JP2016028087A - Oral testosterone ester formulations and methods of treating testosterone deficiency comprising the same - Google Patents

Abstract

The present invention provides an oral testosterone ester formulation that provides optimal serum testosterone levels that are clinically effective in treating men with gonadal dysfunction over a long period of time. At least one lipophilic surfactant having a ratio (w / w) of total lipophilic surfactant to total hydrophilic surfactant in the range of about 6: 1 to 3.5: 1. Stationary containing testosterone undecanoate solubilized in a carrier comprising an agent and at least one hydrophilic surfactant and falling within the range of about 300 to about 1100 ng / dL by oral administration once or twice daily An oral pharmaceutical composition that provides an average serum testosterone concentration for the condition. [Selection figure] None

Description

The present invention relates generally to oral testosterone ester formulations for the treatment of testosterone deficiency. More particularly, the present invention relates to a pharmaceutical composition comprising testosterone undecanoate (TU) that enhances and prolongs absorption and pharmacokinetics.

BACKGROUND OF THE INVENTION Testosterone (T) is the major male hormone produced in testicular stromal cells, and normal growth, development and maintenance of male genitals, as well as secondary sexual characteristics (eg, voice depression, Responsible for muscle development, whiskers, etc.) Testosterone is necessary throughout the adult life for proper functioning of the testis and its accessory prostate and seminal vesicles, for well-being, and for maintaining libido and erectile abilities.

  Testosterone deficiency (deficiency of T secretion characterized by a decrease in serum T concentration) can cause medical conditions (eg, gonadal dysfunction) in men. Symptoms associated with male gonadal dysfunction include inability to erect and decreased libido, fatigue and energy loss, depression, regression of secondary sexual characteristics, decreased muscle mass and increased fat mass. Furthermore, male gonadal dysfunction is a risk factor for osteoporosis, metabolic syndrome, type II diabetes, and cardiovascular disease.

  A variety of testosterone replacement therapies are marketed for the treatment of male gonadal dysfunction. Pharmaceutical preparations include both testosterone and testosterone derivatives in the form of intramuscular injections, grafts, oral tablets of alkylated T (eg, methyltestosterone), topical gels, or topical patches. However, all current T therapies cannot adequately provide an easy and clinically effective method for T. For example, intramuscular injection is painful and is associated with significant dose-to-dose variation in serum T levels; T patches are generally associated with decreased T levels in the normal (ie, clinically ineffective) range and are substantially T-gels have been associated with unsafe transport from users to women and children. The only approved oral T therapy methyltestosterone is associated with a significant appearance of liver toxicity. Therefore, over time, current treatments for testosterone deficiency are poor treatments for men with low T doses and are therefore inadequate treatments.

  Testosterone and its esters are either poorly bioavailable (because of large first gut passages and liver metabolism) or are ineffective (because the body is unable to release testosterone from the testosterone prodrug). For example, testosterone and testosterone esters with side chains less than 10 carbons long are absorbed primarily via the portal circulation, resulting in substantially if not all, first pass metabolism. Fatty acid esters having a long carbon chain (ie, having 14 or more carbon atoms) may be absorbed by the intestinal lymph, but the longer the fatty acid chain length, the rate and degree of release of testosterone by ester hydrolysis by esterases. And thus pharmacological activity is very low (ie clinically ineffective).

  In addition to the choice of testosterone esters, there are unique challenges to testosterone ester formulations. The gastrointestinal environment is clearly aqueous in nature, and the drug must be dissolved for absorption. However, testosterone and especially its esters are extremely insoluble in water and aqueous media, so that the formulation does not precipitate the drug in vivo or in solution even if the T or T ester is first solubilized in the formulation. Must be able to remain dissolved or dispersed without leaving the body (but such properties can be examined in vitro, for example, by mixing the contents of the formulation in simulated intestinal fluid) . Furthermore, oral T formulations must effectively release T or T esters according to the desired release profile. Thus, an effective T or T ester combination must balance good solubility with optimal release and satisfaction with the desired plasma or serum concentration profile.

  For these reasons, oral formulations of testosterone and testosterone esters, among others, have not been approved by the US Food and Drug Administration (FDA) to date. In fact, the only oral testosterone product approved to date by the FDA is methyltestosterone (a methyl group that covalently binds to the “nuclear” at position C-17 of testosterone to inhibit liver metabolism, but methyltestosterone is a testosterone (Note also that it is not a prodrug), and this authorization was obtained decades ago. Unfortunately, the use of methyl testosterone is associated with a significant incidence of liver toxicity and is rarely prescribed for the treatment of men with low test testosterone levels.

  As mentioned above, fatty acid esters of testosterone provide yet another potential mode of delivery of testosterone to the body (ie, as a “prodrug”). Once absorbed, testosterone can be released from the ester through the action of nonspecific tissues and plasma esterases. Furthermore, such prodrugs are at least one of the intestinal lymphoids by increasing the relative hydrophobicity of the testosterone moiety and the lipophilicity of the resulting molecule as measured by n-octanol-water partition coefficient (log P) values. Can be absorbed, thereby reducing the first-pass metabolism by the liver. In general, lipophilic compounds having a log P value of at least 5 and an oil solubility of at least 50 mg / mL are mainly transported through the lymphatic system.

  Despite their promise, testosterone prodrugs, including testosterone esters, achieve effective and sustained serum testosterone levels with normal levels of gonadal function (ie, an average serum T concentration of about 300). In the range of ˜1100 ng / dL). Indeed, pharmaceutical preparations for oral administration of testosterone prodrugs, including testosterone esters, have not yet been approved by the FDA.

  Thus, an oral combination of testosterone esters that provides optimal serum testosterone levels that are clinically effective in treating men with gonadal dysfunction (ie, men with serum T concentrations below 300 ng / dL) over time. There is still a need.

SUMMARY OF THE INVENTION In one embodiment of the present invention, at least the ratio of total lipophilic surfactant to total hydrophilic surfactant (w / w) falls within the range of about 6: 1 to 3.5: 1, at least Comprising testosterone undecanoate solubilized in a carrier comprising one lipophilic surfactant and at least one hydrophilic surfactant, from about 300 to about 1100 ng / day by oral administration once or twice daily An oral pharmaceutical composition is provided that provides a steady state average serum testosterone concentration falling within the dL range. The pharmaceutical composition, when administered with a meal, provides a C _max not exceeding 2500 ng / dL, preferably not exceeding 1800 ng / dL, most preferably not exceeding 1500 ng / dL.

  According to a preferred embodiment, the at least one hydrophilic surfactant comprises Cremophor RH40 (polyoxyethylene glycerol trihydroxystearate) and the at least one lipophilic surfactant comprises oleic acid. The pharmaceutical composition of the present invention may contain 18 to 22% by weight of solubilized testosterone undecanoate, and may further contain substantially no monohydric alcohol such as ethanol.

In another embodiment of the invention, comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant, the gonad dysfunction or symptoms thereof oral administration of once or twice daily to a subject having, while avoiding the appearance of _{C max} values of greater than 2500 ng / dL, more preferably while avoiding the appearance of _{C max} values of greater than 1800 ng / dL, most A testosterone undecanoate dosage formulation is provided that provides a steady state average serum testosterone concentration that falls within the range of about 300 to about 1100 ng / dL, preferably while avoiding the appearance of C _max values above 1500 ng / dL. The

  In yet another embodiment of the invention, comprising as little as 20% by weight of testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant. Mean that is statistically insignificant from that observed by oral administration with a meal having a fat content ranging from up to 50% by weight, with oral administration with a meal having a fat content of about 30% by weight Pharmaceutical compositions are provided that provide serum testosterone concentrations.

  In yet another embodiment of the present invention, the ratio of the total lipophilic surfactant to the total hydrophilic surfactant (w / w) is in the range of about 6: 1 to 3.5: 1, at least 1 Serum testosterone rapid for about 5 hours by oral administration once or twice daily, comprising testosterone undecanoate solubilized in a carrier comprising one lipophilic surfactant and at least one hydrophilic surfactant Pharmaceutical compositions are provided that provide a rapid phase half-life and a serum testosterone terminal half-life of about 29 hours.

  In yet another embodiment of the present invention, the ratio of the total lipophilic surfactant to the total hydrophilic surfactant (w / w) is in the range of about 6: 1 to 3.5: 1, at least 1 Testosterone undecanoate solubilized in a carrier comprising a species lipophilic surfactant and at least one hydrophilic surfactant, once or twice daily to a subject having testosterone deficiency or symptoms thereof Oral administration provides a pharmaceutical composition that provides an average serum testosterone concentration on Day 30 of a daily treatment regimen that is substantially identical to that observed on Day 7. In accordance with the present invention, the mean serum testosterone concentration obtained on day 30 of the daily treatment regimen may be substantially the same as that observed on day 60.

In another embodiment of the present invention, at least one ratio of total lipophilic surfactant to total hydrophilic surfactant (w / w) falls within the range of about 6: 1 to 3.5: 1. Steady state average serum testosterone comprising testosterone undecanoate solubilized in a carrier comprising a lipophilic surfactant and at least one hydrophilic surfactant and falling within the range of about 300 to about 1100 ng / dL Provided is a method of treating a testosterone deficiency or symptom thereof comprising orally administering an effective amount of a pharmaceutical composition that provides a concentration to a subject having the testosterone deficiency or symptom thereof. The composition may be administered once a day or twice a day, and may produce a C _max value that falls in the range of about 900-1100 ng / dL.

According to the present invention, the composition may be administered with a meal comprising at least 20% by weight of fat. The method may produce substantially no daytime testosterone pharmacokinetic variation, mean serum T _max may fall in the range of about 3-7 hours after oral administration, and steady state serum upon repeated administration No substantially significant drop in testosterone response is observed.

In a preferred embodiment of the present invention,
(A) 15-25% by weight of solubilized testosterone undecanoate;
(B) 12-18% by weight of at least one hydrophilic surfactant;
(C) 50-65% by weight of at least one lipophilic surfactant;
(D) a mixture of 10-15% by weight borage oil and peppermint oil;
Serum testosterone half-life (T ₁₎ , which is generally free of monohydric alcohols, specifically ethanol, and falls within the range of about 10 hours to about 18 hours upon oral administration to a subject in need. _{/ 2} ) is provided that provides a pharmaceutical composition. Cremophor RH40 is a preferred hydrophilic surfactant and a preferred lipophilic surfactant is oleic acid. Borage oil and peppermint oil are both lipophilic surfactants that are considered.

In particularly preferred embodiments, the composition comprises
(A) 18-22% by weight of solubilized testosterone undecanoate;
(B) 15-17% by weight of at least one hydrophilic surfactant;
(C) 50-55% by weight of at least one lipophilic surfactant; and (d) a mixture of 10-15% by weight borage oil and peppermint oil;
including. The ratio of borage oil to peppermint oil may be in the range of 8: 1 to 3: 1, preferably 6: 1 to 5: 1, most preferably 5: 1 to 4: 1. In addition to Cremophor RH40, Solutol HS-15, Tween 80 and TPGS are preferred hydrophilic surfactants, and in addition to oleic acid, glycerol monooleate, propylene glycol laurate and Capmul MCM are preferred lipophilic interfaces. It is an activator. Combinations of two or more lipophilic surfactants and two or more hydrophilic surfactants are also contemplated.

In another embodiment of the invention,
(A) 15-25% by weight of solubilized testosterone undecanoate;
(B) 12 to 18% by weight of one or more hydrophilic surfactants;
(C) 50-65% by weight of one or more lipophilic surfactants;
(D) a mixture of 10-15% by weight borage oil and peppermint oil;
And no ethanol, a pharmaceutical composition that produces an average (or average) steady state serum testosterone concentration C _ave in a subject that falls within the range of about 300 to about 1100 ng / dL by oral administration once or twice daily There is provided a method of treating a testosterone deficiency comprising orally administering an effective amount of a product to a subject with gonadal dysfunction. The composition may optionally be administered with a meal having a fat content ranging from about 15% to about 25% by weight or more. According to the method, any one or all of the following pharmacokinetic parameters may be realized in the subject:
(A) 900-1100 ng / dL of serum testosterone C _{max in} the subject;
(B) Daytime testosterone pharmacokinetic changes substantially absent;
(C) Serum T _max 3-7 hours after administration of the composition; and (d) Steady state serum testosterone response that does not substantially drop as observed by repeated administration.

  In this regard, prior to describing at least one embodiment of the present invention in detail, the present invention is described in the following description or in the details of construction and arrangement of components illustrated in the drawings. It must be understood that the application is not limited. The invention is capable of embodiments that may be practiced and carried out in various ways in addition to those described. Similarly, it should be understood that the terminology and terminology used herein and in the abstract are for illustrative purposes and should not be considered limiting.

  Thus, those skilled in the art will appreciate that the basic concepts of the present disclosure can be readily used as a basis for the design of other parts, methods and systems for carrying out the multiple objectives of the present invention. For example, some embodiments of the present invention may combine TU with other active drugs, such as other hormones, that partially prevent or reduce symptoms associated with testosterone deficiency in an oral delivery system. It is important, therefore, that the claims be regarded as including such equivalent constructions without departing from the scope and spirit of the invention.

FIG. 6 shows serum T levels over 24 hours by oral administration of the TU combination of the present invention once or twice daily. FIG. 5 shows the serum T response to time course of gonadal dysfunction men administered a combination of the present invention versus a conventional oral TU combination containing TU in oleic acid (Restandol). The T _max value of the serum T level of the subject who consumed the meal of various fat mass (weight%) before oral administration of the TU combination agent of this invention is shown. Fig. 5 shows C _max values of serum T levels of subjects who consumed meals of various fat mass (% by weight) before oral administration of the TU combination of the present invention. FIG. 2 shows the area under the curve (AUC) of serum T levels of subjects who consumed meals of various fat masses (% by weight) before oral administration of the TU combination of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention avoids high C _max values that are considered inappropriate if not tolerated by the US Food and Drug Administration when administered to men with gonad dysfunction no more than twice daily. Oral pharmaceutical compositions comprising TU that provide such male steady state serum testosterone levels (concentrations) that fall within the normal range of desired “normal” or gonadal function (ie, about 300-1100 ng / dL) Offer things. For example, less than 85% of the subjects treated can be can have a _{C max} value of more than 1500 ng / dL, and that any object does is also utilized as have _{C max} values of greater than 2500 ng / dL is the FDA approved guidelines It is stated. Less than 5% of treated subjects may have C _max values that fall within the range of 1800-2500 ng / dL. Moreover, because the combination of the present invention is designed to be a self-emulsifying drug delivery system (SEDDS), a TU-containing emulsion (or dispersion) is formed when mixed with intestinal fluid in the gastrointestinal tract. .

  In one embodiment of the present invention, testosterone and / or the ester at the C-17 position of the testosterone molecule may be delivered orally using the combination of the present invention alone or together with other active ingredients. For example, a combination of testosterone undecanoate and an oral activity inhibitor of type I or type II 5α-reductase, or a combination of testosterone undecanoate and a synthetic progestin may be preferred in some embodiments.

Although many of the embodiments of the present invention are described and exemplified using testosterone undecanoate (ie, TU), other esters of hydrophobic compounds containing T can be administered orally based on the teachings herein. Can be applied for delivery. Indeed, drug delivery systems and compositions obtained therefrom of the present invention, other testosterone esters such as testosterone short chain _(C 2 _~C 6), medium chain _(C 7 _{~C 13)} and long chain _{(C 14} -C ₂₄₎ fatty acid esters, preferably it that may be suitable for oral delivery, such as medium-chain fatty acid ester should be readily apparent to those skilled in the art from the teachings herein.

  The formulation of the present invention comprises a T-ester dissolved in a mixture comprising one or more lipophilic surfactants and one or more hydrophilic surfactants. The lipophilic surfactants defined herein have a hydrophilic-lipophilic balance (HLB) value of less than 10, preferably less than 5. The hydrophilic surfactants defined herein have an HLB value greater than 10. (HLB is an empirical indication of the relationship between hydrophilic and hydrophobic groups in surfactant amphiphilic molecules such as surfactants. It is used to index surfactants. The value varies from about 1 to about 45 and includes both non-ionic and ionic surfactants. The higher the HLB, the higher the water solubility / dispersibility of the surfactant.)

  According to one aspect of the present invention, each component of the delivery system (ie, lipophilic and hydrophilic surfactant) individually has solubilizing properties and contributes in part to the solubilization of the active ingredient. Those lipophilic surfactants that contribute substantially to the dissolution of the drug are defined herein as “primary” solvents. However, it should be understood that solubility can be affected by the temperature of the solvent / formulation. For example, formulations of the present invention comprising about 20% testosterone undecanoate are still soluble above 30 ° C, including the range of 30 to about 40 ° C.

  A hydrophilic surfactant component may be required to achieve the desired formulation dispersion and drug release within the GI tract. That is, the hydrophilic surfactant may be required to release the drug from the lipid carrier matrix or primary solvent in addition to acting as a secondary solvent. In this regard, high HLB surfactants such as Cremophor RH40 may generally be sufficient. The level (amount) of high HLB surfactant can be adjusted to provide optimal drug release without compromising the solubilization of the active ingredient.

  Suitable lipophilic surfactants in the drug delivery system of the present invention include:

Fatty _(C 6 _{-C 24,} preferably _C 10 _{-C 24,} more preferably _C 14 _{-C 24} are), for example octanoic acid, decanoic 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 such as Imwitter 988 (glyceryl mono- / di-caprylate), Imwitter 742 (mono- / di-caprylic acid / glyceryl caprate), Imwitter 308 (glyceryl monocaprylate), Imwitor 191 (glyceryl monostearate), Softigen 701 (glyceryl mono- / di-ricinoleate), Capmul MCM (mono- / di-caprylic acid / glyceryl caprate), Capmul MCM (L) (liquid form of Capmul MCM) , Capmul GMO (glyceryl monooleate), Capmul GDL (glyceryl dilaurate), Maisine (glyceryl monolinoleate), Peceol (glyceryl monooleate), Myvero l 18-92 (monoglyceride distilled from sunflower oil), and Myverol 18-06 (monoglyceride distilled from hydrogenated soybean oil), Precirol ATO 5 (glyceryl palmitostearate) and Gelucire 39/01 (semi-synthetic glycerides) _{I.e. C12-18} mono-, di- and triglycerides). Preferred among this class of lipophilic surfactants are the partial glycerides of oleic acid, palmitic acid and stearic acid, and blends thereof.

  Acetic acid, succinic acid, lactic acid, citric acid, and / or tartaric acid esters of fatty acid mono- and / or di-glycerides such as Myvacet 9-45 (distilled acetylated monoglyceride), Miglyol 829 (caprylic acid / caprin succinate) Glyceryl acid (caprylic / capric diglycylyl succinate), Myverol SMG (mono- / di-succinylated monoglyceride), Imwitter 370 (glyceryl stearate citrate), Imwittor 375 (monostearic acid / citric acid / ro-glyceryl lactate 22) Diacetyl tartaric acid ester of monoglyceride).

  Propylene glycol mono- and / or di-esters of fatty acids such as Lauroglycol (propylene glycol monolaurate), Mirpyl (propylene glycol monomyristate), Captex 200 (dicaprylic acid / propylene glycol dicaprate), Miglyol 840 (dicaprylic acid / Propylene glycol dicaprate) and Neobee M-20 (dicaprylic acid / propylene glycol dicaprate).

  Polyglycerol esters of fatty acids, such as Plrol Oleique (polyglyceryl oleate), Caprol ET (fatty acids mixed with polyglyceryl) and Drewpol 10.10.10 (polyglyceryl oleate).

  Low ethoxylated amounts of castor oil ethoxylate (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).

  Acids formed by reacting ethylene oxide with fatty acids or fatty acid glycerol esters and ester ethoxylates (HLB <10) such as Crodet 04 (polyoxyethylene (4) lauric acid), Citrol 2MS (polyoxyethylene (2) stearin Acid), Marosol 183 (polyoxyethylene (3) stearic acid) and Marlowet G12DO (glyceryl dioleate 12EO). Sorbitan esters of fatty acids such as Span 20 (sorbitan monolaurate), Crill 1 (sorbitan monolaurate) and Crill 4 (sorbitan monooleate).

  Transesterification products of natural or hydrogenated vegetable oil glycerides and polyalkylene polyols (HLB <10), such as Labrafil M1944CS (polyoxyethylated apricot kernel oil), Labrafil M2125CS (polyoxyethylated corn oil) and Gelucire 37/06 (Polyoxyethylated hydrogenated coconut). Labrafil M1944CS is preferred.

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

Pluronic, such as polyoxyethylene-polyoxypropylene copolymer and block copolymer (HLB <10), such as Synperonic PE L42 (HLB = 8) and Synperonic PE L61 (HLB = 3),
Is mentioned.

  If desired, mixtures of suitable lipophilic surfactants such as those listed above may be used, and in some instances they are found to be advantageous.

  Any pharmaceutically acceptable hydrophilic surfactant (ie having an HLB value greater than 10) may be used in the present invention. Some non-limiting examples are:

  Castor oil or hydrogenated castor oil ethoxylate (HLB> 10), for example 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 glyceride), α-tocopherol-polyethylene glycol 1000-succinate (TPGS) and ascorbyl-6 palmitate. Cremophor RH40 is preferred.

  Polyoxyethylene sorbitan fatty acid derivatives such as 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, preferably Gelucire 50/13 (PEG mono- and di-esters of palmitic acid and stearic acid). (In relation to Gelucire, the first number (ie 50) corresponds to the melting point of the material and the second number (ie 13) corresponds to the HLB value.)

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

Alcohol ethoxylates (HLB> 10), such as 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 ether).

  Also known as polyoxyethylene-polyoxypropylene copolymer and block copolymer (HLB> 10) marketed under the tradename Pluronic or Poloxamer, for example, Syperonic PE L44 (HLB = 16) and Syperonic F127 (HLB = 22), respectively Poloxamer 188 and 407.

  Anionic surfactants such as sodium lauryl sulfate, sodium oleate and sodium dioctyl sulfosuccinate.

Alkylphenol surfactants (HLB> 10), such as Triton N-101 (polyoxyethylene (9-10) nonylphenol) and Synperonic NP9 (polyoxyethylene (9) nonylphenol),
Is mentioned.

  As mentioned, in one aspect of the invention, each component of the delivery system (ie, lipophilic and hydrophilic surfactant) has its own solvent properties and contributes in part to the solubilization of the active ingredient. To do. Thus, while not being bound or limited by theory, the present invention does not require additional solvents, such as co-solvents, which are optionally included in the systems and formulations of the present invention. Also good.

  Selective cosolvents suitable for the present invention include, for example, water, short chain monovalent, divalent, and polyhydric alcohols such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, average molecular weights of about 200 to about 10,000 polyethylene glycols, diethylene glycol monoethyl ether (eg, Transcutol HP), and combinations thereof. Preferably all such cosolvents, especially ethanol or monoethanols, are excluded.

Additional oils that can be incorporated into embodiments of the present invention include medium chain (C ₇ -C ₁₃ ) or long chain (C ₁₄ ) with low molecular weight (maximum C ₆ ) mono-, di-, and polyhydric alcohols. -C ₂₂₎ complete glycerol triesters of fatty acids. Some examples of oils used in the present invention include vegetable oils (eg, soybean oil, safflower seed oil, corn oil, olive oil, castor oil, cottonseed oil, peanut oil, sunflower seed oil, coconut oil, palm oil, rapeseed oil Primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond, borage, peppermint and apricot kernel oil), and tallow (eg fish liver oil, shark oil and mink oil).

  In other embodiments of the invention, (1) TU absorption, (2) TU to T metabolism, and / or (3) T to dihydrotestosterone (DHT) metabolism may be biochemically adjusted. Methods and compositions for adjusting (ie, sustaining) the proportion of usable serum testosterone by incorporating ingredients. For example, TU absorption can be enhanced by the inclusion of medium chain to long chain fatty acid esters. In this way, more TU may be prevented from hydrolyzing in the stomach and sent to the bloodstream. In other words, fatty acid esters can competitively inhibit esterases that metabolize TU in other ways. Examples of other esters or combinations thereof include plant extracts used as food additives or benign esters (eg, propylparaben, octyl acetate and ethyl acetate).

  Other components that can modulate TU absorption include “natural” and synthetic inhibitors of 5α-reductase, an enzyme that catalyzes the conversion of T to DHT, present in enterocytes or other tissues. Complete or partial inhibition of this conversion can both increase and persist in serum T levels after oral administration of TU and simultaneously decrease serum DHT levels. Borage oil containing a significant amount of the 5α-reductase inhibitor γ-linolenic acid (GLA) is an example of a “natural” regulator of TU metabolism. Of course, GLA other than borage oil can be added directly as another component of the TU formulation of the present invention. Many natural inhibitors of 5α-reductase are known in the art (eg, epigallocatechin gallate, which is a catechin primarily derived from green tea, and saw palmetto extract of saw palmetto berries), all of which are present. It may be suitable for the invention. Non-limiting examples of synthetic 5α-reductase inhibitors suitable for use in the present invention include compounds such as finasteride, dutasteride.

  The present invention contemplates the use of inhibitors of T metabolism through other mechanisms in addition to 5α-reductase inhibitors. One key point of such inhibition may be the cytochrome P450 isozyme CYP3A4, which is present in enterocytes and liver cells, and is thus capable of metabolizing testosterone. Accordingly, selected embodiments of the present invention include peppermint oils known to contain ingredients that can inhibit CYP3A4 activity.

  Still other optional ingredients that may be included in the compositions of the present invention are those conventionally used in oily drug delivery systems such as tocopherol, tocopherol acetate, ascorbic acid, butylhydroxytoluene (BHT), ascorbyl palmitate , Antioxidants such as butylhydroxyanisole and propyl gallate; pH stabilizers such as citric acid, tartaric acid, fumaric acid, acetic acid, glycine, arginine, lysine and potassium hydrogen phosphate; hydrogenated vegetable oils, beeswax, colloidal Thickeners / suspensions such as silicon dioxide, mannitol, gum, cellulose, silicate, bentonite; flavoring agents such as cherry, lemon, and anise fragrance; aspartame, acesulfame K, sucralose, saccharin and cyclamate Sweetener

  The inventor has learned that the relative proportions of one or more lipophilic surfactants and one or more hydrophilic surfactants can be essential to achieve the desired pharmacokinetics of the present invention. . More specifically, the inventor can not only solubilize relatively large amounts of T-ester (eg, greater than 15%, 18%, 20%, 22%, or 25%), but also from the formulation. A ratio of the total lipophilic surfactant to the total hydrophilic surfactant that can provide the optimal release of T-esters was discovered. Preferably the ratio of oil to hydrophilic surfactant (eg, oleic acid + borage oil + peppermint oil, all considered lipophilic surfactant) (w / w) is about 6: 1 to 1: 1, 6: 1 to 3: 1, 6: 1 to 3.5: 1, or 6: 1 to 4: 1, more preferably about 5: 1 to 3: 1, most preferably about 4: 1 to 3. : 1.

The following relative weight concentrations are preferred (percentage values are based on the total weight of the formulation):
Hydrophilic surfactant: 10-20%, more preferably 12-18%, most preferably 15-17%.
Lipophilic surfactant: 50-70%, more preferably 50-65%, most preferably 50-55%.
Other oils: 5-15%, more preferably 7-15%, most preferably 10-13%.
Drug: 10-30%, more preferably 15-25%, most preferably 18-22%.

  The formulation of the present invention is self-emulsifying and forms a fine emulsion when diluted with intestinal fluid in an aqueous medium or in vivo. In other words, the formulation may have a high content of surfactants and lipids designed to be optimally dispersed when mixed with an aqueous medium. A qualitative description of the self-emulsifying properties of the combination of the present invention can be visually observed when it is dissolved in vitro. On the other hand, quantitative measurements may be made on the particle size of the emulsified droplets utilizing laser light scattering and / or turbidity measurement in a dissolution medium with a UV / VIS spectrophotometer. Any of these methodologies are available and known to those skilled in the art.

  The pharmaceutical composition according to the invention is preferably liquid or semi-solid at ambient temperature. Furthermore, these pharmaceutical compositions are filled into hard capsules if they are converted to solid dosage forms by adsorption onto solid carrier particles such as silicon dioxide, calcium silicate or magnesium aluminometasilicate to obtain a free flowing powder. Or can be compressed into tablets. See, for example, US2003 / 0072798, the disclosure of which is incorporated herein by reference in its entirety. Thus, the term “solubilized” herein should be construed to describe an active pharmaceutical ingredient (API) dissolved in a liquid solution or evenly dispersed in a solid carrier. Sachet-type administration formulations can also be formed and used.

  The present invention preferably includes an API that is solubilized in the presence of a lipid surfactant excipient (eg, any combination of lipophilic surfactant and hydrophilic surfactant referred to above). Thus, the melting point of the surfactant used is one factor that can determine whether the resulting composition is liquid or semi-solid at ambient temperature. Particularly preferred compositions of the invention are liquid oral unit dosage formulations, more preferably filled into hard or soft capsules, such as gelatin or non-gelatin capsules such as those produced with cellulose, carrageenan or pullulan. Techniques for encapsulating liquid-based pharmaceutical preparations are well known to those skilled in the art. Since the delivery systems and formulations of the present invention described herein are not limited to one optional encapsulation method, the specific encapsulation technique need not be discussed further.

  Drug carrier systems and pharmaceutical preparations according to the present invention may be prepared by conventional techniques for liquid-based drug carrier systems. In a typical procedure for preparing the preferred carrier system of the present invention, the lipophilic surfactant component is weighed in a suitable stainless steel container and then the hydrophilic surfactant component is weighed to add any additional ingredients. Add to container together. In a preferred method, the hydrophobic drug may be added first to the lipophilic surfactant component (eg, oleic acid) and completely dissolved before adding the hydrophilic surfactant component. In any instance, use a homogenizing mixer or other high shear device, and use high temperatures to ensure that all ingredients are in a homogeneous liquid state before and after drug addition, especially with high melting point surfactants. Thus, mixing of the components may be performed.

  In the situation where the hydrophobic drug is metered and added to the batched liquid mixture, mixing is continued, preferably at an elevated temperature, until a homogeneous solution is prepared. The formulation may be degassed before encapsulating in either soft or hard capsules. In some instances, the filling formulation may be held at an elevated temperature using a suitable jacketed container to assist in processing. Also in some instances, the homogeneous solution may be filtered (eg, passed through a 5 micron filter) prior to filling the capsule.

  Turning now to testosterone delivery, the pharmaceutical composition of the present invention may be suitable for testosterone therapy. Testosterone is the main endogenous androgen in men. Leydig cells in the testis produce about 7 mg of testosterone per day with a serum concentration in the range of about 300 to about 1100 ng / dL. Women also synthesize testosterone in both the ovary and adrenal gland, but the amount is about one-tenth that observed in men with normal gonadal function. The majority (> 98%) of circulating testosterone is bound to globulin and albumin to which sex hormones bind, but is biologically active only when released in free form. That is, the term “free” is defined as not bound or encapsulated in, for example, a biomolecule, a cell and / or a lipid matrix of the inventive combination described herein. In general, a “free” drug as described herein refers to an drug that is accessible to metabolic enzymes circulating in the serum.

  While the present invention should not be limited to the delivery of testosterone or any particular ester thereof, TU has been found to present unique chemical and physical characteristics that make it suitable for use in some embodiments. It was done. In particular, the inventor has shown that testosterone undecanoate can produce better bioavailability than that found with other equivalent esters (eg, testosterone enanthate (TE)). Learned.

  Moreover, the use of TU in the combination of the present invention results in a substantially lower ratio of DHT to T in serum than reported in other forms of T supplementation methods (such as oral combination of TU). Related (Table 1). Testosterone interacts with the androgen receptor either directly or following conversion to DHT via the action of 5α-reductase. DHT is a more powerful androgen than testosterone, and some scientists believe that high levels increase the risk of prostate cancer. Thus, the present invention provides yet another unexpected advantage over other known testosterone delivery vehicles.

¹ Testosterone: Action, Specialty and Substitution (Nieschlag, E and Behr, HM, eds). Springer-Verlag, Berlin, pp. 365-388, Atkinson, LE, Chang, Y-L and Sinder, PJ. (1998) Long-term experience with testosterone replacement through skin skin.
² Swedloff, RS, et a (2000). Long-term pharmacokinetics of thermal testosterone gel in hypogonal men. J. et al. Clin. Endocrinol. Metab. 85: 4500-4510.
3 Wang, C et al (2004). Long-term testosterone gel (AndroGel (registered trademark) treatment mains benefits ef ent. Ed in med. And med. Ed.
4 Houwing, NS et al (2003). Pharmacokinetic study in three of the different doses of a new formation of oral testosterone undecanoate, Andrew Testocaps. Pharmcotherapy: 23: 1277-1265.
⁵ Gooren, LJG (1994). A ten-year safety study of the oral and testosterone undecanoate. J. et al. Androl. 15: 212-215.

  Specific embodiments of the invention will now be described in non-limiting examples. Table 2 shows the detailed composition of various TU formulations in accordance with the teachings of the present invention. When calculated, T1 mg corresponds to 1.58 mg of T-undecanoate.

  The detailed composition in Table 2 (mg / capsule, and weight%) is based on an approximate fill weight of 800 mg fill weight per No. 00 hard gelatin capsule. However, for testosterone ester amounts less than about 100 mg / capsule, the formulation is proportionally adjusted to a lower total fill weight to make smaller hard gelatin capsules (eg size 0 or less as needed) Can be used.

  It should be understood by those skilled in the art that many, if not all, of the classes (eg, lipophilic, hydrophilic, etc.) can be exchanged for another surfactant of the same class. . Thus, although Table 1 lists formulations containing oleic acid, those skilled in the art will recognize that other lipophilic surfactants (eg, those listed above) may be equally suitable. It is. Similarly, Table 1 lists formulations containing Cremophor RH40 (HLB = 13), although it will be appreciated by those skilled in the art that other hydrophilic surfactants (eg those listed above) may be suitable. Should be recognized. Borage oil, peppermint oil, BHT, and ascorbyl palmitate may be replaced or eliminated by chemically similar substances.

  Preferred TU formulation filled in 00 capsule according to the present invention:

  In vivo and in vitro performance data of the formulation as the invention is continued is described next. However, the scope of the present invention should not be limited to the specific formulations tested in the following examples or examples.

Example 1-1 Day Test Formulation B was tested for a daily pharmacokinetic profile with once or twice daily administration to men with gonadal dysfunction. The study was set up as an open-label, daily-dose sequential crossover pharmacokinetic study. Twelve men with gonadal dysfunction were registered after completing informed consent, and all 12 subjects completed the study. Each subject received a daily dose of Formulation B as follows.
1.1 200 mg T (as TU) by administration once daily, ie 2 capsules / dose 2.1 200 mg (100 mg / dose) T (as TU) by administration twice daily, ie 1 capsule / dose 3 400 mg (200 mg / dose) of T (as TU) by administration twice a day

  The dose was administered to the subject as a capsule 5 minutes after meals (breakfast if administered once daily, breakfast and dinner if administered twice daily). Table 3 shows the relevant PK parameters of the test:

Mean serum T concentrations (C _avg ) 24 hours after dosing showed a positive increase in serum T levels with all regimens tested, with the best response obtained with regimen 3 (C _avg 385 ng / dL). The average peak serum T concentration observed in response to oral T ester preparations evaluated in this study did not exceed the upper limit of normal (ie, 1100 ng / dL). And some subjects had C _max T values above the upper limit of normal values, but most of these peak values were in the range of 1200-1400 ng / dL. None of the subjects in any treatment group produced a C _max greater than 1500 ng / dL.

Mean serum T half-life (T _1/2 ) was approximately 15 hours for regimens 1 and 2, and for regimen 3, T _1/2 was 8 hours. In each regimen, serum DHT concentrations increased in concert with serum T levels. The average DHT: T ratio (R _avg ) for all periods is slightly above the normal range (ie 0.03-0.1) as measured by liquid chromatography and mass spectrometry (LC / MS / MS) But not clinically significant

TU administered at 200 mg twice daily with food as a T equivalent produced the most promising results in 75% of subjects with serum T C _avg exceeding 300 ng / dL (low normal gonadal function) Reached. Similarly, 75% of subjects reached mean serum T within the normal range (ie 0.03-0.1 ng / dL). All subjects who did not reach C _avg of at least 300 ng / dL exceeded 200 ng / dL, indicating that a slight increase in TU dose has become an effective oral T replacement therapy in these subjects.

  Collecting data for baseline serum T showed a coordinated increase in serum T and DHT concentrations in the majority of subjects, regardless of the dose of T-ester that showed excellent dose linearity with oral TU. Observed. Although the DHT: T ratio increased slightly, neither increase was considered clinically significant. Less subject-to-subject variability was observed with that formulation than other T-ester (eg, TE) equivalent formulations. Furthermore, with the “twice daily” dosing regimen, there was no difference in mean peak serum T concentration or 12 hour AUC between morning and evening dosing.

  Regarding safety, headaches were reported as adverse effects in each treatment regimen, but no adverse events were reported from more than one subject. No serious adverse events or deaths occurred during this study, and no subject discontinued the study early due to adverse events. All adverse events were considered mild.

Example 2-7 Days Test Formulation B was tested for two doses of acute tolerability and steady state serum pharmacokinetic profile administered twice daily to men with gonadal dysfunction. The study was set up as an open-label repeated dose crossover pharmacokinetic study (meal effects were studied in one group).

Twenty-nine men with gonadal dysfunction were enrolled after completing informed consent, 24 of which completed the study. Each subject who completed the study received the formulation B regimen as follows.
1. T600 mg (300 mg / dose) as a TU when administered twice a day, ie, 3 capsules / dose for 7 days, 2.1 days T400 mg (200 mg / dose) as a TU, administered twice a day for 8 days Administration

  The dose was administered as a capsule to the subject 30 minutes after the start of the meal (breakfast and dinner), but only on the 8th day in the morning.

The peak exposure to T (C _max ) and total exposure to T (AUC) were proportional doses after calibration with respect to the endogenous baseline T. The time of peak T concentration (T _max ) occurred approximately 4 hours after each treatment dose. It should be noted that the serum concentrations of both TU and DHTU rise and fall within the dosing interval, with concentrations at the beginning and end of the dosing interval being less than 20% of the peak concentration for TU and 25% of the peak concentration for DHTU. Was less than. Baseline T concentrations due to endogenous T production decreased gradually with each treatment. That observation was consistent with the gradual and sustained suppression of gonadotropin by exogenous T, thereby reducing endogenous T production. At least some suppression persisted for a 14 day drug holiday.

Similarly, serum T pharmacokinetics showed no diurnal variation in serum T concentration. Night dosing (approximately 8 pm dosing) produced a concentration-time profile similar to morning dosing (approximately 8 am dosing) (FIG. 1). Due to the similarity between post-morning and post-concentration concentrations (assessed with regimen 1), T (T ) Accurately predicted the full 24-hour PK profile in response to 200 mg. From the simulated results, (a) in 77% of subjects, serum T C _avg over 24 hours reached the normal gonadal function range based on AUC, thereby 75% of the current FDA efficacy requirements for T supplementation products It matched that, and (b) subject also _{C max} is one does not exceed 1500 ng / dL, greater than the current FDA standards of "less than 85% of the target results in a _{C max} of greater than 1500 ng / dL at T supplemented products" It was shown that. Thus, consistent with current FDA-designated efficacy endpoints, none of the subjects had a C _max greater than 2500 ng / dL, and less than 5% of subjects tested were within the range of 1800-2500 ng / dL. C _max of It is noteworthy that these results were achieved without any dose adjustment.

  Table 4 shows a comparison of T morning and afternoon steady state pharmacokinetics with twice daily dosing:

When TU was administered with a high fat diet, it produced a serum T concentration-time profile similar to that administered with a standard diet. In contrast, administration of TU under fasting conditions decreased serum T exposure (C _max and AUC) by more than 50% (Table 5). In all cases, a strong correlation was observed and C _avg calculated and observed C _max, when the specific C _avg in oral T ester formulations targeting, result in predictable peak T levels after administration It was suggested that

  The DHT concentration was only 11-34% of the T concentration, but the DHT concentration followed the T concentration. The conversion from T to DHT showed a slight non-linearity and increased less than the concentration proportionality compared to T. The DHT / T ratio is minimized when the T concentration is highest, the DHT / T ratio before the start of TU treatment is approximately 0.1, the average ratio at steady state during the treatment is 0.24, and oral TU Depending on the collection time after administration, was in the range of approximately 0.1 to 0.35.

  Prior to the start of oral TU treatment, the average estradiol concentration was approximately 11 pg / mL, and the 7th day of various treatments was in the range of 19 pg / mL to 33 pg / mL (pre-dose concentration). The steady state estradiol concentration prior to administration was approximately 20-30 pg / mL.

Example 3-4 Week Study Steady state is reached when Formulation B is treated twice a day with 200 mg of T (as TU) (ie 2 capsules / dose) for men with gonadal dysfunction. A test was also conducted to determine the time required for the test. The study was set up as an open-label repeated dose pharmacokinetic study.

  Fifteen men with gonadal dysfunction were registered after completing informed consent and all subjects completed the study. Each subject received T200 mg as a TU twice daily for 28 days.

  For each subject, a series of “Day 28” PK collection dates were planned for Day 32 of the study. Therefore, each subject responding to administration was administered T400 mg as TU (ie, T200 mg twice a day) for a total of 31 days, with the last morning dose being T200 mg as TU. Subjects who were instructed to administer 30 minutes after the start of the meal (breakfast and dinner) received the dose as a capsule.

  Table 6 shows the relevant PK data for the study:

86.7% of subjects reach serum T C _avg within the normal range, no subject has a C _max concentration greater than 1800 ng / dL, and 13.3 percent of subjects have a C _max concentration greater than 1500 ng / dL. %. (Note: During this study, no dose adjustment was made to determine the subject's dose within the targeted efficacy and safety range.) Responds to TU in the tested formulation The half-life of T was clearly longer than reported for single T or TU administered orally in prior art formulations. For example, as described herein, compared to values estimated to be approximately half based on published serum T profiles after oral administration of prior art TU formulations (ie, 2-3 hours). In a clinical trial of an oral TU combination consistent with the present invention, an elimination half-life (alpha phase) of approximately 5 hours was observed. A long elimination (ie terminal) half-life of 29 hours was also observed with the oral TU formulation of the present invention. However, endogenous T production was suppressed by exogenous T administration, with only limited suppression occurring in the first 3 days, and 5-7 days of continuous treatment were required to produce maximal suppression.

  T and DHT concentrations reached steady state on day 7 of treatment. The concentration of T and DHT is greater on day 3 than on day 5, so that the exogenously administered T suppresses endogenous T, thereby achieving a steady state response to oral TU. It indicates that a certain period of time was required. In fact, the addition of exogenous T suppressed endogenous T levels from 276 ng / dL before treatment to 108 ng / dL 28 days after inhibitory T treatment.

Importantly, however, when serum T reaches a steady state in response to twice-daily oral TU, it is observed that the response of serum T decreases little or not over time. (Ie, there was no tendency for serum T levels to decrease with continuous TU administration). For example, C _avg on day 15 was substantially similar to C _avg observed on day 28 (FIG. 2). In contrast, oral TU formulations in the art have been reported to tend to lower average T over time (Cantrill, JA Clinical Endocrinol (1984) 21: 97-107). . In gonadal dysfunctional men treated with a combination of oral TUs known to those skilled in the art, the serum T response observed after 4 weeks of treatment is greater than the response observed on the first day of treatment of gonadal dysfunctional men. About 30% lower, most of which have a form of primary gonadal dysfunction, i.e. low baseline levels of serum T (e.g. less than 100 ng / dL), thus reducing T with only suppression of endogenous T I can't explain it.

  Serum DHT concentrations closely followed T concentrations, with DHT and DHT / T values rising 4-7 fold during treatment. The average DHT / T ratio at the 12 hour dosing interval was 0.245, but the value at the dosing interval was within the range of the average maximum ratio 0.380 to the average minimum ratio 0.131. Within 36 hours of discontinuing treatment with oral TU, DHT concentrations returned to pre-treatment levels. However, the T concentration did not rapidly return to the pre-treatment level because the appearance did not quickly recover the inhibition of endogenous T production / release.

Estradiol (E2) concentration was shown to increase monotonically until steady state reached on the seventh day of treatment. E2 concentration also showed a systematic variation that followed a change in T at the dosing interval. The mean C _max , C _avg , and C _min values for E2 were 30.6 pg / mL, 22.0 pg / mL, and 15.5 pg / mL, respectively. The E2 concentration returned to pre-treatment levels within 36 hours after cessation of oral TU treatment.

The mean C _max , C _avg , and C _min concentrations at T steady state (morning on day 28) were 995 ng / dL, 516 ng / dL and 199 ng / dL, respectively. The median T _max of T occurred 5.0 hours after administration. C _min was 23.5% of C _{max on} average, and a coefficient of variation of 156% was obtained. The elimination half-life of T could be assessed in only about half of the subjects and the median of their controls was 18.4 hours (mean T _1/2 was 29 hours).

Example 4-Food Effect Test The effects of dietary fat on the pharmacokinetics of Formulation B in gonadal dysfunction men were tested in an open-label, two-center, five-way crossover test. After a 4-10 day washout period, a single dose of T300 mg (TU475 mg, 3 capsules of Formulation B), serum baseline T levels of 205.5 ± 25.3 ng / dL (mean ± SE, range 23 16 men with gonadal dysfunction (˜334.1 ng / dL). Subjects randomized, fasted, or a specific amount of fat (% by weight): very low fat (6-10%); low fat (20%); “normal” dietary fat (30%); Alternatively, the drug was administered 30 minutes after eating a high fat (50%) and containing about 800 calories. The “normal” diet was a priori established as a comparator (ie, reference diet) for statistical comparison purposes. A series of blood samples were taken during a total of 24 hours after drug administration and serum testosterone and dihydrotestosterone (DHT) levels were measured by liquid chromatography and mass spectrometry (LC / MS / MS).

  The observed pharmacokinetic parameters for serum T in response to a single high dose of oral TU (Table 7, FIGS. 3-5) are similar to low and normal fat diets (actually almost biological Equivalence) was found (ie, 90% confidence interval was 85-125%). Similar serum T PK parameters were also observed when comparing normal and high fat diets. And although a higher serum T response was obtained with the high fat diet (although there was no statistical difference), the mean ratio of the least squares method entered 70-143% when compared to the normal fat diet ( Less than 30% clinically insignificant difference).

The variation in PK response appeared to be highest after the first dose of oral TU, or after several doses after the start, and decreased with continued treatment. In conclusion, any effect of dietary fat varied from low to normal to high on serum T PK parameters may not be significant during chronic administration. This stance is consistent with the findings of PK obtained from the 7-day treatment (Example 2) and the findings of PK obtained from the 30-day treatment (Example 3), and are different in repeated dose studies of oral TU. PK under dietary conditions showed similar results for C _mac and C _avg distributions [both studies received 200 mg T (as TU) twice daily].

  Statistical comparisons of serum T responses observed after oral TU can be performed without meals or with a very low fat diet, a low fat diet, or a high fat diet vs. a normal fat diet (ie, a reference diet) It was found that there was no statistically significant difference of p <0.05 level between low fat diet or high fat diet vs. normal fat diet. In contrast, administration of oral TU as a SEDDS combination with fasting or with a very low fat breakfast resulted in a significant difference (ie, reduction) in serum T PK parameters relative to the normal diet. Accordingly, the amount of dietary fat taken with the combination of the present invention may not have a clinically significant effect on the resulting T level, while being substantially different from “normal”. In other words, the patient can tolerate the flexibility of dietary habits that differ depending on the meal and the date of intake, which has not been possible with conventional known oral TU formulations. So far, oral TU formulations known in the art have not been able to achieve any meaningful serum T level in the fasted state.

Example 5 In Vitro Dissolution Test A dissolution test of the combination of the present invention was performed in vitro to evaluate the correlation with the PK profile observed in vivo. In the first test, dissolution of Formulation B was tested. Andriol Testocaps® (TU 40 mg per softgel dissolved in a mixture of castor oil and propylene glycol laurate) was included for comparison. The test was carried out with essentially the same dose of TU, namely Formulation B 1 capsule (158.3 mg TU) and 4 Testocaps softgels (40 mg × 4 = 160 mg TU). Dissolution (ie, the release of TU from each formulation) was tested in a Fed State Simulated Intestinal Fluid (FeSSIF) medium that simulated meal-stimulated intestinal fluid. FeSSIF contains sodium hydroxide, glacial acetic acid, potassium chloride, lecithin, and sodium taurocholate. The final emulsion is adjusted to pH 5.0.

  Data are presented in Tables 8 and 9, with the formulation of the present invention releasing approximately 40% TU within the first 30 minutes and releasing approximately 60% of the total capsule after 4 hours. However, with Testocap®, there is little or no drug release (1%) during the entire 4 hours. The observed main difference in TU dissolution with these two formulations may be due at least in part to the presence of a hydrophilic surfactant in formulation B, such as Cremophor RH40. In contrast, Andriol Testocaps® incorporates only oil (castor oil) and lipophilic surfactant (propylene glycol laurate).

  In the second test, Formulation A was used in the same assay except that 5% Triton X100 potassium phosphate buffer (pH 6.8) was used as the dissolution medium. The results are shown in Table 10 below. In this test, 98% of the TU with the combination of the present invention was released within the first 15 minutes of dissolution, and again the presence of the hydrophilic surfactant Cremophor RH40 ensures this rapid dissolution and TU release. Promoted.

  In yet another embodiment of the present invention, the pharmaceutical compositions disclosed herein may also be suitable for ameliorating some of the side effects of certain male contraceptive strategies. For example, progestin-based male contraception substantially suppresses luteinizing hormone (LH) and follicle stimulating hormone (FSH), thereby suppressing spermatogenesis and clinical azoospermia (2 months of sperm count) Mean that it is less than about 1 million / mL semen). However, the administration of progestin also has the undesirable side effect of significantly reducing steady state serum testosterone levels.

  In such situations, it may be preferable to provide, for example, a progestin preparation simultaneously with testosterone or a testosterone derivative (eg, TU). More preferably, a pharmaceutical preparation according to the present invention comprising progestin (in an amount sufficient to substantially suppress LH and FSH production) in combination with testosterone is provided. In some embodiments, the pharmaceutical preparation is for once daily oral delivery.

  The combination of the present invention can provide a long-release combination that can deliver testosterone to the serum over several hours. Indeed, the half-life of serum testosterone according to the invention is 3-7 hours, preferably more than 4, 5, or 6 hours. In contrast, serum testosterone half-life in men is considered within the range of 10-100 minutes.

  While not being bound or limited by theory, it is believed that the combination of the present invention, in one aspect, achieves these results by enhancing drug absorption by the intestinal lymph system rather than portal circulation. In another embodiment, which is also not bound or limited by theory, it is believed that by using an ester of testosterone, the time required to cause ester degradation contributes to a longer T half-life.

  Oral administration of the present invention can maintain desired serum testosterone levels when performed by a patient in need of about one testosterone therapy about every 12 hours. In a more preferred embodiment, oral administration is performed by a patient in need of testosterone therapy about once every 24 hours. In general, “desired” testosterone levels are those levels found in human subjects characterized by having no testosterone deficiency.

  While the invention has been described in connection with specific embodiments, it will be understood that further modifications are possible and this application is intended to include any variations, uses, or modifications used by the invention. In general, the principles of the invention and known or routine practice in the technical field to which the invention belongs may be applied to the essential features previously presented herein, and may be In accordance with the scope, including deviations from the present disclosure.

Claims (26)

  At least one lipophilic surfactant and at least one, wherein the ratio of the total lipophilic surfactant to the total hydrophilic surfactant (w / w) falls within the range of about 6: 1 to 3.5: 1; Steady state average serum comprising testosterone undecanoate solubilized in a carrier comprising a species of hydrophilic surfactant and falling within the range of about 300 to about 1100 ng / dL by oral administration once or twice daily An oral pharmaceutical composition that provides testosterone concentrations. 2. The pharmaceutical composition according to claim 1 which provides a C _max not exceeding 2500 ng / dL when administered with a meal. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides a C _max not exceeding 1800 ng / dL when administered with a meal. 2. A pharmaceutical composition according to claim 1 which provides a C _max not exceeding 1500 ng / dL when administered with a meal.   The oral pharmaceutical composition according to claim 1, wherein the at least one hydrophilic surfactant comprises Cremophor RH40 (polyoxyethylene glycerol trihydroxystearate).   The oral pharmaceutical composition according to claim 1, wherein the at least one lipophilic surfactant comprises oleic acid.   2. An oral pharmaceutical composition according to claim 1 comprising 18-22% by weight solubilized testosterone undecanoate.   The oral pharmaceutical composition according to claim 7, wherein the testosterone undecanoate is solubilized in a carrier substantially free of ethanol.   The oral pharmaceutical composition according to claim 1, comprising 15 to 17% by weight of at least one hydrophilic surfactant.   The oral pharmaceutical composition according to claim 1, comprising 50 to 55% by weight of at least one lipophilic surfactant. One or more daily doses to a subject having testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant, or having gonad dysfunction or symptoms thereof A testosterone undecanoate that provides a steady state mean serum testosterone concentration that falls within the range of about 300 to about 1100 ng / dL, while avoiding the appearance of C _max values above 2500 ng / dL by two oral administrations. Administration formulation. 12. A dosage formulation according to claim 11, avoiding the appearance of _Cmax values above 1800 ng / dL. 12. A dosage formulation according to claim 11, avoiding the appearance of _Cmax values above 1500 ng / dL.   Testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant, ranging from as little as 20% to as much as 50% by weight. A pharmaceutical composition that provides an average serum testosterone concentration that is not statistically significant by oral administration with a diet having a fat mass as observed by oral administration with a diet having a fat mass of about 30% by weight.   At least one lipophilic surfactant and at least one, wherein the ratio of the total lipophilic surfactant to the total hydrophilic surfactant (w / w) falls within the range of about 6: 1 to 3.5: 1; Serum testosterone rapid phase half-life of about 5 hours and about 29 hours of serum testosterone by oral administration once or twice daily, comprising testosterone undecanoate solubilized in a carrier comprising a species of hydrophilic surfactant A pharmaceutical composition that provides a terminal half-life.   At least one lipophilic surfactant and at least one, wherein the ratio of the total lipophilic surfactant to the total hydrophilic surfactant (w / w) falls within the range of about 6: 1 to 3.5: 1; 30 days of daily treatment regimen by oral administration once or twice daily to a subject comprising testosterone deficiency or symptoms thereof, comprising testosterone undecanoate solubilized in a carrier comprising a species of hydrophilic surfactant In the eye, a pharmaceutical composition that provides a mean serum testosterone concentration that is substantially identical to that observed on day 7.   17. The pharmaceutical composition of claim 16, wherein the mean serum testosterone concentration obtained on day 30 of the daily treatment regimen is substantially the same as that observed on day 60.   At least one lipophilic surfactant and at least one, wherein the ratio of the total lipophilic surfactant to the total hydrophilic surfactant (w / w) falls within the range of about 6: 1 to 3.5: 1; Effect of a pharmaceutical composition comprising testosterone undecanoate solubilized in a carrier comprising a species of hydrophilic surfactant and providing a steady state average serum testosterone concentration falling within the range of about 300 to about 1100 ng / dL A method of treating testosterone deficiency or a symptom thereof, comprising orally administering an appropriate amount to a subject having testosterone deficiency or a symptom thereof.   The method of claim 18, wherein the composition is administered once a day.   The method of claim 18, wherein the composition is administered twice daily. The method of claim 18, wherein the method produces a C _max value that falls within a range of about 900-1100 ng / dL.   19. The method of claim 18, wherein the composition is administered with a meal comprising at least 20% by weight fat.   19. The method of claim 18, wherein the method does not substantially produce daytime testosterone pharmacokinetic variation. 19. The method of claim 18, wherein said method produces a mean serum T _max that falls in the range of about 3-7 hours after oral administration. 25. The method of claim 24, wherein the mean serum _Tmax falls in the range of about 4-5 hours after oral administration.   19. The method of claim 18, wherein no substantially significant drop in steady state serum testosterone response is observed upon repeated administration.