fat (30%); or high fat (50%). A "normal" meal is intended to be determined as a comparator (i.e., a reference meal) for statistical comparison. Serial blood samples 24 hours after drug administration were collected to determine serum testosterone and Dihydrotestosterone (DHT) levels by liquid chromatography-mass spectrometry (LC/MS).

The pharmacokinetic parameters of serum T in response to a single oral high dose TU were found to be similar (table 7, figures 3-5) to the low and normal fat diets-indeed bioequivalent (i.e., 90% confidence interval between 85-125%). Similar serum T PK parameters were also observed when compared to normal and high fat diets. While high fat diets produced higher serum T responses (although statistically no difference occurred), the average ratio of least squares means was between 70-143% when compared to normal fat diet-the clinical significance difference was < 30%.

¹C_AvgIs AUC_0-∞τ calculation (τ = dosing interval =12 hours, BID dosing)

The variability of PK response appears to be highest after the first dose, or after the first few doses of oral TU, and decreases as treatment continues. Thus, any effect of dietary fat in the low-normal-high range on serum T PK parameters appeared to be insignificant during long-term dosing. This is consistent with PK results for 7 days treatment (example 2) and 30 days treatment (example 3), where PK still shows C at different diet events in repeated dose studies of oral TU_maxAnd C_avgSimilar results for distribution [ both studies administered 200mg T (as TU), BID]。

A statistical comparison of the observed serum T responses after oral TU, relative to a normal fat diet (i.e., reference diet), without or with very low fat, or high fat diets revealed: there was no statistically significant difference between the low or high fat diet and the normal diet at p <0.05 level. In contrast, administration of oral TU in the form of SEDDS formulation when fasting or eating very low fat breakfast resulted in significantly different (i.e. lower) serum T PK parameters than the normal diet. Thus, the fat content of the diet administered with the formulation of the invention may be substantially different from "normal", which has no clinically significant effect on the T levels obtained. Thus, the subject is allowed flexibility in the dietary habits of each meal and each day, which was not possible with the previously known oral TU formulations. Oral TU formulations known in the art have not been able to achieve any meaningful serum T levels in the fasting state to date.

Example 5 in vitro dissolution test

Dissolution studies of the formulations of the invention were performed in vitro to evaluate the correlation with PK profiles observed in vivo. In the first study, the dissolution of formulation B was studied. For comparison, Andriol was included(40 mg TU dissolved in a mixture of castor oil and propylene glycol laurate per soft capsule.) the study was conducted with substantially equivalent doses of TU, i.e., 1 formulation B capsule (158.3 mg TU) and 4 Testocaps soft capsules (4 × 40mg =160mg TU). dissolution (i.e., release of TU from the respective formulations) was studied in simulated intestinal fluid (FeSSIF) medium in a satiated state which simulates intestinal fluid stimulated by the diet.

The data presented in tables 8 and 9 indicate that the formulation of the present invention releases about 40% TU within the first 30 minutes and about 60% of the entire capsule after 4 hours. However, forLittle or no drug release (1%) was observed over the 4 hours. The major difference in TU dissolution observed from these two formulations may be due at least in part to the presence of a hydrophilic surfactant (e.g., Cremophor RH 40) in formulation B. In contrast, AndriolOnly oil (castor oil) and lipophilic surfactant (propylene glycol laurate).

In the second study, formulation a was subjected to a similar experiment, but using 5% Triton X100 potassium phosphate buffer (ph 6.8) as dissolution medium. The results are provided in table 10 below. In this study, 98% TU was released from the formulation of the invention within the first 15 minutes of dissolution, and this rapid dissolution and TU release was certainly facilitated again by the presence of the hydrophilic surfactant Cremophor RH 40.

In another embodiment of the present invention, the pharmaceutical compositions disclosed herein may be equally suitable for alleviating the side effects of some strategies for male contraception. For example, progesterone-based male contraception substantially inhibits Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH), and thus inhibits spermatogenesis, resulting in clinical azoospermia (defined as less than about 1 million sperm/mL of semen for 2 consecutive months). However, administration of progesterone also has the undesirable side effect of significantly reducing steady-state serum testosterone levels.

For example, in such cases, it is preferred to provide a progesterone formulation that also contains testosterone or a testosterone derivative (e.g., TU). More preferably, a pharmaceutical formulation according to the invention is provided comprising progesterone in an amount sufficient to substantially inhibit LH and FSH production-and testosterone. In some embodiments, the pharmaceutical formulation is delivered orally once daily.

The formulations of the present invention can provide extended release formulations to deliver testosterone to the serum within hours. Indeed, the half-life of serum testosterone according to the invention is between 3 and 7 hours, preferably more than 4, 5 or 6 hours. In contrast, the serum half-life of male testosterone is considered to be in the range of 10 to 100 minutes.

Without being bound or limited by theory, it is believed that in one aspect, the formulations of the present invention may achieve these effects by enhancing absorption of the Chinese medicine from the gut lymphatic system rather than through the portal circulation. On the other hand, again without being bound or limited by theory, it is believed that by using an ester of testosterone, the time required for de-esterification results in a longer T half-life.

The oral dosage of the invention may be administered orally by a subject in need of testosterone therapy about every 12 hours to maintain the desired serum testosterone level. In a more preferred embodiment, the oral dose is administered orally by a subject in need of testosterone therapy about once every 24 hours. Generally, the "desired" testosterone levels will be those found in human subjects characterized as not having testosterone deficiency.

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this specification is intended to cover all of the following variations, uses, or adaptations of the invention. In general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

Claims (10)

1. An oral pharmaceutical composition comprising testosterone undecanoate dissolved in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio (w/w) of total lipophilic surfactant to total hydrophilic surfactant in the range of 6:1 to 3.5:1, wherein the lipophilic surfactant has a hydrophilic-lipophilic balance value of less than 5 and the hydrophilic surfactant has a hydrophilic-lipophilic balance value of more than 10, wherein the composition comprises 50-70 wt% of the at least one lipophilic surfactant and the composition comprises 10-20 wt% of the at least one hydrophilic surfactant, wherein the dissolved testosterone undecanoate constitutes 18 to 22 wt% of the composition, which composition provides a steady state average serum testosterone level in the range of 300 to 1100ng/dL after once daily or twice daily oral administration The ketone concentration.

2. The oral pharmaceutical composition of claim 1, wherein said at least one hydrophilic surfactant is polyoxyethylene glyceryl-trihydroxy-stearate.

3. The oral pharmaceutical composition of claim 1, wherein said at least one hydrophilic surfactant is Cremophor RH 40.

4. The oral pharmaceutical composition of claim 1, wherein said at least one lipophilic surfactant is oleic acid.

5. The oral pharmaceutical composition of claim 1, wherein said testosterone undecanoate is dissolved in a carrier that is substantially free of ethanol.

6. The oral pharmaceutical composition of claim 1, comprising 15 to 17% by weight of the at least one hydrophilic surfactant.

7. The oral pharmaceutical composition of claim 1, comprising 50 to 55 weight% of said at least one lipophilic surfactant.

8. A pharmaceutical composition comprising testosterone undecanoate dissolved in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a ratio (w/w) of total lipophilic surfactant to total hydrophilic surfactant in the range of 6:1 to 3.5:1, wherein the lipophilic surfactant has a hydrophilic-lipophilic balance value of less than 5 and the hydrophilic surfactant has a hydrophilic-lipophilic balance value of greater than 10, wherein the composition comprises 50-70 wt% of the at least one lipophilic surfactant and the composition comprises 10-20 wt% of the at least one hydrophilic surfactant to provide a steady state average serum testosterone concentration in the range of 300 to 1100ng/dL, wherein the dissolved testosterone undecanoate constitutes 18 to 22 wt% of the composition, the composition is used in a method of treating testosterone deficiency or a symptom thereof, the method comprising orally administering an effective amount of the pharmaceutical composition to a subject suffering from testosterone deficiency or a symptom thereof.

9. The pharmaceutical composition for use in the method of claim 8, wherein the composition is administered once daily.

10. The pharmaceutical composition for use in the method of claim 8, wherein the composition is administered twice daily.