WO2016105465A1 - Oral compositions for insoluble compounds - Google Patents

Abstract

Described herein are compositions and methods for testosterone replacement therapy (TRT) concerning gelcap dosage forms containing lipid-dissolved testosterone that form micelles when in contact with an aqueous medium.

Description

ORAL COMPOSITIONS FOR INSOLUBLE COMPOUNDS

FIELD OF THE INVENTION

[001] The present invention concerns compositions for oral administration of insoluble drug compounds, such as steroid hormones, and dosage forms, delivery systems and methods of using and preparing the same. In particular, the compositions and delivery systems comprise one or more hydrophobic steroid hormone, one or more lipid solubilizers and, optionally, one or more surfactant, wherein the composition forms micelles when contacting or being exposed to an aqueous environment.

BACKGROUND

[002] Hormone replacement therapy (HRT) can present challenges due to the characteristics of the hormone and preferred routes of administration for increasing patient compliance or reducing unintended side effects. Delivery of hormones to a patient by injection, or by transmucosal or transdermal routes can present undesired results that may be overcome by oral administration. However, oral administration of hormones can present a "first-pass effect" whereby the hormone is first metabolized in the gut and/or liver before distribution in systemic circulation. This metabolism of the hormone can significantly reduce the bioavailability of the hormone and require administration of higher doses to reach desired therapeutic levels.

[003] In addition, in the case of hormones or water-insoluble drugs, oral administration can require modification of the active pharmaceutical ingredient (API), such as formation of salts or esters of the API, to increase solubility of the API. Moreover, currently available orally administered hormone compositions can exhibit a "food effect," with poor absorption when taken while fasting or with a low fat meal. Absorption is improved when taken with fatty foods due in part to the presence of bile salts released in the stomach to aid absorption of lipids (such as omega-3 fatty acids) and drugs which are dissolved in a lipid or mixture of lipids.

[004] Compositions having high amounts of omega-3 fatty acid esters, however, can have practical limitations due to undesirable side effects. For example, oxidative degradation of omega-3 fatty acid esters can result in indigestion or an unpleasant aftertaste following administration, especially when consumed in large quantities. These side effects associated with the administration of omega-3 fatty acid ester-containing compositions are known to significantly reduce patient compliance.

[005] Thus, there is a need for improved compositions that are less susceptible to food effect and which attain high bioavailability and efficacy at lower doses and with minimal side effects or undesirable properties that may reduce patient compliance. Specifically, there is a need for delivery systems to administer steroid hormones for medicinal indications with favorable pharmacokinetics that foster increased patient compliance and/or provide increased patient comfort during administration. Ideally, orally delivered hormone compositions that significantly reduce or eliminate a food effect can provide acceptable bioavailability at relatively lower doses and thereby improve patient compliance, which can lead to more effective and efficient treatment of the target condition or disease.

[006] One such target condition or disease is hypogonadism. Hypogonadism refers to diminished functional activity of the testes in males and ovaries in females. Hypogonadism resulting from defects of the gonads is traditionally referred to as primary hypogonadism, whereas hypogonadism resulting from hypothalamic or pituitary defects are termed secondary hypogonadism. Endogenous androgens, including testosterone (T) and dihydrotestosterone (DHT)> are responsible for the normal growth and development of the male sex organs, and for the maintenance of secondary sex characteristics. Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations in association with accompanying signs and symptoms, such as decreased sexual desire, regression of secondary sexual characteristics, fatigue, changes in mood, changes in body fat and lean body mass, and osteoporosis.

[007] Another treatment population is aging men who have low serum testosterone concentrations for no apparent reason other than age, and who experience non-specific symptoms of aging that overlap with those of classic hypogonadism. Serum concentrations of testosterone decrease as men age. Testosterone concentrations can fall below the lower limit of the normal range (about 300-1200 ng/dL). This phenomenon is sometimes referred to as "andropause," "age-related hypogonadism," or simply, "Low-T." Low or absent serum testosterone concentrations due to hypogonadism can be successfully restored with exogenous testosterone replacement therapy (T T).

[008] TRT for male hypogonadism is currently available in the United States using testosterone in a number of formulations, including: topical gels (for example, AndroGel 1% and 1.62%, Testim, Fortesta, and others), a topical solution (Axiron), a transdermal system (Androderm), a buccal system (Striant), an intranasal gel (Natesto), intramuscular injections (testosterone enanthate, testosterone cypionate, and testosterone undecanoate), oral methyltestosterone, and subcutaneously implanted pellets (Testopel). Each of these current therapies has its own disadvantages associated with it. For example, topical formulations are inconvenient and risk unintended transference. Modified forms of testosterone, such as the esters (e.g., testosterone undecanoate), are used in place of the endogenous form of testosterone to facilitate solubility of the hormone, but may require higher doses to reach therapeutic levels.

[009] "Bio-identical" or "natural hormones" (as opposed to synthetic or esterified forms of the hormone), are identical in chemical structure to the hormones naturally produced by the human body, and are preferred for hormone replacement therapy, including TRT. Bio- identical testosterone is available in FDA-approved products. However, no FDA-approved oral product containing bio-identical testosterone currently exists on the market.

SUMMARY OF THE INVENTION

[0010] According to various embodiments of the disclosure, natural or bio-identical testosterone replacement therapy (TRT) is provided comprising delivery via orally administered pharmaceutical formulations comprising solubilized testosterone. Various examples of formulations comprising bio-identical testosterone, and the use of these formulations for testosterone replacement therapy in accordance with the invention are set forth herein.

[0011] In a preferred embodiment, the subject invention concerns compositions comprising bio-identical testosterone dissolved or solubilized in a lipid solvent or lipid solubilizer, e.g., mono-, di-, or tri-glyceride esters of caprylic (octanoic) acid or capric (decanoic) acid, or a mixture thereof. Alternatively, the bio-identical testosterone can be dissolved or solubilized in propylene glycol caprylate. The lipid solvent generally comprises about 200 milligrams/gram (mg/G) to about 999 mg/G of the total composition, preferably about 500 mg/G to about 900 mg/G, more preferably about 600 mg/G to about 875 mg/G, and most preferably approximately 650 ± 20 mg/G, 750 ± 20 mg/G, or 850 ± 20 mg/G of the composition.

[0012] In certain embodiments provided herein, the compositions are free of free fatty acids (FFAs) and may be referred to as "non-free fatty acid" formulations or compositions or "FFA- free" formulations or compositions.

[0013] In an alternative embodiment, the compositions of the subject invention can comprise at least one free fatty acid.

[0014] The composition can also comprise one or more co-solvents, such as propylene glycol. When present, the co-solvent can be provided at a range of about 50-100 mg/G of the composition. One embodiment comprises between about 80-90 mg/G of the composition, and more preferably about 85.7 mg/G of the composition.

[0015] In a preferred embodiment, the composition can comprise one or more surface acting agent or a mixture of surface acting agents, e.g., an emulsifier or surfactant, such as Kolliphor, Poloxamer, or TPGS-1000, at a ratio ranging from about 1:1 to about 1:10 of surface acting agent:lipid solubilizer. Preferably, the ratio of surface acting agent:lipid solubilizer is about 1:2 to about 1:9, and more preferably about 1:3.

[0016] The testosterone used as the active pharmaceutical ingredient (API) in the composition is preferably a bio-identical testosterone. More preferably, the bio-identical testosterone is micronized, e.g., comprising particle sizes in the range of about 0.1 microns to about 100 microns in diameter, preferably an average or mean particle size of less than about 50 microns in diameter, more preferably less than about 25 microns, and most preferably not more than (nmt) about 15 microns in diameter.

[0017] In the subject compositions, testosterone can be solubilized and provided at a concentration of about 0.1 to about 100 mg/G of the total composition weight, preferably from about 10 to about 75 mg/G, and more preferably between about 25 mg/G and about 50 mg/G of the composition. One preferred formulation comprises a total dose of about 50 mg of native testosterone. Preliminary sample formulations having slightly lower amounts of testosterone and exhibited complete solubility of the testosterone in the sample formulation. Certain sample formulations comprise about 47 to about 48 (for example, 47.6) mg/G of testosterone in the total composition.

[0018] One embodiment comprises between about 50 mg/G to about 100 mg/G of testosterone, and preferably about 70 mg/G of testosterone based on the total weight of the composition. Preliminary sample formulations comprising about 70 mg/G of testosterone based on the total weight of the composition exhibited complete solubility of the testosterone API in the sample formulation.

[0019] Expressed relative to its solubility, the amount of testosterone is preferably provided in the composition at about 70% to about 90%, preferably about 80% of the solubility saturation level of the hormone in the lipid solubilizer or lipid solubilizer/surfactant composition.

[0020] The composition can further comprise at least one emulsifier, such as a polysorbate, e.g., polyoxyethylene sorbitan monoleate, which is known as Polysorbate 80. In a preferred embodiment, the emulsifier is provided at a concentration of about 1.0 to about 200 mg/G of the total composition weight, preferably from about 5.0 to about 150 mg/G, and more preferably between about 45 mg G and about 145 mg/G of the composition. For example, certain embodiments of the compositions of the subject invention comprise about 47-48 mg emulsifier/G of the composition (actual: 47.6 mg/G); other compositions comprise between about 90-100 mg/G (actual: 95.2 mg/G); and still others comprise between 145-150 mg/G (actual: 142.9 mg/G) of the composition.

[0021] The composition can also comprise an ionic or nonionic surfactant. Preferably, the surfactant is nonionic, e.g., a poloxamer, castor oil or a polyethoxylated castor oil, or tocopherol polyethylene glycol succinate (TPGS), referred to as Vitamin E TPGS or TPGS 1000. The surfactant is generally provided at a 1:1 ratio with the emulsifier, but can range from 1:5 to about 5:1 surfactant:emulsifier. Thus, in a preferred embodiment, the surfactant is provided at a concentration of about 1.0 to about 200 mg/G of the total composition weight, preferably from about 5.0 to about 150 mg/G, and more preferably between about 45 mg/G and about 145 mg/G of the composition. For example, certain embodiments of the compositions of the subject invention comprise about 47-48 mg surfactant/G of the composition (one embodiment: 47.6 mg/G); other compositions comprise between about 90-100 mg/G (one embodiment: 95.2 mg/G); and still others comprise between 145-150 mg/G (one embodiment: 142.9 mg/G) of the composition.

[0022] The testosterone composition, comprising a lipid solubilizer with or without a co- solvent, and optionally, one or more surface acting agent, or combinations thereof, form a liquid or gel composition which can be filled into a gelatin capsule for administration as an oral dosage form. The liquid or gel composition, or "fill," comprising testosterone solubilized in a lipid or oil, which is filled into a gelatin capsule to provide a gelcap dosage form, can advantageously provide good solubility for a water-insoluble active pharmaceutical ingredient (API), such as the steroid hormone, testosterone, providing concentrations of solubilized testosterone ranging from about 2% to about 10% testosterone, preferably about 3% to about 5% testosterone, and more preferably about 4.76% testosterone. [0023] One advantage of the subject composition can include spontaneous formation of micelles (self-micellization) upon introduction to an aqueous environment or medium, such as gastric juice or intestinal fluid. Formation of micelles can be advantageous in that the API is delivered to the bloodstream effectively and efficiently, whereby the bioavailability of the API is increased, without or substantially free or independent of food effect and without or substantially free or independent of a first-pass effect.

[0024] Micelles are distinguished from liposomes in that a micelle is a single-layer lipid vesicle, whereas liposomes are a double-layer lipid vesicle. Micelles dissolve into and become part of the lipid lining of the gut and thereby directly deliver the dissolved API to the bloodstream. The subject composition is micellar-forming and is not liposome-forming, i.e., is a non-liposome-forming composition. Micelles formed by the subject composition range in size from about 1 micron to about 10 microns in size and are relatively uniform, having a median size of less than about 5 microns, and preferably about 2-3 microns ± about 0.5 microns.

[0025] For purposes of illustration, a particle size analysis can be conducted by using the Beckman Device. A sample API comprising micronized testosterone in accordance with various embodiments can be provided for analysis. Approximately 0.01 g of a sample API in accordance with various embodiments would be combined with Coulter IB and 10 mL of deionized water. Sonication is performed for 15 seconds. The Beckman Device, equipped with a ULM, performs analysis for 90 seconds. The Beckman Device is configured to use the Fraunhofer optical model. The Beckman Device yields that a sample has an X50, an X75 and X25 particle size, for example, X50 of of 4.279 microns, an X75 of 7.442 microns, and an X25 of 1.590 microns. The Beckman Device also yields a mean particle size, e.g., 4.975 microns, a median particle size, e.g., 4.279 microns, and a mode particle size, e.g., 6.453 microns, with a standard deviation, e.g., 3.956 microns. A graphic depiction of an exemplary particle distribution obtained is shown in FIG. 1.

[0026] Micelles can provide advantageous absorption through the intestinal wall of an animal. However, an absorption enhancing agent, such as Poloxamer or TGPS 100 can also be included in the formulation of the composition. TPGS, being a complex of or having a Vitamin E component, can further provide stabilizing or antioxidant properties to the composition.

[0027] The subject invention further comprises a dosage form, such as a gelatin capsule for oral administration, containing a composition comprising a therapeutically effective amount of bio-identical testosterone as described, and a method for treating a condition or symptom resulting from primary or secondary hypogonadism or "low T." A method of treating hypogonadism according to the subject invention comprises administering to a patient in need of treatment of hypogonadism, one or more dosage form comprising a composition as described. The one or more dosage form can be administered from one to four times per day (QD, BID, TID or QID).

[0028] A method of the invention comprises administering a therapeutically effective dose of bio-identical testosterone in a composition or dosage form as described for the subject invention, which can provide a level of testosterone within the normal limits, e.g., a blood serum or plasma concentration between about 300 ng/dL to about 1200 ng/dL of testosterone.

[0029] Frequently, higher recommended oral dosages of pharmaceuticals are necessary to treat a given condition, symptom or disease state because many active ingredients are not completely absorbed by a patient in need of treatment. In other words, a better-absorbed dosage form of a medicament such as, for example, testosterone, or dosage forms that provide greater consistency of absorption of testosterone in a subject can be administered at dosage strengths lower than presently recommended, and can result in effective treatment with a reduced or minimized side effect profile, among other potential benefits.

[0030] Accordingly, it is an object of the subject invention to provide an oral dosage form comprising a bio-identical steroid hormone, e.g., testosterone, wherein the dosage form can provide certain unexpected advantages, such as good solubility for the active pharmaceutical ingredient, commercially acceptable stability, good bioavailability, lower dosage strengths, less frequent dosing or administration, lower-to-no food effect, better patient compliance, or any combination of these advantages. [0031] Embodiments are also provided wherein the compositions described herein are packaged together as a kit with instructions on how to use the compositions for treating a condition of low testosterone due to hypogonadism, whether primary, secondary, or age- related. For example, the dosage forms described herein can be packaged as blister packs or in bottles with instructions for using the dosage forms. Instructions can be provided as a package insert or directly on a label attached to the blister pack, bottle or on secondary packaging in which the blister pack or bottle was provided to a human subject. The instructions can include, for example, dosing frequency, administration of the dosage forms with or without food, the active ingredient provided in the dosage forms, and the conditions or disorders that would benefit from administration of the dosage forms.

[0032] In certain embodiments, the compositions described herein can be administered with or without food to a human subject in need of such administration wherein the bioavailability of the testosterone in the compositions is substantially independent of food effect.

[0033] In certain embodiments, administration of the compositions described herein can provide for a blood serum concentration in a human subject of at least about 300 nmol/mL of testosterone within about four hours after administration of the certain embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG. 1 illustrates a graph of the particle distribution obtained from a self-micellizing composition of the subject invention.

[0035] FIG. 2 depicts a Microscope Image (1000X) of Formula 1 with particle size measurements in red.

[0036] FIG. 3 depicts a microscope Image (1000X) of Formula 2 with particle size measurements in red.

[0037] FIG. 4 depicts a microscope Image (1000X) of Formula 3 with particle size measurements in red.

[0038] FIG. 5 depicts a microscope Image (1000X) of Formula 5.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0040] The term "active(s)", "active ingredient(s)", "active agents," "pharmaceutically active ingredient," of active pharmaceutical ingredient" or its abbreviation, "API" means a chemical entity intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in a subject.

[0041] The term "aqueous medium" refers to any solution or suspension, that comprises water, including for example, without limitation, water by itself; phosphate buffered saline pH 7.4, Sprite, apple juice, G-2 fruit punch, and chocolate milk. In certain embodiments, an aqueous medium comprises at least one fluid having an acidic pH. In certain other embodiments, an aqueous medium comprises a biological fluid such as, for example and without limitation, stomach acid. In other embodiments, the aqueous medium comprises simulated stomach acid comprising 0.1N HCI.

[0042] The term "AUC," as used herein, refers to the area under the curve that represents changes in blood concentration of testosterone over time. The term, "C_max" as used herein, refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of testosterone over time. The term, "T_max" as used herein, refers to the time that it takes for testosterone blood concentration to reach the maximum value. The term "micronized testosterone" as used herein, includes micronized testosterone having an X50 particle size value below about 15 microns and/or having an X90 particle size value below about 25 microns. Collectively AUC, Cmax and, optionally, T_max are the principle pharmacokinetic parameters that can characterize the pharmacokinetic responses of a particular drug product such as testosterone in an animal or human subject.

[0043] The term "bioavailability," as used herein means the concentration of an active ingredient (e.g., testosterone) in the blood (serum or plasma). The relative bioavailability may be measured as the concentration in the blood (serum or plasma) versus time. Other pharmacokinetic (pK) indicators may be used to measure and assess bioavailability, determined by suitable metrics including AUC, Cmax, and optionally, T_max. [0044] "Carrier" refers to any substance suitable as a vehicle for delivering a molecule or composition to a suitable in vivo site of absorption. Examples of such carriers include, but are not limited to water, phosphate buffered saline (PBS), Ringer's solution, dextrose solution, serum-containing solutions, Hank's solution and other aqueous physiologically-balanced solutions.

[0045] A "coloring agent" provides coloration to the composition or dosage form. Such coloring agents include food grade dyes.

[0046] The term "ester" refers to the replacement of the hydrogen in the carboxylic acid group of a polyunsaturated fatty acid molecule with another substituent. Typical esters are known to those in the art, a discussion of which is provided by Higuchi, T. et al., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series, Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, Amer. Pharma. Assoc., Pergamon Press (1987), and Protective Groups in Organic Chemistry, McOmie ed., Plenum Press, New York (1973), each of which is incorporated herein by reference in the entirety. Examples of common esters include methyl, ethyl, trichloroethyl, propyl, butyl, pentyl, tert-butyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, monoglyceride, diglyceride, triglyceride.

[0047] The term "excipients," as used herein, refer to non-active pharmaceutical ingredients or substances such as carriers, solvents, oils, lubricants and others used in formulating pharmaceutical products. They are generally safe for administering to animals, including humans, according to established governmental standards, including those promulgated by the United States Food and Drug Administration.

[0048] The term "free fatty acid" refers to one or more polyunsaturated fatty acids that have not been modified or do not have any other groups attached.

[0049] "Fully solubilized testosterone" as used herein means testosterone which is about 100% in solution.

[0050] The term "functional food" as used herein means any edible or drinkable foods or dietary components (e.g., juices, milk, yogurt, butter, margarine, or baking products) that are fortified or enhanced with any of the compositions described herein. The functional food can be, e.g., solid, liquid, gel semisolid, or a combination thereof. The term "functional food" also encompasses edible and drinkable nutritional supplements.

[0051] The term "hydrophilic-lipophilic balance" or "HLB," as used herein, refers to the relative affinity of a substance or composition for aqueous and oily phases. Substances or compositions generally have an average HLB of about 6 to about 20. Hydrophilic-lipophilic balance values can be determined in a variety of the formulas or experimental methods HLB values can be calculated based on methods and equations known to those of ordinary skill in the art, such as those described in United States Patent 5,585,192.

[0052] The term "medium chain," as used herein means any medium chain carbon-containing substance, including C4-C18, and including C6-C12 substances, fatty acid esters of glycerol, fatty acids, and mono-, di-, and tri-glycerides of such substances.

[0053] As used herein, the term "micelle" (plural micelles, micella, or micellae) refers to an aggregate of molecules that have assembled into an approximately spherical core/shell architecture, and are suspended in an aqueous phase. A typical micelle in aqueous solution forms an aggregate with the hydrophilic "head" regions in contact with surrounding solvent and/or in contact with the polar region of one or more surface active agent(s), sequestering the hydrophobic regions in the micelle center. Micelles are approximately spherical in shape.

[0054] The term "monoglyceride" refers to a fatty acid chain, such as DHA or EPA molecule, covalently bonded to a glycerol molecule through an ester linkage. As used herein, the term "diglyceride" refers to a fatty acid chain such as DHA or EPA, covalently bonded to a glycerol molecule through an ester linkage, wherein the glycerol molecule is further bonded to one additional fatty acid chain, which may or may not be DHA or EPA, through one additional ester linkage. As used herein, the term "triglyceride" refers to a fatty acid chain, such as DHA or EPA, covalently bonded to a glycerol molecule through an ester linkage, wherein the glycerol molecule is further bonded to two additional fatty acid chains, either or both of which may or may not be DHA or EPA, through two additional ester linkages. Reference to a monoglyceride, di-glyceride, or tri-glyceride means a respective molecule comprising substantially one, two or three fatty acid chains covalently bonded to a glycerol molecule through an ester linkage, and substantially free of another glyceride. Mixtures of mono-, di- and/or triglycerides can be provided. For example, a mixture of mono-glycerides and di-glycerides is substantially free of tri-glycerides.

[0055] "Natural," as used herein with reference to hormones discussed herein, means bio- identical hormones formulated to match the chemical structure and effect of those that occur naturally in the human body (endogenous). An exemplary natural androgen is testosterone, e.g., 17-OH testosterone, which is naturally produced in the human body.

[0056] The term "oil" as used herein may be any pharmaceutically acceptable substance, other than peanut oil, that would suspend and/or solubilize any suitable testosterone, starting material, or precursor, including micronized testosterone as described herein. More specifically, oils may include, for example and without limitation, medium chain fatty acids, generally of the group known as medium chain fatty acids consisting of at least one mono-, di-, and triglyceride, or derivatives thereof, or combinations thereof.

[0057] "Partially solubilized testosterone" as used herein means testosterone which is in any state of solubilization up to but not including about 100%.

[0058] A "preservative" includes but is not limited to potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol,phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride, tocopherols and their derivatives, and the like as are well known in the art.

[0059] The term "self-micellizes" or "self-micellization" as used herein refers to the process in which micelles are formed in an aqueous medium without the introduction of energy, including agitation or shearing

[0060] The term "solubilizer," as used herein, means any substance or mixture of substances that may be used to enhance the solubility of an insoluble or substantially insoluble compound, drug, active pharmaceutical ingredient, e.g., a hormone such as testosterone, testosterone, including, for example and without limitation, appropriate pharmaceutically acceptable excipients, such as solvents, co-solvents, surfactants, emulsifiers, oils and carriers.

[0061] The term "subject" refers to a mammal, including but not limited to a dog, cat, horse, cow, pig, sheep, goat, chicken, rodent, primate or human. Subjects include animals such as house pets (e.g., dogs, cats, and the like), agricultural stock subjects (e.g., cows, horses, pigs, chickens, etc.), laboratory subjects (e.g., mice, rats, rabbits, etc.), but are not so limited. The human subject may be a pediatric, adult, or a geriatric subject. The human subject may be of either gender.

[0062] The term "substantially pure" as used herein means at least 90% pure.

[0063] The term "treatment", or a derivative thereof, means partial or complete inhibition of the stated disease state or reversal of the stated condition when a formulation described herein is administered prophylactically or following the onset of the disease state or condition.

[0064] The term "uniform distribution" means at least one of uniform dispersion, solubility, or lack of agglomeration of testosterone in a dissolution test compared to other oral dosage forms comprising testosterone or a testosterone salt or ester at a similar dosage strength and the same USP dissolution apparatus.

[0065] The term "X50," as used herein, means that one-half of the particles in a sample are smaller in diameter than a given number. For example, micronized testosterone having an X50 of 5 microns means that, for a given sample of micronized testosterone, one-half of the particles have a diameter of less than 5 microns. Similarly, the term "X90" means that ninety percent (90%) of the particles in a sample are smaller in diameter than a given number.

Description of the Preferred Embodiments

[0066] Provided herein by way of examples which are in no way limiting on the invention, are formulations comprising solubilized or at least partially solubilized hormone, preferably a steroid hormone, and more preferably, testosterone, including micronized testosterone. The formulation concepts provided herein may be used with other natural or synthetic forms of testosterone. Micronization specifications, aspects and embodiments are further defined herein.

[0067] Generally, the pharmaceutical formulations described herein are prepared and administered as filled capsules, typically soft capsules of one or more materials well known in the art including, for example and without limitation, soft gelatin capsules. Micronized testosterone, as described herein, may also be prepared for administration in tablets or other well-known orally administered dosage forms using standard techniques. Alternatively, micronized testosterone can be prepared in a composition described herein, and formulated as a drink or orally administered functional food composition.

[0068] Another aspect of the present disclosure includes a pharmaceutical formulation of micronized testosterone which can provide increased testosterone bioavailability in a treated subject compared to the bioavailability provided by other oral dosage forms comprising testosterone when administered at equal dosage strengths.

[0069] Testosterone, as the active pharmaceutical ingredient (API), may be micronized via any one of the multiple methods typically utilized by the ordinarily skilled artisan. In various embodiments, micronized testosterone has an X50 particle size value of less than about 50 microns, less than about 40 microns, less than about 25 microns and/or less than about 15 microns. In various embodiments, micronized testosterone has an X90 particle size value of less than about 25 microns, less than about 20 microns, and/or less than about 15 microns.

[0070] Particle size may be determined in any suitable manner. For example, a Beckman Coulter LS 13 320 Laser Diffraction Particle Size Analyzer (the "Beckman Device") may be used to determine particle size. As described above, particle size may be represented by various metrics, for example, through an X50 particle size, and/or X90 particle size, or similar descriptions of particle size.

[0071] Testosterone formulations of the present disclosure are prepared via blending with a pharmaceutically acceptable oil; generally, the oil comprises at least one medium chain fatty acid such as medium chain fatty acids consisting of at least one mono-, di-, or triglyceride, or derivatives thereof, or combinations thereof. Optionally added are other excipients including, for example and without limitation, one or more emulsifiers, one or more surfactants, and one or more excipients, such as an antioxidant, stabilizer, carrier, filler, and the like.

[0072] In other embodiments, a lubricant is used. Any suitable lubricant may be used, such as for example lecithin. Lecithin may comprise a mixture of phospholipids.

[0073] In additional embodiments, an antioxidant is used. Any suitable anti-oxidant may be used such as, for example and without limitation butylated hydroxytoluene (BHT), BHA, alpha- tocopherols, and the like.

[0074] For example, in various embodiments, a pharmaceutical formulation comprises about 20% to about 80% carrier by weight, about 0.1% to about 5% lubricant by weight, and about 0.01% to about 0.1% antioxidant by weight.

[0075] The choice of excipient will, to a large extent, depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Excipients used in various embodiments may include colorants, flavoring agents, preservatives and taste-masking agents. Colorants, for example, may comprise about 0.1% to about 2% by weight. Preservatives may comprise methyl and propyl paraben, for example, in a ratio of about 10:1, and at a proportion of about 0.005% and 0.05% by weight.

[0076] Sufficient oil is used to form a suspension of micronized testosterone and, preferably a fully solubilized testosterone composition. Pharmaceutically acceptable oils include, without limitation, the use of at least one of a caproic fatty acid; a caprylic fatty acid; a capric fatty acid; a tauric acid; a myristic acid; a linoleic acid; a succinic acid; a glycerin; mono-, di-, or triglycerides and combinations and derivatives thereof; a polyethylene glycol; a polyethylene glycol glyceride (GELUCIRE, a polyethylene glycol glyceride); GATTEFOSSE SAS, Saint-Priest, France); a propylene glycol; a caprylic/capric triglyceride (MIGLYOL or caprylic/capric triglyceride); SASOL Germany GMBH, Hamburg; MIGLYOL (caprylic/capric triglyceride) includes MIGLYOL 810 (Caprylic/Capric Triglyceride), MIGLYOL 812 (Caprylic/Capric Triglyceride), MIGLYOL 816 (Caprylic/Capric Triglyceride) and MIGLYOL 829 (Caprylic/Capric/Succinic Triglyceride); a caproic/caprylic/capric/lauric triglyceride; a caprylic/capric/linoleic triglyceride; a caprylic/capric/succinic triglyceride; a propylene glycol monocaprylate; propylene glycol monocaprate; (CAPMUL PG-8 or CAPRIOL 90: Propylene Glycol Monocaprylate Type II, NF) and CAPMUL PG-10 (Propylene Glycol Monocaprate); the CAPMUL brands are owned by ABITEC, Columbus Ohio and CAPRYOL brands are owned by Gattefosse, Saint-Priest Cedex, France); a propylene glycol dicaprylate; a propylene glycol dicaprylate; medium chain mono- and di-glycerides (CAPMUL MCM (Medium Chain Mono- and Diglycerides)); a diethylene glycol mono ester (including 2-(2-Ethoxyethoxy)ethanol: TRANSCUTOL (diethylene glycol mono ester)); a diethylene glycol monoethyl; esters of saturated coconut and palm kernel oil and derivatives thereof; triglycerides of fractionated vegetable fatty acids, and combinations and derivatives thereof.

[0077] In other aspects and embodiments, testosterone can be fully solubilized using, for example and without limitation, sufficient amounts of: TRANSCUTOL (Diethylene glycol monoethyl ether) and MIGLYOL (caprylic/capric triglyceride); TRANSCUTOL (Diethylene glycol monoethyl ether), MIGLYOL (caprylic/capric triglyceride) and CAPMUL PG-8 (Propylene Glycol Monocaprylate) and/or CAPMUL PG-10 (Propylene Glycol Monocaprate); CAPMUL MCM (Medium Chain Mono- and Diglycerides); CAPMUL MCM (Medium Chain Mono- and Diglycerides) and a non-ionic surfactant; and CAPMUL MCM (Medium Chain Mono- and Diglycerides) and GELUCIRE (a polyethylene glycol glyceride).

[0078] Various ratios of these oils can be used for full solubilization of testosterone. CAPMUL MCM (Medium Chain Mono- and Diglycerides) and a non-ionic surfactant can be used at ratios including, for example and without limitation: 50:50, 65:35, 70:30, 75:25, 80:20, 85:15 and 90:10. CAPMUL MCM (Medium Chain Mono- and Diglycerides) or GELUCIRE (a polyethylene glycol glyceride) can be used at ratios including, for example and without limitation, 6:4, 7:3, 8:2, and 9:1.

[0079] Combinations of these oils can produce partially solubilized testosterone, depending upon the desired unit dosage amount of testosterone. The greater the amount of testosterone per unit dosage form, the less testosterone may be solubilized. The upward limit of dosage strength per unit dose it generally limited only by the practical size of the final dosage form. [0080] For example, in one alternative embodiment, the composition comprises a mixture of EPA and DHA ethyl esters, as previously described in the art for formulations comprising insoluble or substantially insoluble hormones, but not previously described for formulations comprising testosterone.

[0081] Anionic, cationic and/or non-ionic or zwitterionic surfactants can be used in embodiments of the presently disclosed formulations containing testosterone. In certain embodiments, a non-ionic surfactant is used. Exemplary non-ionic surfactants may include, for example and without limitation, one or more of oleic acid, linoleic acid, palmitic acid, and stearic acid. In further embodiments, the non-ionic surfactant may comprise polyethylene sorbitol esters, including polysorbate 80, which is commercially available under the trademark TWEEN 80^® (Sigma Aldrich, St. Louis, Mo.), Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) or TPGS1000. Polysorbate 80 comprises approximately 60%-70% oleic acid with the remainder comprising primarily linoleic acids, palmitic acids, and stearic acids. Polysorbate 80 may be used in amounts ranging from about 5 to 50%, and in certain embodiments, about 30% of the formulation total mass. These surfactants can enhance solubility of insoluble or substantially insoluble compounds in a formulation of the invention and can further advantageously enhance absorption in vivo.

[0082] In various other embodiments, the non-ionic surfactant is selected from one or more of glycerol and polyethylene glycol esters of long chain fatty acids, for example, lauroyl macrogol-32 glycerides and/or lauroyl polyoxyl-32 glycerides, commercially available as Gelucire, including, for example, Gelucire 44/11 and Gelucire 44/14. These surfactants may be used at concentrations greater than about 0.01%, and typically in various amounts of about 0.01%-10.0%, 10.1%-20%, and 20.1%-30%.

[0083] In certain embodiments, the surface active agent is selected from the group consisting of at least one anionic surface active agent, at least one non-ionic surface active agent, and a combination thereof.

[0084] In certain embodiments comprising at least one surface active agent, the at least one surface active agent has a hydrophilic-lipophilic balance (HLB) of about 8.0. [0085] In certain embodiments comprising at least one surface active agent, the surface active agent can be a non-ionic surface active agent selected from the group consisting of at least one polysorbate, at least one poloxamer, and a combination thereof.

[0086] In certain embodiments, the at least one surface active agent comprises a polysorbate present from about 15% wt/wt to about 31% wt/wt of the composition. Commonly available polysorbates include Polysorbate 20 (Polyoxyethylene (20) sorbitan monolaurate); Polysorbate 40 (Polyoxyethylene (20) sorbitan monopalmitate); Polysorbate 60 (Polyoxyethylene (20) sorbitan monostearate); and Polysorbate 80 (Polyoxyethylene (20) sorbitan monooleate). In certain embodiments, the polysorbate is polysorbate 80.

[0087] In certain other embodiments, the at least one surface active agent comprises a poloxamer present from about 0.1% to about 5% wt/wt of the composition.

[0088] In certain embodiments, the compositions described herein comprise a combination of polysorbate 80 and the poloxamer, Pluronic F87 [(HO(C₂H40)64(C3H₆0)37(C2H40)64H].

[0089] In certain embodiments, the subject invention can comprise an absorption enhancer, such as a fatty acid (e.g., an omega-3 fatty acid), TPGS-1000, lecithin, d-limonene, or the like as would be readily understood in the art. TPSG-1000 can advantageously provide stabilizing and/or antioxidant properties to the composition. In these embodiments comprising a fatty acid, a preferred embodiment contains no free fatty acid, i.e., the formulation is FFA-free.

[0090] In accordance with various aspects and embodiments, the solubility proportion (i.e., the proportion of a solute that enters solution) is notable. In particular, it is desirable to obtain a target dosage of testosterone in an amount of solution that may be readily administered via a capsule. For example, if it is desired to have a dose of testosterone in a capsule of between about 0.1 mg to about 500 mg, it would also be desirable to have a total solution weight to be between about 100 mg to about 1000 mg, preferably about 300 mg to about 900 mg and more preferably about 750 to about 800 mg. In various embodiments, the following weight ratios of testosterone to total solution is from about 0.1 mg to about 500 mg per 1000 mg of solution, from about 1 mg to about 100 mg per 1000 mg of solution; from about 10 mg to about 50 mg per 1000 mg of solution, and preferably between about 40 mg to about 49 mg per 1000 mg of solution.

[0091] Other aspects of the present disclosure can further provide: more uniform dissolution of testosterone, and reduced intra- and inter-patient blood level variability in formulations of testosterone of the present disclosure when compared to other oral dosage forms comprising testosterone or a testosterone salt or ester at equal doses. Blood level variability is also compared at equal sampling times following administration. Not to be limited by theory, these aspects are believed to be influenced by the percentage of solubilized testosterone in a respective formulation wherein such more uniform dissolution of testosterone, and lower intra- and inter-patient blood level variability, are influenced by a greater proportion of solubilized testosterone relative to total testosterone. A reduced food effect with the present formulations comprising testosterone can also be implicated.

[0092] More uniform dissolution of testosterone in a formulation of the present disclosure compared to the dissolution of other oral dosage forms comprising testosterone or a testosterone salt or ester at equal dosage strengths and using the same USP apparatus can be determined using standard techniques established for API dissolution testing, including that which is described in the examples below.

[0093] Reduced intra- and inter-patient variability of testosterone formulated pursuant to the present disclosure compared to other oral dosage forms comprising testosterone or a testosterone salt or ester can be demonstrated via a fed bio-study such as that described below.

[0094] Other aspects of the present disclosure include the use of formulations as described herein wherein testosterone is the API in said formulation for the treatment of an animal, including humans, for hypogonadism or increasing blood levels of testosterone.

[0095] An exemplary cyclic/sequential regimen comprises delivery of from about 0.1 mg to about 100 mg of testosterone daily. Other exemplary dosage strengths for testosterone for use in the formulations described herein include, without limitation, 1.0, 5.0, 10.0, 20.0, 30.0, 40.0, 50.0, 60.0, 70.0, 80.0, 90.0, and all integers and fractions of doses between 1.0 and 100.0 mg of testosterone per day.

[0096] As with all oils, solubilizers, excipients and any other additives used in the formulations described herein, each is to be non-toxic and pharmaceutically acceptable.

[0097] Methods of manufacture in accordance with various embodiments comprise heating an oily vehicle carrier (the lipid solubilizer) to 40°C +/- 5°C. Heating may be accomplished through any suitable means. The heating may be performed in any suitable vessel, such as a stainless steel vessel. The oily vehicle may be any oily vehicle described herein, for example, CAPMUL MCM (Medium Chain Mono- and Diglycerides).

[0098] Following heating of the lipid solubilizer, an optional surface acting agent is mixed with the oily vehicle. Mixing may be facilitated by an impellor, agitator, or other suitable means.

[0099] The heating and/or mixing steps may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N₂. Mixing may be performed in any suitable vessel, such as a stainless steel vessel.

[00100] Micronized testosterone is then added into the mixture of the oily vehicle and optional surface acting agent and mixing is continued. Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means, and may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N₂.

[00101] Following homogeneous mixing of the lipid solubilizer, optional surface acting agent, and testosterone, the mixture is cooled to room temperature. Cooling may be allowed to occur without intervention or cooling may be aided by application of a cooling system.

[00102] Separately, preparation of the softgel capsule, i.e. gel mass, comprises mixing glyercin with water. The water may be purified by any suitable means, such as reverse osmosis, ozonation, filtration (e.g., through a carbon column) or the like. Mixing may be facilitated by an impellor, agitator, or other suitable means, and may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N₂. Heating may be performed until the temperature reaches 80°C +/- 5°C. Gelatin is added to the glycerin water mixture, and mixed. Mixing may be facilitated by an impellor, agitator, or other suitable means, and may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. A vacuum may be drawn to de-aerate the mixture.

[00103] A coloring agent, such as a dye, can be added to the gelatin capsule mixture. A coloring agent may comprise products sold under the trademark OPATINT or other suitable agent. Coloring agent may be added under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. The resulting mixture is de-gassed. The resulting capsule material is suitable for use as a gel capsule in production of a softgel capsule.

[00104] In a softgel capsule assembly process, fill material is heated to any suitable temperature. In various embodiments, the fill material is heated to 30°C +/- 3°C. Fill material maybe heated in a fill hopper. A fill hopper may comprise a device configured to hold a volume of the fill material and/or to dispense the fill material in controlled volumes.

[00105] Filling may be performed by injecting, placing, or otherwise disposing the fill material within a volume defined by the gel capsule material. The filling may occur in an encapsulator. The spreader boxes may be a temperature of 55°C +/- 10°C. The wedge temperature may be 38°C +/- 3°C. The drum cooling temperature may be 4°C +/- 2°C. The encapsulator may be lubricated using, for example, MIGLYOL 812 (Caprylic/Capric Triglyceride) or other suitable lubricant. Filling may comprise producing a ribbon of thickness 0.85 mm +/- 0.05 mm using spreader box knobs. The fill material may be injected into the gel to produce a fill weight having target weight +/- 5% (e.g., 650 +/- 33 mg and 325 +/- 16.3 mg).

[00106] The process further comprises drying the softgel capsules. Drying may be performed in a tumble dryer, tray dryer, or combinations thereof. For example, drying may be performed in a tumble drying basket for between about 10 minutes and about 120 minutes. Drying may continue in a drying room for about 24 hours to about 72 hours. The softgel capsules can be inspected and/or polished if desired. Polishing may be performed with isopropyl alcohol. [00107] Packaging may be accomplished through any suitable means. Packaging may comprise packing softgel capsules into a blister pack, bottle, box, pouch, or other acceptable packaging.

[00108] As referenced above, the formulations of the present disclosure are generally orally administered, typically via, for example, capsules such as soft capsules, but alternatively can be provided as, or mixed with, a drink composition. The present formulations can also be used to form transdermal patches using standard technology known in the art. Solubilized formulations of the present invention can also be formulated for intraperitoneal administration using techniques well known in the art.

[00109] According to various embodiments described herein, monthly regimen of capsules, e.g., a 28-day or 30-day supply, can be packaged in a single kit (e.g., a blister pack) which may have administration days identified to improve compliance and reduce associated symptoms, among others. A blister pack can have a plurality of scores or perforations separating blister pack into daily doses. Each daily dose may further comprise a single blister or a plurality of blisters. In various embodiments, each unit dose may contain micronized and/or partially solubilized, or fully solubilized testosterone in amounts as set forth herein above, although other dose ranges may be contemplated. In addition, kits having other configurations are also contemplated herein. For example, without limitation, kits having such blister packs may contain any number of capsules.

[00110] Orally administered formulations of the present disclosure containing micronized and/or partially solubilized, or fully solubilized, testosterone are also used for the treatment of hypogonadism or other conditions, symptoms or disease states indicated to be treated with supplemental testosterone.

[00111] Additional objects of the present disclosure include: providing increased patient compliance secondary to ease of use; providing increased physician adoption secondary to ease of use/instruction with less worry of side effects from inappropriate usage; providing decreased side-effects from erroneous use; providing better efficacy/control of symptoms secondary to appropriate use; reducing the metabolic and vascular side effects of the commonly used synthetic hormones. [00112] The invention is further defined by reference to the following examples, which are not meant to limit the scope of the present invention. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, may be practiced without departing from the purpose and interest of the invention.

EXAMPLES

Example 1 - Solubility of Testosterone in Various Solvent Carriers

[00113] Various formulations and use of lipid solvents were determined for providing sufficient solubility for testosterone. Initial solubility experiments were done by mixing testosterone with various solvents, saturating the solution with the testosterone, equilibrating for at least 3 days and filtering un-dissolved particles, the analyzing the clear supernatant for the amount of testosterone dissolved by HPLC.

[00114] The solubility of Testosterone was also determined on a visual basis by adding solvent incrementally to a known quantity of Testosterone at room temperature until a clear solution was formed. Table 1, below, lists the solubility of Testosterone in the solvents evaluated. Testosterone had low solubility in the majority of the solvents.

Table 1: Solubility of Testosterone in Various Solvent Carriers

(Table 1 cont.)

Solvent Solubility (mg/g)

12. Polysorbate 80, NF <13.3*

13. Labrasol (Caprylocaproyl Polyoxyglycerides) 21.7

14. Captex 8000 (Triglycerides of Caprylic Acid) <13.1*

15. Com Oil <12.1*

16 Labrafac PG (Propylen4e Glycol Dicaprylate / Caprate) <12.5*

17. Propylene Glycol, USP 26.9

18. PEG 400 <13.1*

19. Soybean Oil USP <13.7*

20. Castor Oil <13.6*

21. d-Limonene <11.2*

* The solubility of Testosterone in these Solvents / Oil was minimal and below the value stated.

Example 2 - Evaluation of Capmul MCM with Various Surfactants

[00115] Capmul MCM/surfactant mixtures were evaluated for miscibility and stability. These mixtures were also evaluated for their ability to form a uniform dispersion by adding 0.05 grams of the mixture to 15 grams of water.

Table 2: Miscibility/Oispersion Formation of Capmul MCM with Surfactant Mixtures

6 7:3 Polysorbate 80 : Clear uniform liquid Translucent to Clear

Capmul MCM, NF

Poloxamer 407 (Poloxamer ppt out) Solution

Surfactant Mix (3:1)

7 9:1 Polysorbate 80 : Clear uniform liquid Translucent to Turbid

Capmul MCM, NF

TPGS1000

Surfactant Mix (3:1)

8 8:2 Polysorbate 80 : Clear uniform liquid Translucent Solution

Capmul MCM, NF

TPGS1000

Surfactant Mix (3:1)

9 7:3 Polysorbate 80 : Clear uniform liquid Translucent solution

Capmul MCM, NF

TPGS1000

Surfactant Mix (3:1)

10 8:2 olliphor RH : Clear uniform liquid Translucent solution

Capmul MCM, NF

Poloxamer 407 (Poloxamer ppt out)

Surfactant Mix (3:1)

11 7:3 Kolliphor RH40 : Clear uniform liquid Translucent solution

Capmul MCM, NF

Poloxamer 407 (Poloxamer ppt out)

Surfactant Mix (3:1)

12 9:1 Kolliphor RH40 : Clear uniform liquid Translucent to turbid

Capmul MCM, NF:

Poloxamer 407 (Poloxamer ppt out)

Propylene Glycol (90:10)

Surfactant Mix (9:1)

*0.05g of mixture added to 15 g water

[00116] Polysorbate 80, Kolliphor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) and TP6S1000, used in ratios listed in Table 2, provided good stability. A precipitate was formed in all of the mixtures containing poloxamer 407, including its use with propylene glycol.

Example 3 - Evaluation of Testosterone Fill Formulations

A. Evaluation of Testosterone in Capmul MCM Based Fill Formulations

[00117] Table 3 below lists Testosterone/Capmul MC /Surfactant Mixtures evaluated for miscibility, dispersion formation ability and solution stability in the presence of 5% water. All formulations contain Testosterone at about 47 mg/g concentration (~20% below the saturation concentration of Testosterone in Capmul MCM.) A buffer is included to prevent the drug from precipitating out of solution during the stress conditions of freeze thaw testing and exposure to 5% water. Table 3: Miscibility, Dispersion Formation and Solution Stability of Testosterone in Capmul MCM Based Formulations

*0.05g of mixture added to 15 g pH 1.2 water

[00118] All of the formulations performed well in the presence of water. However, the poloxamer containing formulas (Formulas 4-6) resulted in a precipitate being formed when not in the presence of water. The identity of this precipitate is unknown.

[00119] These mixtures were also evaluated for their ability to form a uniform dispersion by adding 0.05 grams of the mixture to 15 grams of pH 1.2 water. All formed uniform, stable dispersions with no precipitate noted except for Formula 6 which had noticeable oil droplets. The dispersions formed with more surfactant (30%: Formulas 1 and 9) were more translucent than the formulations that had lower surfactant amounts (10%: Formulas 3, 5, 6 and 7) which tended to be more turbid or cloudy. Clear dispersions suggest a smaller particle size. B. Evaluation of Testosterone in Capryol 90 Based Fill Formulations

[00120] Table 4 below lists the Testosterone/Capryol 90/Surfactant Mixtures that were evaluated for miscibility, dispersion formation ability and solution stability in the presence of 5% water. All formulations contain Testosterone at about 70 mg/g concentration.

Table 4: Miscibility, Dispersion Formation and Solution Stability of Testosterone in Capryol 90 Based Formulations

*0.05g of mixture added to 15 g pH 1.2 water

[00121] Formula 1 formed a precipitate. The formulations were also evaluated for solution stability by adding 5% water. These formulations performed well in the presence of water. While oil droplets were noted for Formulas 2 and 3 there was no precipitate formed. These mixtures were also evaluated for their ability to form a uniform dispersion by adding 0.05 grams of the mixture to 15 grams of pH 1.2 water. All formed stable dispersions with no precipitate formed, though oil droplets were noted in Formulas 2 and 3.

Example 4 - Preparation of Testosterone Fill Formulations

[00122] A fill formulation in accordance with the subject invention was prepared as follows: Lipid solubilizer (e.g., CAPMUL MCM), emulsifier (e.g., Polysorbate 80), and surfactant (e.g., Kolliphor RH 40), are mixed and heated to about 45° C. Testosterone is added and mixed until dissolved and passed through a colloid mill. The resultant fill mass can be used for encapsulation. Examples of fill formulations prepared are presented in Tables 5-12, below: Table 5 - Formula 1

Table 6 - Formula 2

Table 7 - Formula 3

Table 8 - Formula 4

Table 11 - Formula 7

Example 5 - Freeze Thaw Stress Testinfi

[00123] Table 13 below outlines the conditions for the freeze thaw stress testing. This visual test evaluates whether the formulation is robust from a miscibility standpoint.

Table 13: Freeze Thaw Study Protocol

Example 6 - Globule size measurement using Olympus DP26 Microscope

[00124] Dispersions of selected formulas (Formulas 1-3 & 5) were formed by adding 0.05 grams of the fill formulation to 15 grams of pH 1.2 water. The resulting dispersions were viewed under microscope at 1000X magnification to determine the approximate particle size and the uniformity of the dispersion. The microscope images of these formulas are presented in Figs 1 through 4.

[00125] All of the formulas appeared to form uniformly sized dispersions. Formula 1 shown in Fig 1 had small globules that were around 400 nm in size, while Formulas 2 and 3, as shown in Figs 2 and 3, respectively, had larger globule sizes at around 500 and 600 nm. This globule size estimate is in agreement with the qualitative evaluation of this series of dispersions that show that the larger particle size results in a turbid to cloudy dispersion while the smaller particle size results in an almost transparent dispersion. Formula 5, shown in Fig 4, has the smallest globule size of the series and was too small to measure with our microscope.

Example 7 - Testosterone Dosage Form Stability Studies

[00126] In addition to determining physical stability of the testosterone solutions over time, it is necessary to determine if the fill material will be stable following the encapsulation process. Additional studies can be performed to assess the stability of testosterone in solvent mixtures following encapsulation into a soft gel capsule.

[00127] Stability studies were carried out on the following encapsulated formulations comprising 50 mg or 70 mg of testosterone: mass Formula 9, Testosterone Capsules, 50 mg

mass Formula 10, Testosterone Capsules, 50 mg

[00128] The formulations were stored under accelerated conditions, and assays measuring testosterone impurities were conducted at time-zero (prior to storage under 40/75 accelerated conditions) and at one-month and two-months following the date of being placed in storage. The results of the stability studies for each of the above formulae (using either 150 bloom gelatin "A" or 200 bloom gelatin "B") are presented in Table 14, below:

Table 14. Assay and RC Summary Results (Initial, 1MACC, 2MACC)

[00129] Dissolution studies were carried out for the above formulations 9-11, using a Type II Apparatus (75 rpm) and a 5% SLS dissolution medium. Micronized testosterone (USP) was used as a standard. The results of the dissolution studies are presented below:

Dissolution Summary Results (Initial, 1MACC, 2MACC)

[00130] Cross-linking of the gelatin, which can affect stability and/or dissolution of the dosage form, may be minimized or eliminated by adding ingredients in the gel material or in the fill formulation which minimize or eliminate the cross-linking. For example, use of a gel comprising about 10% to about 15% sorbitol or addition of about 0.5% w/w of an antioxidant to the fill formulation may minimize cross-linking. One example of an antioxidant useful for a fill formulation according to the subject invention is Vitamin E preparation, such as D-alpha- tocopherol. Formulations comprising an antioxidant can include the following: Fill Formula with Tocopherol

[00131] This following study protocol can be used to establish bio-availability and bio- equivalence parameters for a product of the present invention comprising testosterone (47.6 mg) as prepared via the process described herein, and compared to other oral dosage forms comprising testosterone or a testosterone salt or ester at an equivalent dose and administered to twenty-four (24) normal healthy, adult human male subjects under fed conditions.

[00132] The Study Design: An open-label, balanced, randomized, two-treatment, two- period, two-sequence, single-dose, two-way crossover. The subjects will be housed in the clinical facility from at least 11.00 hours pre-dose to at least 48 hours post-dose in each period, with a washout period of at least 14 days between the successive dosing days.

[00133] Subjects will be fasted for at least about 10 hours before being served a high- fat, high-calorie breakfast, followed by dosing, then followed by a 4.0 hour, post-dose additional period of fasting. Standard meals will be provided at about 04.00, 09.00, 13.00, 25.00, 29.00, 34.00 and 38.00 hours post-dose, respectively. Water will be restricted at least about 1 hour prior to dosing until about 1 hour post-dose (except for water given during dosing). At other times, drinking water will be provided ad libitum.

[00134] Subjects will be instructed to abstain from consuming caffeine and/or xanthine containing products (i.e. coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.) for at least about 24 hours prior to dosing and throughout the study, grapefruit and\or its juice and poppy containing foods for at least about 48 hours prior to dosing and throughout the study.

[00135] Subjects will remain seated upright for about the first 4.00 hours post-dose and only necessary movements will be allowed during this period. Thereafter subjects will be allowed to ambulate freely during the remaining part of the study. Subjects will not be allowed to lie down (except as directed by the physician secondary to adverse events) during the restriction period.

[00136] Subjects will be instructed not to take any prescription medications within 14 days prior to study check in and throughout the study. Subjects will be instructed not to take any over the counter medicinal products, herbal medications, etc. within 7 days prior to study check-in and throughout the study.

[00137] After overnight fasting of at least about 10.0 hours, a high-fat high-calorie breakfast will be served about 30 minutes prior to administration of investigational product(s). All subjects will be required to consume their entire breakfast within about 30 minutes of it being served, a single dose of either test product (T) of testosterone mg or the reference product Capsules will be administered with about 240 mL of water under fed condition, at ambient temperature in each period in sitting posture. A thorough mouth check will be done to assess the compliance to dosing.

[00138] All dosed study subjects will be assessed for laboratory tests at the end of the study or as applicable.

[00139] In each period, twenty-three (23) blood samples will be collected. The pre-dose (10 mL) blood samples at -01.00, -00.50, 00.00 hours and the post-dose blood samples (08 mL each) will be collected at 00.25, 00.50, 00.67, 00.83, 01.00, 01.33, 01.67, 02.00, 02.50, 03.00, 04.00, 05.00, 06.00, 07.00, 08.00, 10.00, 12.00, 18.00, 24.00 and 48.00 hours in labeled K2EDTA--vacutainers via an indwelling cannula placed in one of the forearm veins of the subjects. Each intravenous indwelling cannula will be kept in situ as long as possible by injecting about 0.5 mL of 10 lU/mL of heparin in normal saline solution to maintain the cannula for collection of the post-dose samples. In such cases blood samples will be collected after discarding the first 0.5 mL of heparin containing blood. Each cannula will be removed after the 24.00 hour sample was drawn or earlier or if blocked.

[00140] At the end of the study, the samples will be transferred to the bio-analytical facility in a box containing sufficient dry ice to maintain the integrity of the samples. These samples will be stored at a temperature of -70°C +/- 20°C in the bio-analytical facility until analysis.

[00141] Testosterone (Corrected and Uncorrected) in plasma samples will be assayed using a validated LC- S/MS method.

[00142] Fasted studies using this protocol will also be conducted. However, rather than the high-fat meal prior to administration of the test and reference drug, each subject will be fasted for a period of at least twelve (12) hours prior to dose administration.

[00143] Certain aspects, modes, embodiments, variations and features of the invention are described herein in various levels of detail to provide further understanding of embodiments related to compositions comprising bio-identical testosterone, and methods related to using such compositions. In certain embodiments, an EPA ester and DHA ester are present in specific weight ratio percentages and relative amounts. As noted, these compositions have beneficial effects on certain risk factors for CVD, including the lowering of serum triglycerides and serum cholesterol.

[00144] In other embodiments, the compositions described herein can be formulated as a fill material for a soft gelatin capsule. Likewise, when the contents of the soft gelatin capsule come into contact with an aqueous medium, the composition forms micelles upon disintegration of the capsule.

[00145] A capsule may be prepared, e.g., by placing the compositions described above inside a capsule shell. In some embodiments the compositions described herein can be filled into soft capsules. A capsule shell may be made of methylcellulose, hydroxypropylmethyl cellulose, polyvinyl alcohols, or denatured gelatins or starch or other material. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. In some embodiments the unit dosage form is a gel capsule. In some embodiments the capsule shell is a glycerin capsule shell, for example product no. GSU0051 manufactured by SwissCaps and which meets USP 25 requirements (SwissCaps, USA 14193 SW 119th Ave., Miami/Fla., U.S. 33186). In other embodiments the capsule is a bovine gelatin shell, for example, SwissCaps product no. GSU0708.

[00146] Other suitable capsule shell materials include polyethylene, polypropylene, poly(methylmethacrylate), polyvinylchloride, polystyrene, polyurethanes, polytetrafluoroethylene, nylons, polyformaldehydes, polyesters, cellulose acetate, and nitrocellulose. The capsule shell itself may contain small amounts of dyes, opaquing agents, plasticizers, and preservatives. Conventional methods for preparing other solid dosage forms, for example, capsules, suppositories, and the like are also well known. Gelatin capsule shells may be made also be made of tapioca, grass, vegetable derived or fish derived gelatin. For example, K-CAPS (Capsuline, Inc. Pompano Beach, Fla.) is a certified Kosher soft capsule shell of vegetable origin. Other vegetarian derived gelatin capsules may, be made of vegetable derived hydroxypropylmethyl cellulose (HPMC). Capsules shells may also contain Modified Maize Starch, Glycerol, and Carrageenan as a gelling agent.

[00147] In other embodiments the capsule has a shell comprising the material of the rate-limiting membrane, including coating materials, and filled with the compositions described herein. Capsule shells may be made of a porous or a pH-sensitive polymer made by a thermal forming process. In certain embodiments the capsule shell in the form of an asymmetric membrane; i.e., a membrane that has a thin skin on one surface and most of whose thickness is constituted of a highly permeable porous material.

[00148] Yet another useful capsule, a "swelling plug device", can be used. The compositions described herein can be incorporated into a non-dissolving capsule-half of the device which is sealed at one end by a hydrogel plug. This hydrogel plug swells in an aqueous environment, and, after swelling for a predetermined time, exits the capsule thus opening a port through which the active agent can leave the capsule and be delivered to the aqueous environment. Preferred hydrogel-plugged capsules are those which exhibit substantially no release of active agent from the dosage form until the dosage form has exited the stomach and has resided in the small intestine for about 15 minutes or more, preferably about 30 minutes or more, thus assuring that minimal Omega-3 fatty acid ester is released in the stomach or the small intestine. Hydrogel-plugged capsules of this type have been described in patent application WO90/19168.

[00149] The dosage forms may contain a plasticizer, particularly in a capsule shell. Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose, triacetin, glycerin, sorbitol, sorbitan or combinations thereof.

[00150] In additional embodiments, the compositions can be formulated as a liquid or gel for parenteral administration.

[00151] Compositions can be formulated as one or more dosage units. In some embodiments, it can be advantageous to formulate oral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit forms described in some embodiments can refer to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active composition calculated to produce the desired therapeutic effect in association with the suitable pharmaceutical carrier. In certain embodiments, the dosage form may optionally contain a flavorant such as orange oil, substantially pure d-limonene, and an antioxidant such as tocopherol, ascorbyl palmitate or a combination of antioxidants.

[00152] In certain embodiments, the compositions described herein comprise micelles pre-formed prior to administration to a subject in need of such administration. Such preformed micelles are stable at room temperature.

[00153] Accordingly, either such pre-formed micelles or the pre-micellized compositions described herein can be added to foods, which can then be consumed as part of a healthy diet for enriching a subject's testosterone levels or as a dietary treatment in addition to the oral/parenteral administration of the compositions described herein as prescribed by a health professional. [00154] In certain embodiments, a functional food is in the form of edible or drinkable compositions, e.g., foodstuffs such as chewable or edible bars, confectionary products (e.g., chocolate bars), cookies, juice drinks, baked or simulated baked goods (e.g., brownies), biscuits, lozenges or chewing gum. Examples of chewable or edible bars include chocolate bars or energy bars. Such functional foods can be particularly useful to people participating in sports or other forms of exercise.

[00155] In certain embodiments, the functional foods may also be in the form of, for example, butter, margarine, bread, cake, milk shakes, ice cream, yogurt and other fermented milk product.

[00156] In certain embodiments, the functional food can also be in the form of a liquid or gel to be sprayed on meats, salads or other foods.

[00157] Other forms of the functional foods can be breakfast cereals, such as for example, grain flakes, muesli, bran, oatmeal. When the functional food product is in a drinkable form, the compositions described herein can be added directly to the drink, such as for example plain milk, flavored milk, fermented milk products or juices. The compositions will form micelles comprising the testosterone in the drinkable product.

[00158] When the functional food is in the form of a solid edible product, the compositions described herein can be first added to an aqueous medium, wherein the composition will form micelles as described herein. The aqueous medium comprising the micelles can subsequently be either sprayed onto the solid edible product or mixed into the ingredients when manufacturing the edible product.

Claims

1. A pharmaceutical composition comprising solubilized testosterone and a lipid solubilizer, wherein said composition forms micelles when contacting an aqueous medium.

2. The composition of claim 1, wherein the testosterone is bio-identical testosterone.

3. The composition of claim 1 herein the testosterone is micronized.

4. The composition of claim 1 wherein the lipid solubilizer is selected from caproic fatty acid; a caprylic fatty acid; a capric fatty acid; a tauric acid; a myristic acid; a linoleic acid; a succinic acid; a glycerin; mono-, di-, or triglyceride; a polyethylene glycol; a polyethylene glycol glyceride; a propylene glycol; a caprylic/capric triglyceride caprylic/capric/succinic triglyceride; caproic/caprylic/capric/lauric triglyceride; caprylic/capric/linoleic triglyceride; propylene glycol monoca pry late; propylene glycol monocaprate; propylene glycol monocaprylate; propylene glycol dicaprylate; medium chain mono- and di-glycerides; diethylene glycol mono ester; diethylene glycol monoethyl; esters of saturated coconut and palm kernel oil; triglycerides of fractionated vegetable fatty acids; diethylene glycol monoethyl ether; polyethylene glycol glyceride; and derivatives and combinations thereof.

5. The composition of claim 1 wherein the lipid solubilizer is a mixture of medium chain mono- and diglycerides.

6. The composition of claim 1 wherein the lipid solubilizer is propylene glycol monocaprylate.

7. The composition of claim 1 wherein the composition comprises from about 10 mg to about 100 mg of testosterone per gram of the total composition.

8. The composition of claim 1 wherein the composition comprises from about 25 mg to about 75 mg of testosterone per gram of the total composition.

9. The composition of claim 1 wherein the composition comprises from about 40 mg to about 50 mg of testosterone per gram of the total composition.

10. The composition of claim 1 wherein the composition comprises from about 47 to about 48 mg of testosterone per gram of the total composition.

11. The composition of claim 1, further comprising at least one surface acting agent.

12. The composition of claim 11 wherein the surface acting agent is a surfactant or emulsifier.

13. The composition of claim 11 wherein the surface acting agent is an anionic, cationic, non-ionic or zwitterionic.

14. The composition of claim 11 wherein the surface acting agent is non-ionic surface acting agent selected from oleic acid, linoleic acid, palmitic acid, stearic acid, polyethylene sorbitol esters, polyoxyl hydrogenated castor oil, tocopheryl polyethylene glycol succinate, and derivatives or mixtures thereof.

15. The composition of claim 1, further comprising one or more excipients selected from a colorant, a flavoring agents, a preservative, a taste-masking agent, an antioxidant, a stabilizer, a carrier, a filler, and a lubricant.

16. The composition of claim 1 comprising about 25 to about 75 mg testosterone and about 600 to about 900 mg lipid solubilizer per gram of the total composition.

17. The composition of claim 16 comprising about 47.6 mg testosterone per gram of the composition.

18. The composition of claim 16 comprising about 70 mg testosterone per gram of the composition.

19. The composition of claim 16 comprising about 666.6 mg caprylic/capric mono/diglyceride per gram of the composition.

20. The composition of claim 16 comprising about 857.2 mg caprylic/capric mono/diglyceride per gram of the composition.

21. The composition of claim 16 comprising about 762 mg caprylic/capric mono/diglyceride per gram of the composition.

22. The composition of claim 11 comprising about 40 mg to about 150 mg of at least one surface acting agent per gram of the composition.

23. The composition of claim 11 comprising about 80 mg to about 300 mg of a mixture of at least two surface acting agents per gram of the composition.

24. The composition of claim 1, comprising:

25. The composition of claim 1, comprising

26. The composition of claim 11 wherein said at least one surface active agent has

hydrophilic-lipophilic balance of at least 8.0.

27. The composition of claim 1 further comprising at least one antioxidant selected from the group consisting of any of at least one tocopherol, at least one tocotrienol, or a combination thereof.

28. The composition of claim 1 wherein said composition forms micelles in an aqueous medium having an acidic pH.

29. The composition of claim 1 wherein said composition forms micelles in 0.1N HCI.

30. The composition of claim 1 wherein said micelles have a diameter of from about 1 micron to about 10 microns.

31. The composition of claim 1 wherein said composition is without food effect when administered to a human subject in need of such administration.

32. The composition of claim 1 wherein said composition when administered to a human subject having serum testosterone levels below about 300 mg/dL blood serum, raises testosterone levels within normal range.

33. The composition of claim 32 wherein normal range is between about 300 and about 1200 mg/dL.

34. The composition of claim 1 wherein the composition is formulated as an oral dosage form.

35. The composition of claim 1 contained in a gelatin capsule for oral administration.

36. A method of treating or reversing a condition or disorder in a patient in need of raising serum testosterone levels, said method comprising:

a. providing a composition of claim 1, and

b. administering said composition to the patient in need of raising serum testosterone levels.

37. The method of claim 36 wherein the patient is a human male.

38. The method of claim 36 wherein the composition is administered at least once per day and not more than four times per day.

39. The method of claim 36 wherein the composition is administered in one, two, three, or four dosage forms per administration.

40. A kit comprising the composition of claim 1 in a package together with instructions for using said composition to treat a condition or disorder in a patient in need of increasing serum levels of testosterone.

41. The kit of claim 40 wherein said composition is in a dosage form of a gel or liquid capsule packaged in a blister package or in bottles.

42. The kit of claim 40 wherein said instructions include administering said composition with or without food.