Testosterone ester triglyceride formulations

Abstract

To provide testosterone ester triglyceride formulations for parenteral administration.SOLUTION: The present invention provides testosterone ester triglyceride formulations, optionally further including adducts. Methods of in-situ control of the manufacture or formation of such adducts are also provided.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 552,190, filed Aug. 30, 2017, which is incorporated herein by reference in its entirety.

[0002] Technical Field The present invention relates generally to testosterone ester triglyceride formulations. [Background technology]

[0003] Testosterone is the primary male hormone and an anabolic steroid. In men, testosterone plays an important role in the development of male reproductive tissues such as the testes and prostate, and promotes secondary sexual characteristics such as increased muscle and bone mass, and the development of body hair. Testosterone enanthate is a heptanoic acid-derived ester of testosterone and is therefore a prodrug of testosterone. Testosterone enanthate is less polar than free testosterone and is absorbed more slowly from the lipid phase when administered parenterally, resulting in sustained in vivo delivery of testosterone. Thus, testosterone enanthate can be administered at longer time intervals, for example, at intervals of 1 to 4 weeks. Summary of the Invention

[0004] In one embodiment, the present invention provides a compound represented by formula 1:

[0005] [ka]

[0006] a testosterone ester of formula 2:

[0007] [ka]

[0008] wherein R1 is an alkyl or alkenyl substituent; and each of R2, R3, and R4 is an acyl group corresponding to fatty acids such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. In some embodiments, R1 is propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, ethyl ... , undecyl, dodecyl, cyclopentylethyl, or unsaturated analogs thereof. In some embodiments, the testosterone ester is testosterone enanthate, testosterone cypionate, testosterone propionate, or testosterone undecanoate. In some embodiments, the pharmaceutical formulation is for parenteral administration. In some embodiments, the testosterone ester is testosterone enanthate. In some embodiments, the triglyceride is one of LLL, OLL, OOL, OOO, PLL, POL, POO, or SOL. In some embodiments, the pharma- ceutically acceptable carrier comprises a vegetable oil. In some embodiments, the vegetable oil is sesame oil. In some embodiments, the antioxidant is one or more of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and / or monosodium glutamate.

[0009] In one embodiment, the present invention relates to a pharmaceutical formulation comprising testosterone enanthate, sesame oil, and BHT. In one embodiment, the present invention relates to a pharmaceutical formulation comprising testosterone enanthate, sesame oil, and tocopherol. In some embodiments, the pharmaceutical formulation is for parenteral administration.

[0010] In one embodiment, the present invention provides a compound of formula 3:

[0011] [ka]

[0012] In some embodiments, the testosterone ester adduct has the formula: R1 is an alkyl or alkenyl substituent which may be the same or different at each independent occurrence; R5 is an acyl group corresponding to an unsaturated fatty acid; G is a glycerol, monoglyceride, or diglyceride residue; n is 1, 2, or 3; and the testosterone residue is linked to the allylic or diallylic carbon of R5. In some embodiments, the testosterone ester adduct has the formula 4:

[0013] [ka]

[0014] In some embodiments, R1 is propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, and / or one of their unsaturated analogs. In some embodiments, R1 is hexyl.

[0015] In some embodiments, the present invention provides compounds of Formulas 5-9:

[0016] [ka]

[0017] [ka]

[0018] wherein each of R6 and R7 is independently an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid.

[0019] In some embodiments, the present invention provides a compound of formula 10:

[0020] [ka]

[0021] This relates to a testosterone ester adduct of In some embodiments, the present invention provides a compound of formula 11:

[0022] [ka]

[0023] This relates to a testosterone ester adduct of In yet another aspect, the present invention relates to the above-mentioned testosterone ester formulations, which may be combined with the above-mentioned testosterone adducts. Such adducts may be useful at least for purposes of formulation stability. In some aspects, such adducts may be useful for tagging, identifying, or authenticating the testosterone ester formulation.

[0024] Thus, in some embodiments, the present invention relates to a pharmaceutical formulation comprising a testosterone ester of formula 1, a pharma- ceutically acceptable carrier comprising one or more triglycerides of formula 2, and a testosterone ester adduct of any one of formulas 3-11, wherein: R1 is an alkyl or alkenyl substituent; and each of R2, R3, and R4 is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. In some embodiments, R1, at each independent occurrence, is selected from the group consisting of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, and / or unsaturated analogs thereof. In some embodiments, the pharmaceutical formulation is for parenteral administration. In some embodiments, the testosterone ester is selected from the group consisting of testosterone enanthate, testosterone cypionate, testosterone propionate, or testosterone undecanoate. In some embodiments, the testosterone ester is testosterone enanthate. In some embodiments, the triglyceride is one of LLL, OLL, OOL, OOO, PLL, POL, POO, and SOL. In some embodiments, the pharma- ceutically acceptable carrier comprises a vegetable oil. In some embodiments, the pharmaceutical formulation further comprises an antioxidant. In some embodiments, the antioxidant is one or more of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and / or monosodium glutamate.

[0025] In such embodiments, the concentration of the adduct of the present invention may be between 0.000 mg / ml and the concentration of the testosterone ester of the formulation. In one embodiment, the present invention relates to a pharmaceutical formulation that includes testosterone enanthate, sesame oil, BHT, and one or more testosterone adducts of Formulas 3-11.

[0026] In some embodiments, the adduct has formula 10. In some embodiments, the adduct has formula 11. In some embodiments, the concentration of testosterone enanthate is 50 mg / mL to 200 mg / mL. In some embodiments, the concentration of BHT is 0.01% to 0.1%, or 0.1 mg / mL to 1 mg / mL. In some embodiments, the concentration of testosterone ester adducts is less than the concentration of testosterone enanthate. In some embodiments, the total concentration of testosterone ester adducts is less than the concentration of testosterone enanthate. In some embodiments, the pharmaceutical formulation is for parenteral administration.

[0027] In one aspect, the invention relates to a stable testosterone ester pharmaceutical formulation comprising a testosterone ester of Formula 1, an antioxidant, and a pharma- ceutical acceptable carrier comprising one or more triglycerides of Formula 2, wherein: R1 is an alkyl or alkenyl substituent; each of R2, R3, and R4 is an acyl group corresponding to a fatty acid, such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid; and the stress (e.g., light) stability of the formulation is assessed by measuring the concentration of available testosterone ester 30-60 days after making the formulation and comparing it to the initial testosterone ester concentration of the formulation.

[0028] In some embodiments, the pharmaceutical formulation is for parenteral administration. In one embodiment, the present invention relates to a photostable testosterone ester pharmaceutical formulation comprising a testosterone ester of formula 1, an antioxidant, and a pharma- ceutical acceptable carrier comprising one or more triglycerides of formula 2, where R1 is an alkyl or alkenyl substituent; each of R2, R3, and R4 is an acyl group corresponding to a fatty acid such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid; and the photostability of the formulation is evaluated by measuring the concentration of available testosterone ester and comparing it to the initial testosterone ester concentration of the formulation between 30 and 60 days after making the formulation, and by detecting any presence in the formulation and measuring the concentration of one or more testosterone ester adducts of any one of formulas 3-11. In some embodiments, the pharmaceutical formulation is for parenteral administration.

[0029] In one aspect, the present invention relates to a photostable testosterone ester pharmaceutical formulation comprising a testosterone ester of formula 1, an antioxidant, and a pharma- ceutical acceptable carrier comprising a triglyceride of formula 2, wherein: R1 is an alkyl or alkenyl substituent; each of R2, R3, and R4 is an acyl group corresponding to a fatty acid, such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid; and the photostability of the formulation is such that the pharmaceutical formulation is photoinduced at 200 watt-hours / m 2 of UV light and 1.2 million In some embodiments, the pharmaceutical formulation is for parenteral administration.

[0030] In one aspect, the present invention relates to a photostable testosterone ester pharmaceutical formulation comprising a testosterone ester of formula 1, an antioxidant, and a pharma- ceutical acceptable carrier comprising a triglyceride of formula 2, wherein: R1 is an alkyl or alkenyl substituent; each of R2, R3, and R4 is an acyl group corresponding to a fatty acid, such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid; and the photostability of the formulation is such that the pharmaceutical formulation is photoinduced at 200 watt-hours / m 2 and 1.2 million lux hours of visible light exposure, measuring the concentration of available testosterone ester and comparing it to the initial testosterone ester concentration in the formulation to detect the presence and concentration of any one of testosterone ester adducts of formulas 3-11 in the formulation. In some embodiments, the pharmaceutical formulation is for parenteral administration.

[0031] In one embodiment, the present invention relates to a photostable testosterone ester pharmaceutical formulation, wherein the concentration of available testosterone ester in the formulation is at least 66.8%-75.0% of the initial testosterone ester concentration in the formulation. In some embodiments, the pharmaceutical formulation is for parenteral administration.

[0032] In some embodiments, the present invention relates to a photostable testosterone ester pharmaceutical formulation comprising a testosterone ester adduct of any one of formulas 3-11, wherein the concentration of the testosterone ester adduct in the formulation is less than the concentration of available testosterone ester in the formulation. In some embodiments, the pharmaceutical formulation is for parenteral administration.

[0033] In one embodiment, the present invention relates to a method for measuring the photostability of a testosterone ester pharmaceutical formulation comprising a testosterone ester of formula 1 and a pharma- ceutical acceptable carrier comprising one or more triglycerides of formula 2, the method comprising the steps of measuring an initial testosterone ester concentration in the formulation, then measuring the concentration of available testosterone ester in the formulation after a period of time, and comparing the two concentrations, where R1 is an alkyl or alkenyl substituent; each of R2, R3, and R4 is an acyl group corresponding to a fatty acid such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid. In some embodiments, the method includes injecting the pharmaceutical formulation into a 200 Watt-hour / m 2 and 1.2 million lux hours or more of UV light and visible light exposure. In some embodiments, the pharmaceutical formulation further comprises an antioxidant such as butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and / or monosodium glutamate. In some embodiments, the period is between 30 and 60 days. In some embodiments, the method further comprises detecting the presence and measuring the concentration of a testosterone ester adduct of any one of formulas 3-11 in the pharmaceutical formulation.

[0034] The foregoing summary, as well as the following detailed description of aspects of the present invention, will be better understood when read in conjunction with the appended drawings. [Brief description of the drawings]

[0035] [Figure 1] FIG. 1 illustrates the overlap of UV (242 nm) chromatograms: control sample (blue) and photostressed sample (pink). [Diagram 2] FIG. 2 illustrates the chromatogram after stress treatment of the crude product mix. [Diagram 3] FIG. 3 illustrates the chromatogram of purified fraction 1. [Figure 4] FIG. 4 illustrates the chromatogram of purified fraction 2. [Diagram 5] FIG. 5 illustrates the chromatogram of purified fraction 3. [Figure 6] FIG. 6 illustrates the chromatogram of purified fraction 4. [Figure 7] FIG. 7 illustrates the 1H NMR spectrum of the purified product from fraction 1. [Figure 8] FIG. 8 illustrates the 1H NMR spectrum of the purified product from fraction 1; this expanded NMR spectrum shows the proton splitting pattern of molecules that are the major components of purified fraction 1. [Figure 9] FIG. 9 illustrates the 13C NMR spectrum of the purified product from fraction 1; the absence of a 13C peak at 205-220 ppm characteristic of the ketone carbonyl (C=O) carbon suggests that the carbonyl carbon of testosterone enanthate is modified, e.g., by formation of a -COC- bond. [Figure 10] FIG. 10 illustrates an expanded 13C NMR spectrum (130-175 ppm) of the purified product from fraction 1. [Figure 11] FIG. 11 illustrates an expanded 13C NMR spectrum (2-84 ppm) of the purified product from fraction 1. [Figure 12] FIG. 12 illustrates the 13C DEPT NMR spectrum of the purified product from fraction 1. [Figure 13] FIG. 13 illustrates the MS spectrum of purified fraction 1 at MRM transitions 1304>1304, 1306>1306, 1706>1706, and 1704>1704. [Figure 14] FIG. 14 illustrates the MS2 spectrum of m / z=1304 using collision energy=90 eV. [Figure 15] FIG. 15 illustrates the MS2 spectrum of m / z=1306 using collision energy=90 eV. [Figure 16] FIG. 16 illustrates the mass spectrum (light stressed sample, region 1, major response at approximately 9.8 minutes in CAD); proposed empirical formula: C80H124O9 (mass error: -1.9 ppm). [Figure 17] FIG. 17 illustrates the mass spectrum (light stressed sample, region 1, minor response at about 10.4 min in the CAD). [Figure 18] FIG. 18 illustrates the extracted ion chromatogram (XIC) (light stressed sample, m / z 626). [Figure 19] FIG. 19 illustrates the mass spectrum of the control sample, region 2. [Figure 20] FIG. 20 illustrates the mass spectrum of the light stressed sample, region 2. [Figure 21] FIG. 21 illustrates the XIC of the light-stressed sample (m / z 933 (blue), 935 (pink), and 937 (orange)). [Figure 22] FIG. 22 illustrates the mass spectrum of the control sample, region 3. [Diagram 23] FIG. 23 illustrates the mass spectrum of 100 samples, region 3. [Figure 24] FIG. 24 illustrates the XICs of the photostressed sample (m / z 901 (blue), 903 (pink), 905 (orange), 907 (green), and 909 (light blue)). [Diagram 25] FIG. 25 illustrates the XICs of the photostressed sample (m / z 1302 (blue), 1304 (pink), 1306 (orange), 1308 (green), and 1310 (light blue)). [Figure 26] FIG. 26 illustrates the XICs of the photostressed sample (m / z 1702 (blue), 1704 (pink), 1706 (orange), and 1708 (green)). [Figure 27] FIG. 27 illustrates the mass spectrum of the control sample, region 4. [Figure 28] FIG. 28 illustrates the mass spectrum of the photostressed sample, region 4. [Figure 29] FIG. 29 illustrates the XIC of the light stressed sample (m / z 1782 (blue) and 1758 (pink)). [Diagram 30] FIG. 30 illustrates exemplary chromatograms (Charged Aerosol Detection-CAD; pink=stress; black=control) of a control sample and an ICH photolysis sample. [Diagram 31] FIG. 31 illustrates the chromatogram (UV) of tocopherols. [Diagram 32] FIG. 32 illustrates the chromatogram (CAD) of tocopherols. [Diagram 33] FIG. 33 illustrates the chromatogram (UV 242 nm) of the control sample. [Diagram 34] FIG. 34 illustrates the chromatogram (CAD) of the control sample. [Diagram 35] FIG. 35 illustrates the chromatogram (UV 242 nm) of the light exposed sample. [Diagram 36] FIG. 36 illustrates the chromatogram (UV 242 nm) of a light-exposed tocopherol-containing sample. [Figure 37] FIG. 37 illustrates the superimposed chromatograms (control sample--black, tocopherol-containing sample--blue (242 nm)). [Figure 38] FIG. 38 illustrates the overlaid chromatograms (control sample--black, tocopherol-containing sample--green (CAD)). [Figure 39] FIG. 39 illustrates the overlaid chromatograms (light exposed sample - red, control sample - black (UV)). [Diagram 40] FIG. 40 illustrates the overlaid chromatograms (light exposed sample - black, control sample - brown (CAD)). [Diagram 41] FIG. 41 illustrates the overlaid chromatograms (light exposed sample - black, sample + tocopherol - blue (UV)). [Diagram 42] FIG. 42 illustrates the overlaid chromatograms (light exposed sample - black, sample + additive - green (CAD)). [Diagram 43] FIG. 43 illustrates the overlaid chromatograms (control sample-black, light exposed sample-blue). [Diagram 44] FIG. 44 illustrates the overlaid chromatograms (control sample--black, sample+tocopherol--green). [Diagram 45] FIG. 45 illustrates the overlaid chromatograms (control sample--black, sample+tocopherol--green). [Figure 46] FIG. 46 illustrates the overlaid chromatograms: TE peaks (control sample-black, sample+tocopherol-green, sample-blue).

[0036] The above-identified drawings illustrate embodiments disclosed herein; however, as noted in the discussion, other embodiments are contemplated. This disclosure presents illustrated embodiments by way of representation and not by way of limitation. Those skilled in the art can devise numerous other modifications and embodiments which fall within the scope and spirit of the principles of the embodiments disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0037] The present invention relates to testosterone ester formulations, testosterone ester adducts, combinations of testosterone ester formulations and, optionally, testosterone ester adducts, and methods for controlling the in situ production or formation of testosterone ester adducts.

[0038] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0039] As used herein, the terms “administer,” “administration,” or “administering” refer to: (1) any agent or substance in accordance with the present disclosure; Thus, providing, giving, dispensing, and / or prescribing by or under the direction of a healthcare professional or his / her authorized representative; and / or (2) In accordance with this disclosure, reference is made to being administered, taken, or consumed by a subject, e.g., a mammal, including a human.

[0040] As used herein, the terms "co-administration," "co-administration of," "administered in combination with," "administering in combination with," "simultaneous," and "concurrent" include administration of two or more active pharmaceutical ingredients to a subject such that the active pharmaceutical ingredients and / or their metabolites are both present in the subject at the same time. Concurrent administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. In some embodiments, simultaneous administration in separate compositions and administration in a composition in which the two agents are present are preferred.

[0041] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein sufficient to effect the intended application, including but not limited to the treatment of a disease. A therapeutically effective amount is an amount sufficient to effect the intended application, whether in vitro or in vivo. In vivo, or the subject and disease state being treated (e.g., the subject's weight, age, and sex), the severity of the disease state, the mode of administration, etc., can vary, and can be readily determined by one of skill in the art. The term also applies to a dose that induces a particular response in a target cell (e.g., reduced platelet adhesion and / or cell migration). The specific dose will vary depending on the subject to which it is to be administered, the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is delivered.

[0042] A "therapeutic effect," as that term is used herein, includes a therapeutic benefit and / or a prophylactic benefit. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0043] As used herein, the terms "treat", "treatment" and / or "treating" may refer to the management of a disease, disorder, pathological condition, or a symptom thereof, with the intent to cure, ameliorate, stabilize, and / or control the disease, disorder, pathological condition, or a symptom thereof. More specifically, with respect to the control of a disease, disorder, or pathological condition, "control" may include the absence of disease progression as assessed by response to the methods described herein, which may be complete (e.g., eliminating the disease) or partial (e.g., reducing or improving symptoms associated with the condition). As used herein, "prevent", "preventing", and / or "preventing .... The term "prevention" may refer to reducing the risk of developing a disease, disorder, or pathological condition.

[0044] The term "pharmaceutically acceptable salts" refers to salts derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, potassium, potassium phosphate ... Examples of suitable base addition salts include ammonium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharma-ceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts. The term "cocrystal" refers to molecular complexes derived from many cocrystal formers known in the art. Unlike salts, cocrystals typically do not involve hydrogen transfer between the cocrystal and the drug, but instead involve intermolecular interactions such as hydrogen bonding, aromatic ring stacking, or dispersion forces between the cocrystal former and the drug in the crystal structure.

[0045] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "physiologically compatible" carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as a conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the present invention is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the compositions and methods described herein.

[0046] "Prodrug" refers to a derivative of a compound described herein, whose pharmacological action results from conversion to an active compound by chemical or metabolic processes in vivo. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues is covalently bonded to a free amino, hydroxyl, or carboxylic acid group of a testosterone ester via an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids, which are usually represented by one-letter or three-letter symbols, but also include, for example, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also contemplated. For example, a free carboxyl group can be derivatized as an amide or alkyl ester (e.g., methyl ester, and acetoxymethyl ester). Prodrug esters as utilized in the present invention include esters and carbonates formed by reacting one or more hydroxyls of the compounds of the present method with alkyl, alkoxy, or aryl substituted acylating agents using techniques known to those skilled in the art to generate acetates, pivalates, methyl carbonates, benzoates, and the like. As further examples, free hydroxyl groups can be derivatized using groups including, but not limited to, hemisuccinate, phosphate, dimethylaminoacetate, and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groups are also included, as well as carbonate, sulfonate, and sulfate prodrugs of hydroxyl groups. Free amines can also be derivatized to amides, sulfonamides, or phosphonamides. All of the prodrug moieties described herein may incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.Additionally, any compound that can be converted in vivo to provide a bioactive agent (e.g., testosterone esters and / or testosterone) is a prodrug within the scope of the present invention. Various forms of prodrugs are well known in the art. (a) "The Practice of Medicinal Chemistry" by Camille G. Wermuth et al. (Academic Press, 1996); (b) "Design of Prodrugs" "The Study of Prodrugs" edited by H. Bundgaard (Elsevier, 1985); (c) Drug Design and Development A Textbook of Drug Design and Development by P. Krogsgaard-Larson and H. Bundgaard (Harwood Academic Publishers, 1991) A comprehensive description of drug and prodrug derivatives is described. In general, prodrugs can be designed to improve the penetration of drugs into biological membranes to obtain improved drug absorption, to extend the duration of drug action (sustained release of parent drug from prodrug, reduced first-pass metabolism of drug), to target drug action (e.g., organ or tumor targeting, lymphocyte targeting), to modify or improve the water solubility of drugs (e.g., intravenous preparations and eye drops), to improve topical delivery of drugs (e.g., drug delivery to skin and eyes), to improve the chemical / enzymatic stability of drugs, or to reduce off-target drug action, and more generally to improve the therapeutic efficacy of the compounds utilized in the present invention.

[0047] Unless otherwise stated, chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isomerically enriched atoms. For example, compounds in which one or more hydrogen atoms are replaced by deuterium or tritium, or compounds in which one or more carbon atoms are replaced by 13 C-enriched carbon or 14Compounds substituted at C-enriched carbons are also within the scope of the invention.

[0048] As used herein, triglycerides can be referred to using a three-letter code, with each letter representing a particular fatty acid. Individual fatty acids, substituent fatty acids, substituted fatty acids, or fatty acid radicals can be referred to by their one-letter initials. See, e.g., The United States Pharmacopeial Convention (2015), "Sesame Oil." For example, fatty acid radicals can be written as linoleic (L), oleic (O), palmitic (P), and stearic (S), and common abbreviations for triglycerides are trilinolein (LLL), 1,2-dilinoleoyl-3-oleoyl-rac-glycerol (OLL), 1,2-dilinoleoyl-3-palmitoyl-rac-glycerol (PLL), 1,2-dioleoyl-3-linoleoyl-rac-glycerol (OOL), 1-palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol (POL), triolein (OOO), 1-linoleoyl-2-oleoyl-3-stearoyl-rac-glycerol (SOL), 1,2-dioleoyl-3-palmitoyl-rac-glycerol (POO), etc. Where necessary, the one-letter codes for fatty acids are underlined to distinguish the fatty acid radicals (underlined) from the one-letter codes that describe the different entities. For example, " O " can be distinguished from the "O" for oxygen.

[0049] In this specification, when a range is used to describe a physical or chemical property, such as, for example, a molecular weight or a chemical formula, it is intended to include all combinations and subcombinations of the ranges and specific embodiments therein. The use of the term "about" when referring to a numerical value or numerical range means that the numerical value or numerical range referred to is an approximation within a range of experimental variability (or within a range of statistical experimental error), and therefore the numerical value or numerical range may vary. This variability is typically 0% to 15%, 0% to 10%, 0% to 5%, etc., of the stated numerical value or numerical range.

[0050] As used herein, the term "about" means that amounts, dimensions, formulations, parameters, shapes, and other quantities and characteristics are not, and need not be, exact, but may be approximate and / or larger or smaller, as desired, to reflect tolerances, conversion factors, rounding, measurement errors, and the like, and other factors known to those of skill in the art. In general, a quantity, dimension, formulation, parameter, shape, or other quantity or characteristic is "about" or "approximate," whether or not expressly stated as such.

[0051] "Comprising" and "consisting essentially of The transitional terms "of" and "consisting of," when used in the original and amended forms of the accompanying claims, define the scope of the claim with respect to what additional unrecited claim elements or steps, if any, are excluded from the scope of the claim. The term "comprising" is intended to be inclusive or open-ended and does not exclude additional unrecited elements, methods, steps, or materials. The term "consisting of" excludes any element, step, or material other than those specified in the claim (in this case, impurities normally associated with the particular material). The term "consisting essentially of" limits the scope of the claim to the specified elements, steps, or materials, and those that do not materially affect the basic and novel characteristics of the claimed invention. All compounds, compositions, formulations, and methods described herein that embody the present invention may, in alternative embodiments, be more specifically defined by any of the transitional phrases "comprising," "consisting essentially of," and "consisting of." The term "comprising" (and related terms such as "comprise," "having," or "including") includes, for example, the following: The term "composition of matter," "method of matter," or "consisting essentially of" includes such aspects as any composition of matter, method, or process aspect.

[0052] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms and containing no unsaturation, having from 1 to 10 carbon atoms (e.g., (C 1-10 ) alkyl or C 1-10The term "alkyl" refers to a cyclic alkyl group. Whenever it appears herein, a numerical range such as "1-10" represents each integer in the given range, for example, "1-10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, but this definition is also intended to include occurrences of the term "alkyl" where no numerical range is specifically recited. Exemplary alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl, ter-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. The alkyl moiety may be attached to the remainder of the molecule by a single bond, such as, for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and 3-methylhexyl. Unless otherwise specifically stated in the specification, alkyl groups are independently selected from the group consisting of heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(Ra )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2), or PO3(R a )2 (where each R a is optionally substituted by one or more of the following substituents which are independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl. The alkyl portion may be either saturated or unsaturated, branched, straight chain, or cyclic.

[0053] An "alkene" or "alkenyl" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms. It represents a group consisting of a carbon atom and at least one carbon-carbon triple bond.

[0054] "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 10 carbon atoms (i.e., (C 2-10 ) alkenyl or C 2-10alkenyl). Whenever it appears herein, a numerical range such as "2 to 10" represents each integer in the given range, for example, "2 to 10 carbon atoms" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms. The alkenyl moiety may be attached to the remainder of the molecule by a single bond, such as, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and penta-1,4-dienyl. Unless otherwise specifically stated herein, alkenyl groups may independently be alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2), or PO3(R a )2 (where each Ra is optionally substituted by one or more of the following substituents which are independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0055] "Alkenyl-cycloalkyl" refers to an -(alkenyl)cycloalkyl radical, where the alkenyl and cycloalkyl are as disclosed herein and may be optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl, respectively.

[0056] "Cycloalkyl" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen and may be saturated or partially unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms (i.e., (C 3-10 ) cycloalkyl or C 3-10 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" represents each integer in the given range, for example, "3 to 10 carbon atoms" means that the cycloalkyl group can consist of from 3 carbon atoms, and so on up to 10 carbon atoms. Illustrative cycloalkyl groups include, but are not limited to, the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless otherwise specifically stated herein, cycloalkyl groups are independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamido, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a -(wherein t is 1 or 2), -S(O) t Ra - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (where: t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2), or PO3(R a )2 (where each R a is optionally substituted by one or more of the following substituents which are independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0057] "Cycloalkyl-alkenyl" refers to a -(cycloalkyl)alkenyl radical, where the cycloalkyl and alkenyl are as disclosed herein and may be optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.

[0058] "Acyl" refers to (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and (heterocycloalkyl)-C(O)- groups, which are attached to the parent structure via a carbonyl functionality. If the R radical is heteroaryl or heterocycloalkyl, the atoms of the heterocycle or chain contribute to the total number of atoms in the chain or ring. Unless otherwise specifically stated in the specification, the alkyl, aryl, or heteroaryl portion of the acyl group can be independently selected from alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2), or PO3(R a )2 (where each R ais optionally substituted by one or more of the following substituents which are independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0059] "Ester" refers to a chemical group of the formula: -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). Procedures and specific groups for making esters are known to those of skill in the art and can be readily found in such seminal sources as Greene and Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York, NY (1999), which is incorporated herein in its entirety. Unless otherwise specifically stated herein, ester groups include, independently, alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (wherein t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(Ra )2, -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2), or PO3(R a )2 (where each R a are independently hydrogen, alkyl, or fluoroalkyl. , carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0060] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0061] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space, i.e., have different stereochemical configurations. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate racemic mixtures where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either (R) or (S). A resolved compound whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that it rotates plane polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and may give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry, such as (R) or (S). The chemical moieties, pharmaceutical compositions, and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. If the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E- and Z-geometric isomers.

[0062] "Moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded in or attached to a molecule. "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and can occur either prototropic or prototropic. This includes roton shift tautomerization, which is considered part of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" involves the movement of a proton accompanied by a change in bond order, often the interconversion of a single bond and an adjacent double bond. When tautomerization is allowed (e.g., in solution), it is possible to reach a chemical equilibrium of tautomers. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of the tautomers of pyridin-4-ol and pyridin-4(1H)-one.

[0063] "Substituted" means that the referenced group is, for example, acyl, alkyl, aryl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, Alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanate, thiocyanate, isothio Cyanate, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfuryl, sulfonyl, sulfonamidyl, sulfoxy "Optionally substituted" means to attach one or more additional groups, radicals, or moieties individually and independently selected from aryl, sulfonate, urea, amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The substituents themselves can also be substituted, for example, a cycloalkyl substituent can itself have a halide substituent on one or more of its ring carbons. The term "optionally substituted" means optional substitution with the specified groups, radicals, or moieties.

[0064] Detailed Description formulation In one embodiment, the present invention provides a compound represented by formula 1:

[0065] [ka]

[0066] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof; an antioxidant; and a testosterone ester of formula 2:

[0067] [ka]

[0068] wherein R1 is an alkyl or alkenyl substituent; and each of R2, R3, and R4 is an acyl group corresponding to a fatty acid such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. In some embodiments, R1 is propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, or unsaturated analogs thereof. In some embodiments, the testosterone ester is testosterone enanthate, testosterone cypionate, testosterone propionate, or testosterone undecanoate. In some embodiments, the testosterone ester is testosterone enanthate.

[0069] [ka]

[0070] Other drugs may also be used in the formulation, particularly drugs with an α,β-unsaturated ketone moiety, such as cortisone or hydrocortisone. In some embodiments, various other active ingredients can be included in the formulation: nonsteroidal estrogens such as benzestrol, broparestrol, chlorotrianisene, dienestrol, diethylstilbestrol, diethylstilbestrol dipropionate, dimestrol, fosfestrol, hexoestrol, metallenstrol, and metestrol; and steroidal estrogens such as colpolmon, conjugated estrogen hormones, equilenin, equilin, estradiol, 17-β-estradiol, estriol, estrone, ethinyl estradiol, estradiol benzoate, estradiol 17-β-cypionate, polyestradiol phosphate, mestranol, moxestrol, mitatrienediol, quinestradiol, quinestrol; allylestrenol, anagestone, chromaldi acetate, Non, delmadinone acetate, demegestrin, desogestrel, dimethisterone, drospirenone, dydrogesterone, ethinylestrenol, ethisterone, ethynodiol, ethynodiol diacetate, fluorogestone acetate, gestodene, gestnorone caproate, haloprogesterone, 17-hydroxy-16-methylene-δ-progesterone, 17-α-hydroxyprogesterone, 17-α-hydroxygesterone caproate, linethyl Progestogens such as strenol, medrogestone, medroxyprogesterone, megestrol acetate, melengestrol, norethindrone, norethindrone acetate, norethynodrel, norgesterone, norgestimate, norgestrel, norgestrienone, 19-norprogesterone, norvinisterone, pentagestrone, progesterone, natural progesterone, promegestone, quingestrone, trengestone;androgens such as boldenone, cloxotestosterone, fluoxymesterone, mestanolone, mesteronolone, 17-methyltestosterone, 17-β-cypionate testosterone, enanthate testosterone, nicotinate testosterone, phenylacetate testosterone, propionate testosterone, 17-α-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanolone, stanolozole, testosterone, and / or thiomesterone. The active agent may be an antihormonal. For example, the medicament active agent may include, but is not limited to, estrogens, androgens, or progestogens, antiestrogens such as tamoxifen, 4-OH tamoxifen, antiprogestogens, and antiandrogens. Generally, any drug suitable for parenteral administration may be used in the formulation of the present invention;

[0071] Any glyceride suitable for parenteral administration can be used in the formulations of the present invention, including triglycerides, diglycerides, and / or monoglycerides. In some embodiments, the triglyceride is one of LLL, OLL, OOL, OOO, PLL, POL, POO, or SOL. In one embodiment, the triglyceride can also include SSL, SLS, LLS, LSL, MML, MLM, MML, LLM, SSM, SMS, MMM, SSS, and LLL. Long, medium, short, and mixed long chain triglycerides can be used. Triglycerides also include triglycerides containing residues of known fatty acids or other shorter chain saturated or unsaturated acids. Fatty acids include myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoellagic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and / or cerotic acid. Fatty acids are primarily present in the formulations described herein as a residue moiety of triglycerides, diglycerides, or monoglycerides, although independent fatty acids may also be part of the formulations. Any of the triglycerides, diglycerides, monoglycerides, and / or fatty acids described herein can form adducts as described herein with testosterone esters, e.g., testosterone enanthate.

[0072] In some embodiments, the pharma- ceutically acceptable carrier comprises vegetable oil. In some embodiments, the vegetable oil is sesame oil. Other oils, including vegetable oil or non-vegetable oil, such as castor oil, cottonseed oil, soybean oil, and / or sunflower oil, can also be used. In general, any oil suitable for parenteral administration can be used in the formulation of the present invention.

[0073] Any antioxidant suitable for parenteral administration can be used in the formulations of the present invention, hi some embodiments, the antioxidant is one or more of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and / or monosodium glutamate.

[0074] In one embodiment, the present invention relates to a pharmaceutical formulation comprising testosterone enanthate, sesame oil, and BHT.In one embodiment, the present invention relates to a pharmaceutical formulation comprising testosterone enanthate, sesame oil, and tocopherol.

[0075] Additives that may be included in the formulation In another aspect, the present invention provides a compound of formula 3:

[0076] [ka]

[0077] wherein: R1 is an alkyl or alkenyl substituent, which may be the same or different at each independent occurrence; R5 is an acyl group corresponding to an unsaturated fatty acid; G is a glycerol, monoglyceride, or diglyceride residue; n is 1, 2, or 3; and the testosterone residue is linked to the allylic or diallylic carbon of R5.

[0078] Such adducts can be prepared and formulated alone, such as those described herein. The compound may be separated after synthesis or may be combined with other components and formulated. Adducts of formula 3 may be made intentionally or may form unexpectedly or unpredictably under various conditions in pharmaceutical formulations described herein that include glycerides having an α,β-unsaturated ketone moiety and an unsaturated acyl residue, e.g., mono-, di-, or triglycerides. In some aspects, the present invention relates to an isolated testosterone ester adduct of formula 3, or an isolated testosterone ester adduct of any formula described herein.

[0079] In some embodiments, the conditions that lead to the formation of the adducts described herein are referred to as stressor conditions, including, but not limited to, exposure to light and / or exposure to an oxidizing atmosphere, such as exposure to oxygen, and / or exposure to stressor conditions known in the art. Testosterone esters, such as testosterone enanthate (TE), are examples of drugs that contain α,β-unsaturated ketone moieties, and sesame oil is an example of an oil that contains unsaturated acyl moieties, such as triglycerides that contain double bonds and / or homoconjugated double bonds, such as linoleoyl side chains. Without wishing to be bound by a particular theory, the adducts described herein can be made or appear as a result of the addition of α,β-unsaturated ketone compounds, such as testosterone derivatives, to a hydrocarbon chain, such as the hydrocarbon chain contained in a fatty acid, where the addition occurs adjacent to a double bond.

[0080] In some embodiments, the adducts described herein may be produced or appear as a result of autoxidation. Without wishing to be bound by a particular theory, unsaturated acyl moieties and side chains are susceptible to autoxidation in the presence of oxygen, light, or light and oxygen. Autoxidation of these side chains produces hydrogen peroxide radicals, e.g., linoleoyl hydrogen peroxide, along with free radicals, e.g., linoleoyl free radicals, and peroxy radicals, e.g., linoleoyl peroxy radicals (Scheme 5). Because linoleoyl free radicals and linoleoyl peroxy radicals are highly reactive, autoxidation is an autocatalytic chain reaction.

[0081] The degree of oxidation of a mixture of TG can be measured by a USP test called peroxide value (PV). Peroxide value is defined as the amount of oxygen peroxide per kg of fat (milli-equivalent O2 / kg fat). Generally speaking, the PV of a mixture of TG, whether or not it contains a drug, increases over time, indicating that the TG in the mixture is oxidized over time. Without wishing to be bound by a particular theory, it is believed that when TG is oxidized in the presence of an α,β-unsaturated ketone moiety, the ketone moiety may react with the carbon atom attached to the peroxy moiety to produce various adducts as described herein.

[0082] In some embodiments, the testosterone ester adduct has formula 4. In some embodiments, R1 is propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, and / or one of their unsaturated analogs. In some embodiments, R1 is hexyl.

[0083] [ka]

[0084] In some embodiments, the present invention provides compounds of Formulas 5-9:

[0085] [ka]

[0086] [ka]

[0087] wherein each of R6 and R7 is independently an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid.

[0088] In some embodiments, the present invention provides a compound of formula 10:

[0089] [ka]

[0090] This relates to a testosterone ester adduct of In some embodiments, the present invention provides a compound of formula 11:

[0091] [ka]

[0092] This relates to a testosterone ester adduct of The adducts described herein may have various other formulas. Without wishing to be bound by any particular theory, the geometry of the double bonds of the fatty acid chain is generally preserved after the adduct formation process, although in some embodiments, the geometry may change. Also, without wishing to be bound by any particular theory, the adducts generally occur at allylic and diallylic positions, but the adducts may also occur at other positions, such as homoallylic positions. Thus, the following formulas 12 to 16:

[0093] [ka]

[0094] [ka]

[0095] may be formed, where: G is a glycerol, monoglyceride, or diglyceride residue; n is 1, 2, or 3. The following Equations 17 to 22:

[0096] [ka]

[0097] [ka]

[0098] Regioisomeric adducts of the formula: P , L , O , and S corresponds to each fatty acyl group; the testosterone residue is attached at any available position along the fatty acid side chain.

[0099] In some aspects, the testosterone ester triglyceride adducts described herein may be created or formed when a percentage of the initial testosterone ester in the formulation is converted to the adduct over a period of time under various conditions described herein.

[0100] In some embodiments, the percentage of the initial testosterone ester, e.g., testosterone enanthate, in the formulation that is converted to an adduct of the testosterone ester with a triglyceride is less than about 0.001%, about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, ... %, approx. 0.01%, approx. 0.015%, approx. 0.02%, approx. 0.025%, approx. 0.03%, approx. 0.035%, approx. 0.04%, approx. 0.045%, approx. 0.05%, approx. 0.055%, approx. 0.06%, approx. 0.065%, approx. 0.07%, approx. 0.075%, approx. 0.08%, approx. 0.085%, approx. 0.09%, approx. 0.095% , about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, or more than about 1%.

[0101] In some embodiments, the percentage of the initial testosterone ester, e.g., testosterone enanthate, in the formulation that is converted to an adduct of the testosterone ester with a triglyceride is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 9 9%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50%.

[0102] In some embodiments, the antibody is administered after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about After 60 days, about 90 days, about 120 days, about 180 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 36 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 6 years, a proportion of the initial testosterone ester, e.g., testosterone enanthate, is converted to an adduct of testosterone ester with a triglyceride.

[0103] In some embodiments, a percentage of the initial testosterone ester, e.g., testosterone enanthate, is converted to a testosterone ester adduct with a triglyceride during normal storage conditions, e.g., during storage in a prefilled syringe (PFS) or vial. In some embodiments, the PFS can be exposed to ambient light or can be protected from light, e.g., in an opaque container, such as any type of cardboard box. ... 2 and 1.2 million lux hours or more of visible light exposure. In some embodiments, the pharmaceutical formulation is exposed to ambient light or an amount of UV light and / or visible light equivalent to ambient light exposure for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days ... days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 90 days, about 120 days, about 180 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 month, about 2 months, about 3 After exposure for about 2 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 36 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, or other periods, a percentage of the initial testosterone ester, e.g., testosterone enanthate, in the pharmaceutical formulation is converted to an adduct of testosterone ester with a triglyceride.

[0104] Controlling or inhibiting the in situ formation of adducts The creation or formation of testosterone ester triglyceride adducts described herein can be controlled or their formation inhibited in situ by the addition of antioxidants to the formulation.

[0105] Thus, in one aspect, the present invention generally relates to the addition of an antioxidant (such as butylated hydroxytoluene (BHT)) to a testosterone ester formulation, such as an injectable pharmaceutical formulation of testosterone enanthate, thereby controlling the in situ production or creation of the adducts of the present invention.

[0106] Such control can improve the photostability of drug formulations. Without being limited to a particular theory, the invention's success in controlling the in situ formation of adducts is due, in part, to the inhibition of lipid peroxide formation during aging and / or exposure to light of the formulation. The inhibition of peroxide formation, e.g. lipid peroxide formation, is also applied to the components of the formulation before it reaches its final form. The present invention also relates to identifying key products formed under light stress, and these products at least partially explain the decrease in testosterone ester concentration in testosterone ester formulations under various aging conditions.

[0107] Without wishing to be bound by theory, BHT acts as a free radical scavenger during the preparation or creation of the adducts of the present invention. It stops the autoxidation of TG by donating a hydrogen atom to convert the peroxy radical to hydrogen peroxide and the TG radical to TG, while generating the BHT radical, as shown in Scheme 6. Once formed, the BHT radical cannot react further because its large tert-butyl group creates too much steric hindrance and the oxygen atom with the unpaired electron cannot make the necessary contact with other molecules to enable reaction. The formation of the BHT radical stops radical chain reactions, such as the autoxidation of triglycerides, and more specifically, the autoxidation of unsaturated triglyceride side chains.

[0108] Oxidation of triglyceride-containing oils can be effectively controlled or inhibited in the presence of 0.06-0.07% antioxidant (e.g., BHT). In some embodiments, TG oxidation can be inhibited in the presence of about 0.01% to about 0.1% BHT, or other suitable antioxidant, such as tocopherol. In other embodiments, TG oxidation can be inhibited in the presence of about 0.05% to about 0.5% BHT, or other suitable antioxidant. As described herein, the peroxide value (PV) level of a mixture of triglycerides can be maintained at a low level, e.g., <12, over time by adding an antioxidant to the mixture, compared to a PV level of approximately 70-80 without the antioxidant. The level of PV in the formulation can be determined after various periods of time after making the formulation, for example, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, or about 36 months.

[0109] An alternative measure of the concentration of available testosterone esters is to measure degradation in the absence and presence of antioxidants, with the addition of antioxidants resulting in a reduced level of degradation. In some embodiments, the addition of antioxidants to a particular formulation results in the formation of adducts over a period of time that is less than that seen over a similar period in a formulation without the addition of antioxidants. Compared to the above, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26% %, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51% ,About 52%,About 53%,About 54%,About 55%,About 56%,About 57%,About 58%,About 59%,About 60%,About 61%,About 62%,About 63%,About 64%,About 65%,About 66%,About 67%,About 68%,About 69%,About 70%,About 71%,About 72%,About 73%,About 74%,About 75%,About 76%, It is reduced by about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%.

[0110] In some embodiments, the present invention relates to a pharmaceutical formulation comprising a testosterone ester of formula 1, a pharma- ceutically acceptable carrier comprising one or more triglycerides of formula 2, and a testosterone ester adduct of any one of formulas 3-22, wherein: R1 is an alkyl or alkenyl substituent; and each of R2, R3, and R4 is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. In some embodiments, R1, at each independent occurrence, is selected from the group consisting of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, and / or unsaturated analogs thereof. In some embodiments, the testosterone ester is testosterone enanthate, testosterone cypionate, testosterone propionate, or testosterone undecanoate. In some embodiments, the testosterone ester is testosterone enanthate. In some embodiments, the triglyceride is one of LLL, OLL, OOL, OOO, PLL, POL, POO, and SOL. In some embodiments, the pharma- ceutically acceptable carrier comprises a vegetable oil. In some embodiments, the pharmaceutical formulation further comprises an antioxidant. In some embodiments, the antioxidant is one or more of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and / or monosodium glutamate.

[0111] A testosterone ester adduct of any one of formulas 3-22 may optionally be present in any of the formulations described herein, typically as a result of unpredictable or controlled in-situ creation, or as a result of deliberately introducing such an adduct into the formulation. The concentration of this adduct in the formulation may be any concentration, but it will generally be less than the concentration of the corresponding testosterone ester in the formulation at any given moment in time.

[0112] Stable formulation In one aspect, the invention relates to a photostable testosterone ester pharmaceutical formulation comprising a testosterone ester of Formula 1, an antioxidant, and a pharma- ceutical acceptable carrier comprising one or more triglycerides of Formula 2, where: R1 is an alkyl or alkenyl substituent; each of R2, R3, and R4 is an acyl group corresponding to a fatty acid, such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid; and the photostability of the formulation is assessed by measuring the concentration of available testosterone ester 30-60 days after making the formulation and comparing it to the initial testosterone ester concentration of the formulation.

[0113] In one aspect, the present invention relates to a photostable testosterone ester pharmaceutical formulation comprising a pharma- ceutically acceptable carrier comprising a testosterone ester of formula 1, an antioxidant, and one or more triglycerides of formula 2, and optionally an adduct of the present invention, wherein: R1 is an alkyl or alkenyl substituent; and each of R2, R3, and R4 is an acyl group corresponding to a fatty acid such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid.

[0114] The photostability of the formulation is evaluated 30-60 days after preparation of the formulation by measuring the concentration of available testosterone ester and comparing it to the initial testosterone ester concentration in the formulation, and by detecting the presence in the formulation and measuring the concentration of one or more testosterone ester adducts of any one of Formulas 3-22.

[0115] The photostability of any formulation described herein can be evaluated at any time after the initial formulation is made.For example, photostability can be evaluated after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours.

[0116] Photostability may also be assessed after about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 90 days, about 120 days, or about 180 days.

[0117] Photostability may also be evaluated after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks. Photostability may also be evaluated after about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, or about 36 months. Photostability may also be evaluated after about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, or any number of years from the creation of the initial formulation.

[0118] In one aspect, the present invention relates to a photostable testosterone ester pharmaceutical formulation comprising a testosterone ester of formula 1, an antioxidant, and a pharma- ceutical acceptable carrier comprising a triglyceride of formula 2, wherein: R1 is an alkyl or alkenyl substituent; each of R2, R3, and R4 is an acyl group corresponding to a fatty acid, such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid; and the photostability of the formulation is such that the pharmaceutical formulation is photoinduced at a temperature of 200 Watt-hours / m 2 The testosterone ester concentration is evaluated by exposing the formulation to over 100,000 lux of UV light and over 1.2 million lux of visible light exposure, measuring the concentration of available testosterone ester and comparing it to the initial testosterone ester concentration of the formulation.

[0119] In one aspect, the present invention relates to a photostable testosterone ester pharmaceutical formulation comprising a testosterone ester of formula 1, an antioxidant, and a pharma- ceutical acceptable carrier comprising a triglyceride of formula 2, wherein: R1 is an alkyl or alkenyl substituent; each of R2, R3, and R4 is an acyl group corresponding to a fatty acid, such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid; and the photostability of the formulation is such that the pharmaceutical formulation is photoinduced at a temperature of 200 Watt-hours / m 2 and 1.2 million lux hours of visible light exposure, the concentration of available testosterone ester is measured, and compared to the initial testosterone ester concentration of the formulation, and any of Formulas 3 to 22 is used. The testosterone ester adduct is assessed by detecting its presence in the formulation and measuring its concentration.

[0120] The photostability of the formulations described herein is measured by measuring the photostability of the pharmaceutical formulation at 200 watt-hours / m 2Photostability is evaluated by exposure to at least 100,000 lux hours of UV light and at least 1.2 million lux hours of visible light exposure, although any photoexposure value may be used. For example, photostability may be determined after exposing the pharmaceutical formulation to an amount of UV light and / or visible light equivalent to exposure to ambient light for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, or the like.

[0121] Photostability may also be determined after exposing the pharmaceutical formulation to an amount of UV light and / or visible light equivalent to exposure to ambient light for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 90 days, about 120 days, or about 180 days, or the like.

[0122] Photostability may also be determined after exposing the pharmaceutical formulation to an amount of UV light and / or visible light equivalent to exposure to ambient light for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 36 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, or any suitable period of time.

[0123] In one embodiment, the present invention relates to photostable testosterone esters, wherein the concentration of available testosterone ester is at least 66.8%-75.0% of the initial testosterone ester concentration. In some embodiments, the concentration of available testosterone ester at any time after the initial formulation is made is at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, 5%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73% , about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%.

[0124] In some embodiments, the present invention relates to photostable testosterone esters including a testosterone ester adduct of any one of Formulas 3-22, wherein the concentration of the testosterone ester adduct in the formulation is less than the concentration of available testosterone ester at any time after making the initial formulation.

[0125] In one aspect, the present invention provides a pharmaceutical composition comprising a testosterone ester of formula 1 and a pharma- ceutical acceptable carrier comprising one or more triglycerides of formula 2. The present invention relates to a method for measuring the photostability of an agent, the method comprising the steps of: measuring an initial testosterone ester concentration in the formulation; measuring the concentration of available testosterone ester in the formulation after a period of time; and comparing the two concentrations, where R1 is an alkyl or alkenyl substituent; and each of R2, R3, and R4 is an acyl group corresponding to a fatty acid such as linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and / or stearic acid. In some embodiments, the method includes heating the pharmaceutical formulation at 200 Watt-hours / m 2 and 1.2 million lux hours or more of visible light exposure. The photostability may be determined after exposing the pharmaceutical formulation to ambient light for a period of time, or to an amount of UV and / or visible light equivalent to exposure to ambient light for a period of time. In some embodiments, the pharmaceutical formulation further comprises an antioxidant, such as butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and / or monosodium glutamate. In some embodiments, the period of time is between 30 and 60 days. In some embodiments, the method further comprises detecting the presence and measuring the concentration of a testosterone ester adduct of any one of formulas 3-22 in the pharmaceutical formulation.

[0126] Measuring the concentration of available testosterone ester in the formulation can be evaluated at any time after making the initial formulation. For example, the concentration of available testosterone ester in the formulation can be evaluated after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours.

[0127] The concentration of available testosterone ester in the formulation may also be evaluated after about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 90 days, about 120 days, or about 180 days.

[0128] The concentration of available testosterone ester in the formulation may also be evaluated after about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks. The photostability may also be evaluated after about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, or about 36 months. The photostability may also be evaluated after about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, or any number of years from the creation of the initial formulation.

[0129] The concentration of available testosterone ester in the formulation may also be determined after exposing the pharmaceutical formulation to ambient light or to an amount of UV and / or visible light equivalent to exposure to ambient light for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, or the like.

[0130] The concentration of available testosterone ester in the formulation may be adjusted to expose the pharmaceutical formulation to ambient light or to an amount of UV and / or visible light equivalent to exposure to ambient light for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 12 days, about 16 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about It may be determined after 5 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 90 days, about 120 days, or about 180 days, or the like, of exposure.

[0131] The concentration of available testosterone ester in the formulation may also be determined after exposing the pharmaceutical formulation to ambient light, or to an amount of UV and / or visible light equivalent to exposure to ambient light, for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 36 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, or any suitable period of time.

[0132] Pharmaceutical Compositions In some embodiments, the concentration of the testosterone esters described herein may be, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.0% or more of the pharmaceutical formulations described herein. 7%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (w / w, w / v, or v / v).

[0133] In some embodiments, the concentration of testosterone esters described herein is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 1 ... .50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75% ,7.50%,7.25%,7%,6.75%,6.50%,6.25%,6%,5.75%,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,1.25%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0.0 greater than 6%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (w / w, w / v, or v / v).

[0134] In some embodiments, the concentration of the testosterone esters described herein is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, ... The range is from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10% (w / w, w / v, or v / v).

[0135] In some embodiments, the concentration of the testosterone esters described herein ranges from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% (w / w, w / v, or v / v) of the pharmaceutical formulations described herein.

[0136] In some embodiments, the amount of each of the active and / or inactive pharmaceutical ingredients, such as testosterone esters, triglycerides, and / or antioxidants, provided in the pharmaceutical compositions of the present invention is in the range of 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.05 g, 0.25 g, 0.0 ... 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g.

[0137] In some embodiments, the amount of each of the active and / or inactive pharmaceutical ingredients, such as testosterone esters, triglycerides, and / or antioxidants, provided in the pharmaceutical compositions of the present invention is 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0008 g, 0.0009 g, 0.0010 g, 0.0011 g, 0.0012 g, 0.0013 g, 0.0014 g, 0.0015 g, 0.0016 g, 0.0017 g, 0.0018 g, 0.0019 g, 0.0010 g, 0.0011 g, 0.0012 g, 0.0013 g, 0.0014 g 07g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0 045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.00 95g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.3 5g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5 More than g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g.

[0138] Each of the active pharmaceutical ingredients according to the present invention is effective over a wide dosage range. For example, in the treatment of adult humans, dosages may independently range from 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day, with 5 to 40 mg per day being examples of dosages that may be used. Effective dosages of 50 to 200 mg per week are also examples of dosages that may be used. In one embodiment, the effective weekly dosage is about 50 mg. In one embodiment, the effective weekly dosage is about 100 mg. In one embodiment, the effective weekly dosage is about 150 mg. In one embodiment, the effective weekly dosage is about 200 mg. In one embodiment, the effective weekly dosage is about 250 mg.

[0139] The exact dosage will depend on the route of administration, the form in which the compound is administered, the sex and age of the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician. Clinically established dosages of testosterone esters, such as testosterone enanthate, may also be used where appropriate.

[0140] In some embodiments, the amount of testosterone ester adduct in the formulation, e.g., the amount of testosterone ester in the formulation, e.g., the amount of testosterone enanthate adduct relative to the amount of testosterone enanthate, is less than about 0.001% (w / w), about 0.001% (w / w), about 0.002% (w / w), about 0.003% (w / w), about 0.004% (w / w), about 0.005% (w / w), , about 0.006% (w / w), about 0.007% (w / w), about 0.008%, (w / w) about 0.009% (w / w), about 0.01% (w / w), about 0.015% (w / w), about 0.02% (w / w), about 0.025% (w / w), about 0.03% (w / w), about 0.035% (w / w), about 0.04% (w / w), about 0.045% (w / w), about 0.05% (w / w), about 0.055 %(w / w), about 0.06%(w / w), about 0.065%(w / w), about 0.07%(w / w), about 0.075%(w / w), about 0.08%(w / w), about 0.085%(w / w), about 0.09%(w / w), about 0.095%(w / w), about 0.1%(w / w), about 0.15%(w / w), about 0.2%(w / w), about 0.25%(w / w), about 0.3%(w / w), about 0.35%( 0.7% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.85% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1% (w / w), or greater than about 1% (w / w).

[0141] In some embodiments, the lower limit of quantification of testosterone ester adducts relative to the total level of testosterone esters is 0.1%. In some embodiments, the lower limit of quantification of testosterone adducts relative to the total level of testosterone is 0.1%.

[0142] In some embodiments, the amount of testosterone ester adduct in the formulation, e.g., the amount of testosterone ester in the formulation, e.g., the amount of testosterone enanthate adduct relative to the amount of testosterone enanthate, is about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w) ), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), or about 50% (w / w).

[0143] In some embodiments, the concentration of any testosterone enanthate adduct in the formulation is from 0.000 mg / mL to 25 mg / mL, 0.005 mg / mL to 25 mg / mL, 0.025 mg / mL to 37.5 mg / mL, 0.05 mg / mL to 50 mg / mL, 0.075 mg / mL to 62.5 mg / mL, 0.1 mg / mL to 75 mg / mL, 0.125 mg / mL to 100 mg / mL, 0.175 mg / mL to 125 mg / mL, 0.2 mg / mL to 175 mg / mL, 0.25 mg / mL to 200 mg / mL, or 0.275 mg / mL to 150 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is from 0.005 mg / mL to 100 mg / mL.

[0144] In some embodiments, the concentration of the testosterone enanthate adduct is about 0.005 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.0075 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.01 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.0125 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.015 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.0175 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.02 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.0225 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.0250 mg / mL.

[0145] In some embodiments, the concentration of the testosterone enanthate adduct is about 0.05 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.075 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.1 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.125 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.15 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.175 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.2 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.225 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.250 mg / mL.

[0146] In some embodiments, the concentration of the testosterone enanthate adduct is about 0.5 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 0.75 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 1 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 1.25 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 1.5 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 1.75 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 2 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 2.25 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 2.50 mg / mL. In some embodiments, the concentration of the testosterone enanthate adduct is about 2.75 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 3 mg / mL. In some embodiments, the concentration of testosterone enanthate adduct is about 3.25 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 3.50 mg / mL. In some embodiments, the concentration of testosterone enanthate adduct is about 3.75 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 4 mg / mL. In some embodiments, the concentration of testosterone enanthate adduct is about 4.25 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 4.50 mg / mL. In some embodiments, the concentration of testosterone enanthate adduct is about 4.75 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 5 mg / mL.

[0147] In some embodiments, the concentration of testosterone enanthate is 50 mg / mL to 200 mg / mL. In some embodiments, the concentration of BHT is 0.01% to 0.1%. In some embodiments, the concentration of BHT is 0.1 mg / mL to 1 mg / mL. In some embodiments, the concentration of tocopherol is 0.1% to 5%.

[0148] In some embodiments, the concentration of testosterone enanthate is 5 mg / mL to 50 mg / mL, 25 mg / mL to 75 mg / mL, 50 mg / mL to 100 mg / mL, 75 mg / mL to 125 mg / mL, 100 mg / mL to 150 mg / mL, 125 mg / mL to 200 mg / mL, 175 mg / mL to 250 mg / mL, 200 mg / mL to 350 mg / mL, 250 mg / mL to 400 mg / mL, or 275 mg / mL to 500 mg / mL. In some embodiments, the concentration of testosterone enanthate is 50 mg / mL to 200 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 50 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 75 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 100 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 125 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 150 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 175 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 200 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 225 mg / mL. In some embodiments, the concentration of testosterone enanthate is about 250 mg / mL.

[0149] In some embodiments, the concentration of BHT is 0.01% to 0.025%, 0.015% to 0.05%, 0.035% to 0.075%, 0.05% to 0.085%, 0.06% to 0.095%, or 0.075% to 0.1%. In some embodiments, the concentration of BHT is 0.075% to 0.15%, 0.1% to 0.25%, or 0.15% to 0.5%. In some embodiments, the concentration of BHT is 0.01% to 0.1%. In some embodiments, the concentration of BHT is 0.1 mg / mL to 1 mg / mL, 0.25 mg / mL to 0.5 mg / mL, 0.35 mg / mL to 0.75 mg / mL, 0.5 mg / mL to 1.5 mg / mL, or 1 mg / mL to 5 mg / mL. In some embodiments, the concentration of tocopherol is 0.1% to 1%, 0.25% to 2.5%, 1% to 10%, In some embodiments, the concentration of tocopherol is 0.1% to 5%.

[0150] In one embodiment, the present invention relates to a pharmaceutical formulation including testosterone enanthate, sesame oil, BHT, and one or more testosterone adducts of formula 3-22. In some embodiments, the adduct has formula 10. In some embodiments, the adduct has formula 11. In some embodiments, the concentration of testosterone enanthate is 50 mg / mL to 200 mg / mL, or 5 mg / mL to 500 mg / mL. In some embodiments, the concentration of BHT is 0.01% to 0.1%, 0.01% to 1%, 0.1 mg / mL to 1 mg / mL, or 0.1 mg / mL to 10 mg / mL. In some embodiments, the concentration of testosterone ester adducts is less than the concentration of testosterone enanthate. In some embodiments, the total concentration of testosterone ester adducts is less than the concentration of testosterone enanthate.

[0151] Formulations of 100 mg / ml, 150 mg / ml, and 200 mg / ml testosterone ester (e.g., testosterone enanthate) can each be formulated in USP oil (e.g., sesame oil) containing 0.07-1.0% antioxidant (e.g., BHT) and optionally further including an adduct of the present invention.

[0152] Adducts of other testosterone or testosterone derivatives The present disclosure is not limited to testosterone ester adducts with mono-, di-, and / or triglycerides, but includes any testosterone derivative adduct with mono-, di-, and / or triglycerides, including adducts of testosterone with mono-, di-, and / or triglycerides. All methods and conditions for generating, making, controlling, or using the testosterone ester adducts described herein are intended to be used in conjunction with other methods and conditions for generating, making, controlling, or using the testosterone ester adducts described herein, including any adducts of testosterone with mono-, di-, and / or triglycerides. It is equally applicable to adducts.

[0153] In some embodiments, the present invention provides a compound of formula 23:

[0154] [ka]

[0155] wherein: R8, independently at each occurrence, is hydrogen or a suitable substituent for testosterone as described herein or known in the art; R5 is an acyl group corresponding to an unsaturated fatty acid; G is a glycerol, monoglyceride, or diglyceride residue; n is 1, 2, or 3; and the testosterone residue is linked to the allylic or diallylic carbon of R5.

[0156] In some embodiments, the testosterone or testosterone derivative adduct has formula 24:

[0157] [ka]

[0158] wherein: R8, independently at each occurrence, is hydrogen or a suitable substituent for testosterone as described herein or known in the art; G is a glycerol, monoglyceride, or diglyceride residue; and n is 1, 2, or 3.

[0159] In some embodiments, the present invention provides compounds of Formulas 25-29:

[0160] [ka]

[0161] [ka]

[0162] wherein: R8, independently at each occurrence, is hydrogen or a suitable substituent for testosterone as described herein or known in the art; and each of R6 and R7, independently, is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid.

[0163] Pharmaceutical Composition for Injection In some aspects, an injectable pharmaceutical composition is provided that contains an active pharmaceutical ingredient or a combination of active pharmaceutical ingredients, such as a testosterone ester, e.g., testosterone enanthate, and a pharmaceutical excipient suitable for injection.

[0164] Forms in which the compositions of the present invention may be incorporated for administration by injection include aqueous or oily suspensions or emulsions, or sterile aqueous solutions, including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, and similar pharmaceutical carriers. do.

[0165] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be utilized. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be provided by various antibacterial and antifungal preservatives or preservatives, for example, paraben, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0166] Sterile injectable solutions are prepared by incorporating the required amount of pharmaceutical active ingredient or combination of pharmaceutical active ingredients in a suitable solvent with various other ingredients as listed above, as required, and then sterilizing by filtration.Generally, dispersions are prepared by incorporating various sterilized active ingredients and other ingredients as listed above required in a sterile medium containing a basic dispersion medium.In the case of sterile powders for preparing sterile injectable solutions, one preferred preparation method is vacuum drying and freeze-drying technology, which produces a powder of active ingredient plus additional desired ingredients from its solution that has previously been sterile-filtered.

[0167] The administration of the pharmaceutical active ingredient or combination of pharmaceutical active ingredients, or pharmaceutical compositions thereof, can be effected by any method that allows the compound to be delivered to the site of action. These methods include oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intradermal, intravascular, intraperitoneal injection or infusion), topically (e.g., transdermal application), rectal administration, local delivery by catheter or stent, or via inhalation. The pharmaceutical active ingredient or combination of pharmaceutical active ingredients can also be administered intraadipose tissue or intrathecally.

[0168] kit The present invention also provides kits. The kits include a pharmaceutical active ingredient or combination of pharmaceutical active ingredients (single or combined in suitable packaging) and documentation that may include instructions for use, clinical trial considerations, and a list of side effects. Such kits may also include information such as academic references, package inserts, clinical trial results, and / or summaries of the above, which show or demonstrate the activity and / or benefits of the composition, and / or describe dosage, administration, side effects, drug interactions, or other information useful to health care providers. Such information may be based on the results of various tests, for example, tests using laboratory animals, including in vivo models, and tests based on human clinical trials. The kits may further contain another pharmaceutical active ingredient. In selected embodiments, the pharmaceutical active ingredient or combination of pharmaceutical active ingredients is provided as separate compositions in separate containers of the kit. In selected embodiments, the pharmaceutical active ingredient or combination of pharmaceutical active ingredients is provided as a single composition in the container of the kit. Suitable packaging and accessories for use (e.g., measuring cups for liquid preparations, foil wrapping to minimize exposure to air, etc.) are known in the art and may be included in the kits. The kits described herein may be provided, sold, and / or promoted to health care providers, including physicians, nurses, pharmacists, formulary officials, and the like. In selected embodiments, the kits may be sold directly to consumers.

[0169] In some embodiments, the present invention provides kits that include compositions that include a therapeutically effective amount of an active pharmaceutical ingredient (e.g., a testosterone ester) or a combination of active pharmaceutical ingredients, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. These compositions are typically pharmaceutical compositions. The kits are for simultaneous or separate co-administration of the active pharmaceutical ingredients or combination of active pharmaceutical ingredients.

[0170] In some embodiments, the present invention provides a kit in which a composition comprising a therapeutically effective amount of testosterone ester alone or in combination with an active pharmaceutical ingredient or a pharma- ceutical acceptable salt, solvate, hydrate, co-crystal, or prodrug in an oil solution in combination with an antioxidant is contained in a pre-filled syringe (PFS) or vial. In some embodiments, the pre-filled syringe or vial is transparent. The kit includes suitable packaging material to protect the pre-filled syringe or vial from light. In some embodiments, it includes an autoinjector. In other embodiments, it includes an autoinjector with a viewing window that allows inspection of the drug prior to injection. In still other embodiments, the autoinjector is in a carton to prevent light access to the drug.

[0171] A pre-filled syringe or vial may contain a single dose or multiple doses. In some embodiments, a pre-filled syringe or vial containing multiple doses is larger, i.e., has a larger volume, than a pre-filled syringe or vial containing only a single dose. In some embodiments, the testosterone ester triglyceride adducts described herein are formed in the pre-filled syringe or vial during normal storage and / or upon exposure to various amounts of light. In some embodiments, the surface area to volume ratio of the pre-filled syringe or vial decreases as the volume of the pre-filled syringe or vial increases. Without wishing to be bound by a particular theory, in some embodiments, the testosterone ester triglyceride adducts described herein are formed in greater amounts and / or at an accelerated rate when the surface area of ​​the pre-filled syringe or vial containing the testosterone ester formulation exposed to light is greater. Without wishing to be bound by any particular theory, in some embodiments, the testosterone ester triglyceride adducts described herein are formed in lower amounts and / or at a slower rate when the volume of the filled syringe or vial containing the testosterone ester formulation exposed to light is larger. Without wishing to be bound by any particular theory, in some embodiments, the testosterone ester triglyceride adducts described herein are formed in higher amounts and / or at an accelerated rate when the surface area to volume ratio of the filled syringe or vial containing the testosterone ester formulation exposed to light is larger. Without wishing to be bound by any particular theory, in some embodiments, the testosterone ester triglyceride adducts described herein are formed in lower amounts and / or at a slower rate when the surface area to volume ratio of the filled syringe or vial containing the testosterone ester formulation exposed to light is smaller.

[0172] In some embodiments, the percentage of the initial amount of testosterone ester in the formulation that is preserved during storage or exposure to light is higher in larger volume pre-filled syringes or vials. In some embodiments, the percentage of the initial amount of testosterone ester in the formulation that is preserved during storage or exposure to light is higher in pre-filled syringes or vials with lower surface area to volume ratios compared to pre-filled syringes or vials with higher surface area to volume ratios. In some embodiments, the percentage of the initial amount of testosterone ester in the formulation that is preserved during storage or exposure to light is higher in pre-filled syringes or vials with multiple doses compared to pre-filled syringes or vials with single doses.

[0173] In one embodiment, the pre-filled syringe or vial is filled with a formulation comprising about 50 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation comprising about 75 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation comprising about 100 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation comprising about 125 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation comprising about 150 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation comprising about 175 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation comprising about 200 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation containing about 225 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation containing about 250 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation containing about 275 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation containing about 300 mg of testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with a formulation containing multiple doses of 25 mg or 50 mg of testosterone ester.

[0174] In one embodiment, the pre-filled syringe or vial is filled with about 0.1 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 0.2 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 0.3 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 0.4 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 0.5 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 0.6 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 0.7 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 0.8 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 0.9 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 1 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 1.1 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 1.2 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 1.3 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 1.4 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 1.5 mL of the formulation including the testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 1.6 mL of the formulation including the testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 1.7 mL of the formulation including the testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 1.8 mL of the formulation including the testosterone ester.In one embodiment, the pre-filled syringe or vial is filled with about 1.9 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 2 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 2.1 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 2.2 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 2.3 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 2.4 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 2.5 mL of a formulation including a testosterone ester. In one embodiment, the pre-filled syringe or vial is filled with about 2.6 mL of a formulation including testosterone esters. In one embodiment, the pre-filled syringe or vial is filled with about 2.7 mL of a formulation including testosterone esters. In one embodiment, the pre-filled syringe or vial is filled with about 2.8 mL of a formulation including testosterone esters. In one embodiment, the pre-filled syringe or vial is filled with about 2.9 mL of a formulation including testosterone esters. In one embodiment, the pre-filled syringe or vial is filled with about 3 mL of a formulation including testosterone esters. It will be filled.

[0175] Such kits may also include information such as academic references, package inserts, clinical trial results, and / or summaries of the above, which show or substantiate the activity and / or benefits of the composition and / or describe dosing, administration, side effects, drug interactions, or other information useful to health care providers and / or patients. Such information may encourage users to keep the pre-filled syringe or the pre-filled syringe and autoinjector in the carton to protect the pharmaceutical ingredients from light. In the case of kits in which a composition containing a therapeutically effective amount of testosterone ester alone or in combination with a pharmaceutical active ingredient or its pharma-ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug in an oil solution in combination with an antioxidant is contained in a pre-filled syringe or autoinjector, the time that the pre-filled syringe or autoinjector can be allowed to remain outside the light-protective packaging material before use may be increased compared to a similar preparation that does not contain an antioxidant, and this information may be reflected in the information provided in the kit.

[0176] In some aspects, the invention provides (1) a composition that includes a therapeutically effective amount of an active pharmaceutical ingredient (e.g., a testosterone ester), or a combination of active pharmaceutical ingredients, or a pharma- ceutical acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof, and (2) a kit that includes a diagnostic test for determining whether a patient requires testosterone ester administration.

[0177] Dosage and Administration Schedule The amount of a pharmaceutical composition administered using the methods of the invention, such as the dosage of a testosterone ester, will be dependent on the subject, e.g., a human or mammal, being treated, the severity of the disorder or condition, the rate of administration, the disposition of the pharmaceutical active ingredient, and the discretion of the prescribing physician. To achieve effective therapeutic levels, a dosage in the range of 50-100 mg / week for administration to humans may be sufficient. Sometimes, dosages of 50-100 mg / week may be required for several weeks to achieve the desired therapeutic levels. However, effective dosages range from about 0.001 to about 100 mg / kg (body weight) / day, e.g., about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would correspond to about 0.05 to 7 g / day, e.g., about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower end of the aforementioned ranges may be more than sufficient, while in other cases even larger doses may be utilized without causing adverse side effects, e.g., by dividing such larger doses into several lower doses for administration throughout the day. Dosages of pharmaceutical compositions and active pharmaceutical ingredients are expressed in mg / kg (body weight) or mg / m 2 may be provided in units of (body surface area).

[0178] In some embodiments, the pharmaceutical composition or active pharmaceutical ingredient is administered in frequent doses. In some embodiments, the pharmaceutical composition is administered in frequent doses. Dosing may be once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, the pharmaceutical composition is administered from about once per day to about six times per day. In some embodiments, the pharmaceutical composition is administered once a day, while in other embodiments, the pharmaceutical composition is administered twice a day, and in other embodiments, the pharmaceutical composition is administered three times a day.

[0179] Administration of the active pharmaceutical ingredient may continue for as long as necessary. In selected embodiments, the pharmaceutical composition is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In other embodiments, the pharmaceutical composition is required to be administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 weeks. In some embodiments, the pharmaceutical composition is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the pharmaceutical composition is administered chronically on an ongoing basis, for example, for the treatment of chronic effects. In some embodiments, Administration of the pharmaceutical composition continues for less than about 7 days. In yet other embodiments, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous dosing is achieved and maintained for as long as necessary.

[0180] In some embodiments, the effective dose of the medicamentously active ingredient disclosed herein is from about 1 mg to about 500 mg, from about 10 mg to about 300 mg, from about 20 mg to about 250 mg, from about 25 mg to about 200 mg, from about 50 mg to about 200 mg, from about 10 mg to about 200 mg, from about 20 mg to about 150 mg, from about 30 mg to about 120 mg, from about 10 mg to about 90 mg, from about 20 mg to about 80 mg, from about 30 mg to about 70 mg, from about 40 mg to about 60 mg, from about 45 mg to about 55 mg, from about 50 mg to about The range is 100 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 mg to about 202 mg. In some embodiments, the effective dosage of the active pharmaceutical ingredient disclosed herein is less than about 25 mg, less than about 50 mg, less than about 75 mg, less than about 100 mg, less than about 125 mg, less than about 150 mg, less than about 175 mg, less than about 200 mg, less than about 225 mg, or less than about 250 mg. In some embodiments, the effective dosage of the active pharmaceutical ingredient disclosed herein is more than about 25 mg, more than about 50 mg, more than about 75 mg, more than about 100 mg, more than about 125 mg, more than about 150 mg, more than about 175 mg, more than about 200 mg, more than about 225 mg, or more than about 250 mg.

[0181] In some embodiments, the effective dosage of the pharmaceutical active ingredient disclosed herein ranges from about 0.01 mg / kg to about 200 mg / kg, or from about 0.1 to 100 mg / kg, or from about 1 to 50 mg / kg. In some embodiments, the pharmaceutical active ingredient is administered at a dosage of 10 to 200 mg BID, including 50, 60, 70, 80, 90, 100, 150, or 200 mg BID. In some embodiments, the pharmaceutical active ingredient is administered at a dosage of 10 to 500 mg BID, including 1, 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400, or 500 mg BID.

[0182] In some cases, dosage levels below the lower limit of the above range may be more than sufficient, while in other cases, still larger doses may be utilized without causing adverse side effects, for example, by dividing such larger doses into several lower doses for administration throughout the day.As will be understood by those skilled in the art, the actual dosage administered will depend on the pathology being treated, the age, health, and weight of the recipient, the type of concurrent treatment, if any, and the frequency of treatment.Furthermore, the effective dosage may be determined by those skilled in the art based on routine empirical activity tests, in which the bioactivity of the compound is measured by bioassay, thereby determining the appropriate dosage to be administered.

[0183] An effective amount of the combination of active pharmaceutical ingredients may be administered in either single or multiple doses by any of the accepted modes of administration of drugs having similar utilities, including rectal, buccal, intranasal, and transdermal routes, intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, intradermal, oral, topical, or as an inhalant.

[0184] In some embodiments, the compositions described herein further include controlled release, sustained release, or extended release therapeutic dosage forms for administering the compounds described herein, which involve incorporating the compounds into a suitable delivery system in the formation of a composition. The dosage forms control the release of the compounds in such a way that the effective concentration of the compounds in the bloodstream is maintained for an extended period of time, and the blood concentration can remain relatively constant, improving therapeutic outcomes and / or minimizing side effects. In addition, a controlled release system can provide the compounds This will minimize peak-to-trough fluctuations in plasma levels of

[0185] Several patent and non-patent publications are cited herein to describe the state of the art related to the present invention, the entire disclosures of each of which are incorporated herein by reference.

[0186] The following examples further illustrate the invention, but are provided for illustrative purposes only and should not be construed as limiting the invention in any way. EXAMPLES

[0187] Example 1: Structural identification of testosterone enanthate-triglyceride adducts found in testosterone-sesame oil mixtures after light-induced stress The photostress-induced product was generated by irradiating 200 mg / mL testosterone enanthate in sesame oil according to the ICH recommended method for UV / VIS stress treatment. At the end of the stress treatment, an aliquot of the crude product was chromatographed using an analytical column: Synergi Max-RP 80A (150×4.6 mm, 4 μm) with mobile phase A being acetonitrile / water (90 / 10 (v / v)) and mobile phase B being 100% ethanol. The results are illustrated in FIG. 2. Initial results suggested that the testosterone enanthate-triglyceride adduct eluted in the peak in region 3 and not region 4, as shown in FIG. 1.

[0188] This crude product was then purified using a preparative chromatography system using a preparative column: Synergi Max-RP 80A, AXIA Packed New Column (250 x 21.2 mm, 4 μm) and ethanol as the mobile phase. Region 3 was collected in several fractions. Each fraction was tested using the chromatography conditions using the analytical column: Synergi Max-RP 80A (150 x 4.6 mm, 4 μm) described above. The chromatograms of the purified fractions are shown in Figures 3 to 6. Each of these fractions was concentrated to remove excess ethanol solvent to obtain concentrated purified products. Fractions 1 and 2 were more pure than fractions 3 or 4. The purified product from fraction 1 was the most pure, so this purified product was used for the testosterone enanthate structure identification test. The amounts recovered from these purified products after evaporation are listed in Table 1.

[0189] [Table 1]

[0190] Structural identification tests included NMR analysis. Figure 7 shows the structure of the purified product from fraction 1. 1 1 H NMR spectrum of the purified product from fraction 1. 1 1 H NMR spectrum is shown; this expanded NMR spectrum shows the proton splitting pattern of the molecule that is the major component of purified fraction 1. FIG. 9 shows the 1 H NMR spectrum of the purified product from fraction 1. 13 The C NMR spectrum shows a peak at 205-220 ppm characteristic of the ketone carbonyl (C=O) carbon. 13 The absence of a C peak indicates that the carbonyl carbon of testosterone enanthate is not a carbonyl carbon of, for example, a -COC- bond. Figure 10 shows an enlargement of the purified product from fraction 1. 13 C NMR spectrum (130-175 ppm) is shown. Figure 11 shows an enlargement of the purified product from fraction 1. 13 12 shows the C NMR spectrum (2-84 ppm) of the purified product from fraction 1. 13C DEPT NMR spectrum is shown.

[0191] The structural identification study further included LC-UV coupled mass spectrometry. An aliquot of purified fraction 1 was diluted to 10 μg / mL with ethanol and injected into an API 4000 mass spectrometer coupled to an LC-UV system using a Synergi Max-RP 80A (150×4.6 mm, 4 μm) with a gradient run of mobile phase A: acetonitrile / water (90 / 10 (v / v)) and mobile phase B: 100% ethanol. Under these chromatographic conditions, four MRM transitions were simultaneously monitored: m / z=1304>1304, 1306>1306, 1704>1704, and 1706>1706. These MRM transitions were selected because, first, OLL and OOL are the two major triglycerides (TGs) present in sesame oil. OLL constitutes about 13-30% of the triglycerides in sesame oil, and OOL constitutes the other about 14-25%. Second, the linoleoyl fatty acid side chain has two homoconjugated double bonds, and the CH located between the two double bonds is susceptible to adduct formation. Based on the molecular weights of OLL and OOL, these two molecules have monoisotopic masses at approximately 1304 and 1306, respectively, when adducted with one testosterone enanthate (TE) and a sodium atom, which is abundant in solution. When two TE molecules are bound to OLL and OOL, the monoisotopic masses will be 1704 and 1706, respectively (Table 2). And third, screening using MRM mode improves sensitivity.

[0192] [Table 2]

[0193] Molecules with monoisotopic masses equal to 1304, 1306 for the adduct with one TE and 1704, 1706 for the adduct with two TEs were searched for. The results showed that prominent peaks were observed in the transition windows: 1304>1304 and 1306>1306, respectively. In addition, less intense peaks were detected in the transition windows 1704>1704 and 1706>1706 (Figure 13).

[0194] When a 10 μg / mL sample was subjected to MS2 under positive ionization with a collision energy of 90 eV, the ions 1304 and 1306 fragmented to form similar product ions. The molecule with m / z=1304 produced 703.8 and 1023.5 (Figure 14), The molecule with m / z=1306 produced 704 and 1023.8 (Figure 15). Additional MS data is presented in Figures 16-29. Figure 16 shows the mass spectrum (photostressed sample, region 1, major response at approximately 9.8 minutes in CAD); proposed empirical formula: C 80 H 124O9 (mass error: -1.9 ppm). Figure 17 shows the mass spectrum (light stressed sample, region 1, minor response at CAD at approximately 10.4 min). Figure 18 shows the extracted ion chromatogram (XIC) (light stressed sample, m / z 626). Figure 19 shows the mass spectrum of the control sample, region 2. Figure 20 shows the mass spectrum of the light stressed sample, region 2. Figure 21 shows the XIC of the light stressed sample (m / z: 933 (blue), 935 (pink), and 937 (orange)). Figure 22 illustrates the mass spectrum of the control sample, region 3. Figure 23 shows the mass spectrum of the 100 sample, region 3. Figure 24 shows the XIC of the light stressed sample (m / z 901 (blue), 903 (pink), 905 (orange), 907 (green), and 909 (light blue)). FIG. 25 shows the XIC of the light stressed sample, m / z 1302 (blue), 1304 (pink), 1306 (orange), 1308 (green), and 1310 (light blue). FIG. 26 shows the XIC of the light stressed sample, m / z 1702 (blue), 1704 (pink), 1706 (orange), and 1708 (green). FIG. 27 shows the mass spectrum of the control sample, region 4. FIG. 28 shows the mass spectrum of the light stressed sample, region 4. FIG. 29 shows the XIC of the light stressed sample, m / z 1782 (blue) and 1758 (pink).

[0195] About this addition 1 H NMR and 13C NMR studies, coupled with HRMS studies, suggest that the adduct in fraction 1 is a mixture of two major components: an adduct of testosterone enanthate with OLL (adduct A) and an adduct of testosterone enanthate with OOL (adduct B; Scheme 1). These proposed structures are consistent with the sodium testosterone enanthate adducts formed with OLL and OOL, respectively, having m / z=1304 and m / z=1306, respectively. The proposed structure of adduct A is consistent with the sodium testosterone enanthate adduct formed with OLL, and a likely fragmentation pathway for adduct A to produce a product ion with m / z=1023.8 is also described (Scheme 2). The proposed structure of adduct B is consistent with the sodium testosterone enanthate adduct formed with OOL (Scheme 3).

[0196] [ka]

[0197] [ka]

[0198] [ka]

[0199] 1 H NMR and 13 In both C NMR spectra, most of the signals of adduct A and adduct B overlap (Figures 7 to 12). For simplicity, only adduct A (OLL + TE) is assigned as an example (Scheme 4).

[0200] [ka]

[0201] 1H NMR: δ 0.85 (m, 3H, H17’), 0.9 (m, 15H, H17, H17”, H18, Hi, Hq), 1.3 (m, 67 H, H3, H4, H5, H6, H14, H15, H16, H3’, H4’, H5’, H6’, H11’, H12’, H13 ’, H14’, H15’, H16’, H3”, H4”, H5”, H6”, H14”,H15”, H16”, Hx, Hy, Hz, He, Hf, Hg, Hh, Hm, Hn, Ho, Hr), 1.61 (m, 8H, H2, H2’, H2”, Hw), 2.0 (m, 16H, H7, H7’, H7”, H10, H10’, H13, H13”, Hd,), 2.32 (m, 10 H, H1, H1’, H1”, Hv, Hs), 2.77 (m, 2H, H10), 4.15 (m, 3H), 4.30 (m, 3H), 5.32(m, 2H), 5.36 (m, 10H, H8, H9, H11, H12, H8’, H9’, H11’, H12’, H8”, H9”) 13 C NMR: δ 14.3 (C17, C17’, C17”, C18), 22.71 (C16, C16’, C16”, Cz), 22.79 (C2, C2’, C2”, Cw), 22.90, 25.06, 25.29, 25.84, 27.41, 27.44, 27.80, 29.02, 29.27, 29.34, 29.39, 29.54, 29.70, 29.74, 29.84, 29.88, 29.92, 30.66, 31.68, 31.74, 32.12, 32.75, 34.24, 34.41, 62.31 (Ca, Cc), 69.09 (Cb), 128.10, 128.28, 128.45, 129.92, 130.23, 130.44, 173.04, 173.46, 174.13. In conclusion, after light-stress treatment (as specified in the ICH guidelines) of a mixture of testosterone enanthate in sesame oil, a new adduct was formed, which was purified by preparative HPLC and the excess solvent was evaporated to give purified fraction 1 (net weight: 587 mg). 1 H NMR and C 13 According to the NMR data, refined fraction 1 contains two major adducts, namely OLL+TE+Na (adduct A) and OOL+TE+Na (adduct B; Scheme 1). Based on the proton NMR data, the purity of the two adducts (m / z=1304 and m / z=1306 combined) is approximately 86%. Mass spectrum data showed that the two adduct ions have approximately equal intensities under the same ionization conditions. Assuming equivalent ionization energies, the two adducts were present as an approximately 50:50 mixture in this fraction. Thus, refined fraction 1 may be useful to assess for OLL+TE+Na adducts or OOL+TE+Na adducts that may be present as impurities in a given TE-sesame oil product.

[0202] Example 2: Overview of method development for an HPLC-MS method to assess photodegradation in Xyosted drug products Photodegradation products of testosterone enanthate (TE) in Xyosted Drug Product were not detectable by early developmental HPLC methods. These methods consisted of multiple combinations of column polarities ranging from normal to reversed phase, various carbon chain lengths, and mobile phases of different elution strengths ranging from aqueous-based to purely organic solvent-based mobile phases. Because no products were detected in the chromatography where small molecules (both polar and non-polar) typically appear, it was hypothesized that the photodegradation products were most likely not degradation products of the TE molecule, but rather adducts of the TE molecule with triglycerides (TGs), which are major components of sesame oil.

[0203] One of the main challenges in method development was the identification of HPLC-compatible solvents that would dissolve the photodegraded drug sample. After exposure of the drug to ICH light conditions, it was concluded that substantial degradation had occurred, as approximately 60-90% reduction was observed in the assay. The photodegraded drug sample was not completely soluble in the sample diluent used in the preliminary HPLC method, i.e., DMF / ACN:80 / 20, nor did it dissolve well in several other commonly used highly solubilizing solvents, such as DMSO. Among the numerous solvents tested, the only solvents that were able to completely dissolve the photodegraded drug were alcohols (e.g., ethanol or isopropanol). Therefore, ethanol was selected as the eluting mobile phase. Following method optimization, the final optimized HPLC conditions used for photoforced degradation are shown in Table 3.

[0204] [Table 3]

[0205] Example chromatograms of TE injection in unprotected prefilled syringes (PFS) exposed to ICH light conditions and a control (i.e., the same drug product sample not exposed to ICH light conditions) are shown in Figure 1 with UV detection at 242 nm and in Figure 30 with charged aerosol detection. In addition, both light-stressed and control samples were chromatographed under the same conditions listed in Table 3, but with the addition of mass spectrometry (MS) detection. Peak identifications for the peaks shown in Figures 1 and 30 based on the MS results are summarized in Table 4.

[0206] [Table 4]

[0207] The stability-indicating capability of an HPLC method is often determined based on the peak purity of the active peak and the mass balance (which is the sum of the calibration amount and the total impurity amount). Peak purity of the major peak was previously demonstrated, and detection of the photodegradation products using the method in Table 3 did not change this assessment since the photodegradation products elute quite late in this chromatogram. The use of mass balance to assess stability-indicating capability requires well-characterized authentic impurity standards so that the relative response factors (RRFs) of the impurities can be determined and the majority of the impurities can be accurately quantified.

[0208] Alternatively, the stability-indicating ability of the HPLC method can be evaluated based on the inclusiveness of the chromatography and detection. In the proposed HPLC method, its gradient program spans from 70% ethanol / 27% water / 3% acetonitrile to 100% ethanol, which is capable of eluting not only the drug but also all hydrophobic sesame oil components, including TE-TG adducts, so that all photodegradation products are detected. In addition, universal detection (CAD and MS) was used to ensure that the UV chromophore could detect weak potential degradation products.

[0209] As described in Example 1, the fraction with a retention time (RT) of 22.5-24 min, which corresponds to the TE+TG adduct, was isolated by preparative HPLC, and the two major TE-TG adducts were identified as TE-OLL and TE-OLL by MS and NMR. The structures of these TE-TG adducts were presumed to be formed by the reaction of the methylene group located between the two homoconjugated double bonds on the linoleoyl fatty acid side chain of TG, i.e., close to the C11 position, with the carbonyl group on the A ring of TE, as shown in Scheme 1.

[0210] The TG composition of sesame oil according to USP is shown in Table 5. Based on the photolysis shown in Scheme 1, the potential photodegradation products are adducts between TE and TG containing linoleoyl fatty acid, i.e., TE-OLL, TE-OOL, TE-LLL, TE-POL, TE-PLL, and TE-SOL, with TE-OLL and TE-OOL being the predominant degradation products since OLL and OOL are the two major TG components reported in sesame oil. Other degradation products may also include adducts between two TE molecules and one TG molecule containing two linoleoyl fatty acid chains, or adducts between three TE molecules and one TG molecule containing three linoleoyl fatty acid chains.

[0211] [Table 5]

[0212] In preparation for the chromatographic separation of the TE-TG adducts, a limit test for the LC-MS method was developed to selectively evaluate the two major degradation products, namely, TE-OLL and TE-OOL. The chromatographic conditions shown in Table 1 were employed with some minor modifications required for MS detection in this new LC-MS method.

[0213] Example 3: Effect of antioxidants on the photodegradation of testosterone ester triglyceride formulations Sesame oil is the vehicle for Xyosted testosterone enanthate (TE) injectable drug. Sesame oil is composed of various triglycerides (TGs), and the TG composition of United States Pharmacopeia (USP) grade sesame oil is shown in Table 5. TGs with side chains containing homoconjugated double bonds, such as the linoleoyl side chain, are susceptible to autoxidation in the presence of oxygen, or light and oxygen. Autoxidation of the linoleoyl side chain produces linoleoyl hydroperoxides, along with linoleoyl free radicals and linoleoyl peroxy radicals, as shown in Scheme 5. Autoxidation is an autocatalytic chain reaction, since the linoleoyl free radicals and linoleoyl peroxy radicals are reactive.

[0214] [ka]

[0215] In Scheme 5, "In" represents the molecular species that initiates the chain reaction, which can be O2 or light. 1 Note that the linoleic acid free radical formed in is a double allylic one. Once formed, this radical is 2 In the process, the linoleic acid reacts with molecular oxygen to generate a linoleic acid peroxy radical. 3 At , the sesame oil extracts a hydrogen atom from another linoleic acid molecule, which generates linoleic acid hydroperoxide and a new linoleic acid free radical, thereby propagating this chain reaction. The degree of oxidation of TG can be measured by a USP test called peroxide value (PV). Peroxide value is defined as the amount of oxygen peroxide per kilogram of fat (milli-equivalent O2 / kg fat). As shown in Table 6, the PV of the Xyosted drug increased over time, indicating that the sesame oil (or TG) in the drug was oxidized over time.

[0216] [Table 6]

[0217] Butylated hydroxytoluene (BHT) is a known antioxidant that acts as a free radical scavenger, terminating the autoxidation of TG by donating a hydrogen atom and converting the peroxy radical to a hydroperoxide and the TG radical to TG, while generating a BHT radical, as shown in Scheme 6 (R· can be a linoleoyl free radical or a linoleoyl peroxy radical).

[0218] [ka]

[0219] Once formed, the BHT radical cannot react further because its bulky tert-butyl group creates significant steric hindrance and the oxygen atom with the unpaired electron cannot make the contacts with other molecules required to enable the reaction. The formation of the BHT radical terminates the radical chain reaction (e.g., autoxidation in Scheme 5). As shown in Table 6, when stored at 25°C / 60% RH for 24 months, the oxidation of sesame oil was effectively inhibited in the presence of 0.06-0.07% BHT, as the PV level was maintained at a very low level (i.e., <12) compared to a PV level of approximately 70-80 without BHT.

[0220] Exposure of the drug to ICH light conditions, i.e., 200 watt-hours / m 2 After exposure to UV light at 10 ... In the presence of 0.06-0.07% BHT, the levels were reduced by approximately 42% and 32% in the 50 mg / 0.5 mL and 100 mg / 0.5 mL concentration formulations, respectively.

[0221] [Table 7]

[0222] Similar results were obtained using tocopherol as the antioxidant. Samples of 50 mg / 0.5 mL were utilized and exposed to 1×ICH light conditions with or without 10 μL of tocopherol (Table 8, Figures 31-46). Addition of approximately 2% (±)-α-tocopherol to this drug product reduced photodegradation by approximately 62.3% to approximately 47.2% after exposure to 1×ICH light conditions.

[0223] [Table 8]

[0224] While several embodiments of the present invention have been described and / or illustrated above, various other embodiments will be apparent to those skilled in the art in light of the foregoing disclosure. It is therefore understood that the present invention is not limited to the specific embodiments described and / or illustrated, but rather that many changes and modifications may be made without departing from the spirit and scope of the appended claims. This application includes the following inventions. [Item 1] A pharmaceutical formulation for parenteral administration, comprising a compound of formula 1: [ka] a testosterone ester of formula 2: [ka] and a pharma- ceutical acceptable carrier comprising a triglyceride of During the ceremony: R1 is an alkyl or alkenyl substituent; Each of R2, R3, and R4 is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid; The pharmaceutical preparation. [Item 2] The pharmaceutical formulation of item 1, wherein R1 is selected from the group consisting of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, and unsaturated analogs thereof. [Item 3] The pharmaceutical formulation of Item 1, wherein the testosterone ester is testosterone enanthate, testosterone cypionate, testosterone propionate, or testosterone undecanoate. [Item 4] The pharmaceutical formulation of item 1, wherein the testosterone ester is testosterone enanthate. [Item 5] The pharmaceutical formulation of Item 1, wherein the triglyceride is selected from the group consisting of LLL, OLL, OOL, OOO, PLL, POL, POO, and SOL. [Item 6] The pharmaceutical formulation of item 1, wherein the pharma- ceutical acceptable carrier comprises a vegetable oil. [Item 7] The pharmaceutical formulation of Item 6, wherein the vegetable oil is sesame oil. [Item 8] The pharmaceutical formulation of Item 1, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and monosodium glutamate. [Item 9] The pharmaceutical formulation of item 1, wherein the testosterone ester is testosterone enanthate, the pharma- ceutical acceptable carrier comprises sesame oil, and the antioxidant is BHT. [Item 10] The pharmaceutical formulation of item 9, wherein the concentration of testosterone enanthate is 50 mg / mL to 200 mg / mL. [Item 11] The pharmaceutical formulation of item 10, wherein the concentration of BHT is 0.01% to 0.1%. [Item 12] The pharmaceutical formulation of Item 10, wherein the concentration of BHT is 0.1 mg / mL to 1 mg / mL. [Item 13] Expression 3: [ka] A testosterone ester adduct of During the ceremony: R1 is an alkyl or alkenyl substituent which may be the same or different in each independent occurrence; R5 is an acyl group corresponding to an unsaturated fatty acid; G is a glycerol, monoglyceride, or diglyceride residue; n is 1, 2, or 3; and The testosterone residue is linked to the allylic or biallylic carbon of R5. The testosterone ester adduct. [Item 14] Formula 4: [ka] Item 14. The testosterone ester adduct of item 13, having the formula: [Item 15] The testosterone ester adduct of item 13, wherein R1, at each independent occurrence, is selected from the group consisting of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, and unsaturated analogs thereof. [Item 16] The testosterone ester adduct of Item 13, wherein R1 is hexyl. [Item 17] Formula 5, 6, 7, 8, or 9: [ka] [ka] having wherein each of R6 and R7 is independently an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid; Item 13 Testosterone ester adduct. [Item 18] Formula 10: [ka] Item 14. The testosterone ester adduct of item 13, having the formula: [Item 19] Formula 11: [ka] Item 14. The testosterone ester adduct of item 13, having the formula: [Item 20] A pharmaceutical formulation for parenteral administration, comprising a pharma- ceutical acceptable carrier comprising a testosterone ester of formula 1, a triglyceride of formula 2, and optionally a testosterone ester adduct of any one of items 13 to 19 in a concentration of 0.000 mg / ml to 25 mg / ml, wherein: R1 is an alkyl or alkenyl substituent; and Each of R2, R3, and R4 is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid; The pharmaceutical preparation. [Item 21] The pharmaceutical formulation of item 20, wherein R1, at each independent occurrence, is selected from the group consisting of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, and unsaturated analogs thereof. [Item 22] The pharmaceutical formulation of Item 20, wherein the testosterone ester is testosterone enanthate, testosterone cypionate, testosterone propionate, or testosterone undecanoate. [Item 23] The pharmaceutical formulation of Item 20, wherein the testosterone ester is testosterone enanthate. [Item 24] The pharmaceutical formulation of Item 20, wherein the triglyceride is selected from the group consisting of LLL, OLL, OOL, OOO, PLL, POL, POO, and SOL. [Item 25] The pharmaceutical formulation of item 20, wherein the pharma- ceutical acceptable carrier comprises a vegetable oil. [Item 26] The pharmaceutical formulation of Item 20, further comprising an antioxidant. [Item 27] ​​The pharmaceutical formulation of Item 26, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and monosodium glutamate. [Item 28] The pharmaceutical formulation of item 26, wherein the testosterone ester is testosterone enanthate, the pharma- ceutical acceptable carrier comprises sesame oil, the antioxidant is BHT, and the testosterone adduct has formula 10. [Item 29] The pharmaceutical formulation of Item 28, further comprising a testosterone ester adduct of Formula 11. [Item 30] The pharmaceutical formulation of item 26, wherein the testosterone ester is testosterone enanthate, the pharma- ceutical acceptable carrier comprises sesame oil, the antioxidant is BHT, and the testosterone ester adduct has formula 11. [Item 31] The pharmaceutical formulation of Item 26, wherein the concentration of testosterone enanthate is 50 mg / mL to 200 mg / mL. [Item 32] The pharmaceutical formulation of Item 28, wherein the concentration of BHT is 0.01% to 0.1%, or 0.1 mg / mL to 1 mg / mL. [Item 33] The pharmaceutical formulation of Item 28 or 29, wherein the concentration of the testosterone ester adduct of formula 10 is less than the concentration of testosterone enanthate. [Item 34] The pharmaceutical formulation of Item 29 or 30, wherein the concentration of the testosterone ester adduct of formula 11 is less than the concentration of testosterone enanthate. [Item 35] A photostable testosterone ester pharmaceutical formulation for parenteral administration, comprising a pharma- ceutical acceptable carrier comprising a testosterone ester of formula 1, an antioxidant, and a triglyceride of formula 2, wherein: R1 is an alkyl or alkenyl substituent; and Each of R2, R3, and R4 is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid; The pharmaceutical formulation, wherein the photostability of the formulation is assessed by measuring the concentration of available testosterone ester 30-60 days after preparation of the formulation and comparing it to the initial testosterone ester concentration of the formulation. [Item 36] A photostable testosterone ester pharmaceutical formulation for parenteral administration, comprising a pharma- ceutical acceptable carrier comprising a testosterone ester of formula 1, an antioxidant, and a triglyceride of formula 2, wherein: R1 is an alkyl or alkenyl substituent; and Each of R2, R3, and R4 is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid; 20. The pharmaceutical formulation, wherein the photostability of the formulation is assessed 30 to 60 days after preparation of the formulation by measuring the concentration of available testosterone ester and comparing it with the initial testosterone ester concentration in the formulation, and by detecting the presence in the formulation of the testosterone ester adduct of any one of items 13 to 19 and measuring its concentration. [Item 37] A photostable testosterone ester pharmaceutical formulation for parenteral administration, comprising a pharma- ceutical acceptable carrier comprising a testosterone ester of formula 1, an antioxidant, and a triglyceride of formula 2, wherein: R1 is an alkyl or alkenyl substituent; and Each of R2, R3, and R4 is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid. is a aryl group, The photostability of the formulation was measured by subjecting the pharmaceutical formulation to 200 watt-hours / m 2 said pharmaceutical formulation being evaluated by exposing said formulation to at least 100,000 hours of UV light and at least 1.2 million lux hours of visible light exposure, measuring the concentration of available testosterone ester and comparing it to the initial testosterone ester concentration of said formulation. [Item 38] A photostable testosterone ester pharmaceutical formulation for parenteral administration, comprising a pharma- ceutical acceptable carrier comprising a testosterone ester of formula 1, an antioxidant, and a triglyceride of formula 2, wherein: R1 is an alkyl or alkenyl substituent; and Each of R2, R3, and R4 is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid; The photostability of the formulation was measured by subjecting the pharmaceutical formulation to 200 watt-hours / m 220. The pharmaceutical formulation is evaluated by detecting the presence in the formulation of the testosterone ester adduct of any one of items 13 to 19 and measuring its concentration by exposing the formulation to at least 100,000 lux of UV light and at least 1.2 million lux of visible light exposure, measuring the concentration of available testosterone ester and comparing it to the initial testosterone ester concentration in the formulation. [Item 39] The photostable testosterone ester pharmaceutical formulation of any one of items 35 to 38, wherein the concentration of available testosterone ester is at least 66.8% to 75.0% of the initial testosterone ester concentration. [Item 40] The photostable testosterone ester pharmaceutical formulation of items 36 or 38, wherein the concentration of testosterone ester adduct in the formulation is less than the concentration of available testosterone ester. [Item 41] A method for measuring the photostability of a testosterone ester pharmaceutical formulation comprising a testosterone ester of formula 1 and a pharma- ceutical acceptable carrier comprising a triglyceride of formula 2, comprising: measuring the initial testosterone ester concentration of the formulation; measuring the concentration of available testosterone ester in the formulation after a period of time; and Compare these two concentrations, Including, where: R1 is an alkyl or alkenyl substituent; and Each of R2, R3, and R4 is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid; The method. [Item 42] The pharmaceutical preparation is heated to 200 watt-hours / m 2 42. The method of claim 41, further comprising exposing the sample to at least 1.2 million lux of UV light and at least 1.2 million lux of visible light exposure. [Item 43] The method of item 42, wherein the pharmaceutical preparation further comprises an antioxidant selected from the group consisting of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and monosodium glutamate. [Item 44] The method of item 42, wherein the period is between 30 and 60 days. [Item 45] The method of Item 42, further comprising detecting the presence of the testosterone ester adduct of any one of Items 13 to 19 in the pharmaceutical preparation and measuring its concentration.

Claims

1. 1. A pharmaceutical formulation for parenteral administration comprising a compound of formula 1: 【Chemistry 1】 Testosterone esters of formula 2: 【Chemistry 2】 a pharma- ceutical acceptable carrier comprising a triglyceride of formula 3: 【Chemistry 3】 and an antioxidant, During the ceremony: R １ is, at each independent occurrence, an alkyl or alkenyl substituent; R ２ , R ３ , and R ４ each of which is an acyl group corresponding to a fatty acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, ricinoleic acid, linolenic acid, and stearic acid; R 5 is an acyl group corresponding to an unsaturated fatty acid; G is a glycerol, monoglyceride, or diglyceride residue; n is 1, 2, or 3; The pharmaceutical preparation.

2. The pharmaceutical formulation of claim 1, wherein the testosterone residue of formula 3 is linked to an allylic carbon or diallylic carbon of R 5 .

3. The pharmaceutical formulation of claim 1, wherein R 1 , at each independent occurrence, is selected from the group consisting of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopentylethyl, and unsaturated analogs thereof.

4. The pharmaceutical formulation of claim 1, wherein the triglyceride is selected from the group consisting of LLL, OLL, OOL, OOO, PLL, POL, POO, and SOL.

5. The pharmaceutical formulation of claim 1, wherein the pharma- ceutically acceptable carrier comprises a vegetable oil.

6. The pharmaceutical formulation of claim 5, wherein the vegetable oil is sesame oil.

7. The pharmaceutical formulation of claim 1, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), tocopherol, butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid and its salts, vitamin E, niacinamide, methionine, monothioglycerol, sodium disulfite, cysteine, sodium dithionite, gentisic acid, and monosodium glutamate.

8. A testosterone ester adduct having formula 4: 【Chemistry 4】 2. The pharmaceutical formulation of claim 1 having the formula:

9. The testosterone ester adduct of claim 5, 6, 7, 8, 9, 10, or 11: 【Chemistry 5-1】 【Chemistry 5-2】 9. The pharmaceutical formulation of claim 8, having the formula:

10. The pharmaceutical formulation of claim 1, wherein the testosterone ester is testosterone enanthate, testosterone cypionate, testosterone propionate, or testosterone undecanoate.

11. The pharmaceutical formulation of any one of claims 1 to 10, wherein the formulation has a peroxide value of 2 to 12 milliequivalents O2 / kg of fat or oil when measured 3 to 24 months after formulation.

12. The pharmaceutical formulation of claim 1, wherein the decomposition of the testosterone ester of formula 1 to the testosterone ester adduct of formula 3 is reduced by 30% to 50% in the presence of an antioxidant in the formulation.

13. The pharmaceutical formulation of claim 12, wherein the concentration of available testosterone ester is at least 66.8% to 75.0% of the initial testosterone ester concentration.

14. The pharmaceutical formulation of claim 12, wherein the concentration of testosterone ester adduct in the formulation is less than the concentration of available testosterone ester.

15. The pharmaceutical preparation according to any one of claims 1 to 10, wherein the concentration of the antioxidant is 0.01% to 0.1%.

16. The pharmaceutical formulation according to any one of claims 1 to 10, wherein the concentration of the antioxidant is 0.1 mg / mL to 1 mg / mL.

17. The pharmaceutical formulation according to any one of claims 1 to 10, wherein the concentration of the testosterone ester adduct is 0.005 mg / ml to 25 mg / ml.

Images