(12) Patent Application Publication (10) Pub. No.: US 2008/0317844 A1 Dudley Et Al

US 20080317844A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0317844 A1 Dudley et al. (43) Pub. Date: Dec. 25, 2008

(54) PHARMACEUTICAL DELVERY SYSTEMS Related U.S. Application Data FOR HYDROPHOBC DRUGS AND COMPOSITIONS COMPOSITIONS (60) Provisional application No. 60/671,454, filed on Apr. COMPRISING SAME 15, 2005, provisional application No. 60/721,971, filed on Sep. 30, 2005. (75) Inventors: Robert E. Dudley, Rosemary Beach, IL (US); Panayiotis P. Constantinides, Gurnee, IL (US) Publication Classification (51) Int. Cl. Correspondence Address: A69/48 (2006.01) FOLEY AND LARDNER LLP A6II 3/56 (2006.01) SUTESOO A6IP 5/00 (2006.01) 3OOOK STREET NW WASHINGTON, DC 20007 (US) (52) U.S. Cl...... 424/456; 514/179; 514/170: 514/171 (73) Assignee: Clarus Therapeutics, Inc., Northbrook, IL (US) (57) ABSTRACT (21) Appl. No.: 11/911,446 A drug delivery system for oral administration of hydropho PCT Fled: Apr. 14, 2006 bic drugs with enhanced and extended absorption and (22) improved pharmacokinetics is provided. In one embodiment, (86) PCT NO.: PCT/USO6/142O7 formulations comprising testosterone and testosterone esters, e.g., testosterone palmitate, are disclosed. Methods of treat S371 (c)(1), ing a hormone deficiency or effecting male contraception (2), (4) Date: Nov. 12, 2007 with the inventive formulations are also provided. Patent Application Publication Dec. 25, 2008 Sheet 1 of 15 US 2008/0317844 A1

FIGURE 1

es iNpf Normal Range g t

wer 9 s O CD s s was s Lower Limit of Nortarange

O 72 76 80 84 88 92 96 100 104 108 112 116 120 24 128 132 136 140 144 Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 2 of 15 US 2008/0317844 A1

FIGURE 2

ah - 9. 1 o

w s O () " (s wV t C E iower Limit of Normat Range

O 72 76 80 84 88 92 96 100 104 108 112 116 120 124 128 132 136 140 144 Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 3 of 15 US 2008/0317844 A1

FIGURE 3

an - Upper Limit of Normal Rang g 1 o C WM t s O O T s E t Lowerint of Normal Range

72 76 80 84 88 92 96 100 104 108 112 116 120 124 128 132 136 140 144 Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 4 of 15 US 2008/0317844 A1

FIGURE 4

Upper limit of Normal Range 1-n - O a. o Mr. () () S O C) "C Gy w E () Lower Limit of Normal Range

72 76 80 84 88 g2 96 100 104 108 112 116 120 124 128 132 136 140 144 Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 5 Of 15 US 2008/0317844 A1

FIGURE 5

Agha - 9. 10 O) C . M U O O o s s E D

72 76 80 84 88 92 96 100 104 108 112 116 120 124 128 132 136 140 144 Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 6 of 15 US 2008/0317844 A1

FIGURE 6

as - 9. 1

O O C und s E () Lower Limit of Normal Range

72 76 80 84 88 92 96 OO 104 108 112 16 120 124 128 132 136 140 144 Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 7 of 15 US 2008/0317844 A1

FIGURE 7

a Upper Limit of Normal Range 9. 1 O C We 9 O C s () w E Lower Limit of NortaTRange

O 72 76 80 84 88 92 96 100 104 108 112 16 120 124 128 132 136 140 144 Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 8 of 15 US 2008/0317844 A1

FIGURE 8

Upper Limit of Normal Range

ma - s

O d C und E of) Lower Limit of Normal Range

O 72 76 80 84 88 92 96 100 104 108 112 116 120 124 128 132 136 140 144 Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 9 of 15 US 2008/0317844 A1

FIGURE 9

-e- Formulation it 9 o-E-Formulation #23 - A - Formulation #24

20 Patent Application Publication Dec. 25, 2008 Sheet 10 of 15 US 2008/0317844 A1

FIGURE 10

120

100

40 -0-Formulation ii 47 -E-Formulation #50 20 -A-Formulation #51 -G-Formulation #54

1. 2 3 4. 5 Time (hours) Patent Application Publication Dec. 25, 2008 Sheet 11 of 15 US 2008/0317844 A1

FIGURE 11

-E-50 QD -A- 54 BO

Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 12 of 15 US 2008/0317844 A1

FIGURE 12

Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 13 of 15 US 2008/0317844 A1

FIGURE 13

-e- 54 BO -E-5O BID Sinn

Time (hr) Patent Application Publication Dec. 25, 2008 Sheet 14 of 15 US 2008/0317844 A1

FIGURE 14

60 -9-62A -A-64A

-6-70 -E-71 40

Time (Hours) Patent Application Publication Dec. 25, 2008 Sheet 15 of 15 US 2008/0317844A1

FIGURE 15

90 A===s== 80 uta- ass 70

-6-62A - A-64A -e- 70

10 -- 71 -O-71A -g- 78

Time (Hours) US 2008/0317844 A1 Dec. 25, 2008

PHARMACEUTICAL DELVERY SYSTEMS prises a lipophilic surfactant that provides for the controlled FOR HYDROPHOBC DRUGS AND release of TP. said lipid components together providing for COMPOSITIONS COMPOSITIONS the solubilization of TP. The pharmaceutical composition COMPRISING SAME may further comprise at least three lipid components at least the first of which comprises a hydrophilic surfactant, at least CLAIM OF PRIORITY the second of which comprises a lipophilic Surfactant that 0001. This application claims priority to U.S. provisional provides for the controlled release of TP and at least the third of which comprises a lipophilic surfactant that further pro application Nos. 60/671,454 filed Apr. 15, 2005 and 60/721, vides for the solubilization of TP. As well, the pharmaceutical 971 filed Sep. 30, 2005, both of which disclosures have been composition may further comprise a second lipid-soluble incorporated by reference herein in their entirety. therapeutic agent, Such as a synthetic progestin. Formulations FIELD OF THE INVENTION comprising same may be preferably in the form of an orally active male contraceptive. 0002 The present invention relates generally to pharma 0008. The first lipid component may exhibit an HLB of 10 ceutical delivery systems of hydrophobic drugs and compo to 45, preferably 10 to 30, and more preferably 10 to 20. The sitions comprising same. More particularly, the present second lipid component may exhibit an HLB of less than invention relates to pharmaceutical compositions comprising about 10, preferably less than about 7, and more preferably testosterone and esters thereof with enhanced and extended less than about 5. Further, the second lipid component may absorption and pharmacokinetics. exhibit a melting point in the range of about 25°C. to about 80° C., preferably about 35° C. to about 65° C., and more BACKGROUND OF THE INVENTION preferably about 40° C. to about 60° C. The second lipid 0003. Many pharmaceutically active compounds intended component may be chosen from the group consisting of for oral administration are poorly soluble in water providing stearic acid, palmitic acid, glycerol and PEG esters thereof, a challenge to formulate these drugs in a drug delivery system Precirol ATO 5 and Gelucires. that exhibits the desirable pharmacokinetic profiles in vivo. 0009. In some embodiments, the lipophilic surfactant fur Poor oral bioavailability may lead to ineffective therapy, the ther comprises a “sustained’ or controlled-release' surfactant need for higher dosing and/or undesirable side effects. As which may be chosen from the group consisting of Stearic well, pharmaceutical preparations with relatively short half acid, palmitic acid, glycerol and PEG esters thereof. Precirol lives require frequent dosing at the expense of patient incon AT05, Imwitor 191, Myverol 18-06, Imwitor 370, Imwitor Venience and higher therapy costs. 375, Caprol ET, Cithrol 2MS, Marosol 183 and combinations 0004 Sex hormones (e.g., testosterone and its esters) are thereof. The hydrophilic surfactant may be a poloxyl deriva marginally water Soluble, and attempts have been made to tive of castor oil. Commercially available products of this increase their bioavailability, particularly when taken orally. class are Supplied under the tradenames, Cremophor or Eto However, administration of testosterone, per se, presents cas and include, Cremophor EL and RH 40 and Etocas 35 and additional challenges. Indeed, while testosterone given by 40. Chemophor, RH40 or Etocas 40 are preferred. mouth is essentially completely absorbed into the portal cir 0010 Compositions of the present invention may com culation, because of extensive first-pass hepatic metabolism, prise, based on weight, 10-70% alipophilic surfactant; 1-40% the serum concentration of testosterone following this route a controlled release surfactant; and 5-60% a hydrophilic sur of administration is low unless very large doses are adminis factant; and preferably 30-50% alipophilic surfactant; 5-25% tered. To overcome this problem, attempts have been made to a controlled release surfactant; and 30-40% a hydrophilic alkylate testosterone at the C-17 position (e.g., with a methyl surfactant. The compositions further comprise about 5 to group to form methyltestosterone) thereby reducing metabo about 50 percent, by weight, testosterone palmitate, prefer lism by the liver. Unfortunately, however, mere alkylation of ably, about 20 to about 40 percent, by weight, testosterone testosterone has not yielded desirable bioavailability and has palmitate. The inventive pharmaceutical compositions may been associated with potentially serious hepatotoxicity. also comprise one or more cosolvents and/or filled into a hard 0005. Other attempts have managed to increase the tran or soft gelatin capsule. sient bioavailability of testosterone and its derivatives with 0011. In another aspect of the present invention, a method lipophilic solvents and Surfactants. Nonetheless, even in of preventing or alleviating the symptoms of testosterone cases where bioavailability was enhanced, the delivery sys deficiency in a mammalian Subject is provided comprising tems failed to maintain desirable serum concentrations over administering to the mammalian Subject an effective amount an extended period of time. oftestosterone palmitate (TP) solubilized in two or more lipid 0006. Accordingly, there is a need for a drug delivery components, such that the administration of said solubilized system that can provide enhanced bioavailability of hydro TP raises the mammalian subject's steady state serum level of phobic drugs in vivo. In addition, with respect to testosterone testosterone to within those levels found in mammalian sub therapy, there is a need for an oral drug delivery system that jects having no testosterone deficiency and providing at least may provide enhanced bioavailability of testosterone and/or Some relief from Such symptoms. In human males, the admin an ester thereof in vivo over an extended period of time. istering is preferably once or twice daily and the mammal’s steady state serum level of testosterone is raised to fall within SUMMARY OF THE INVENTION a range of about 300 ng/dl to about 1100 ng/dl. With human 0007. In one embodiment of the present invention, a phar females, a similar dosing schedule (with a lower daily TP maceutical composition is provided comprising testosterone dose) is preferred to achieve serum testosterone levels of palmitate (TP), or a testosterone ester thereof, and two or approximately 10 to 100 ng/dl. In some embodiments, the more lipid components at least the first of which comprises a method may raise the mammal’s steady state serum level of hydrophilic Surfactant and at least the second of which com testosterone by 150%, 200%, 300% or 400%. The method US 2008/0317844 A1 Dec. 25, 2008

may further comprise administering an amount of a synthetic of a formulation of TP, which maximizes diurnal variation progestin Sufficient to inhibit gonadotropin release in said while producing an early Tmax, preferably compatible with mammalian Subject and produce severe oligospermia or early morning, once-daily dosing. aZospermia. 0018 FIG. 2 depicts a steady-state pharmacokinetic pro 0012. In yet another aspect of the present invention, a file of the serum concentration of testosterone upon ingestion method of delivering steady-state serum levels of testosterone of a formulation of TP which maximizes diurnal variation effective to provide at least some relief from symptoms of testosterone deficiency is provided comprising solubilizing while producing a late Tmax, preferably compatible with testosterone palmitate (TP) in two or more lipid components night-time, once-daily dosing. at least the first of which comprises a hydrophilic surfactant 0019 FIG. 3 depicts a steady-state pharmacokinetic pro and at least the second of which comprises a lipophilic Sur file of the serum concentration of testosterone upon ingestion factant that provides for the controlled release of TP and of a formulation of TP which provides physiological diurnal administering an effective amount of the solubilized TP to a variation and an early Tmax, preferably compatible with Subject suffering from the symptoms of testosterone defi early morning, once-daily dosing. ciency. The method can further comprise solubilizing TP in at 0020 FIG. 4 depicts a steady-state pharmacokinetic pro least three lipid components at least the first of which com file of the serum concentration of testosterone upon ingestion prises a hydrophilic Surfactant, at least the second of which of a formulation of TP, which provides physiological diurnal comprises a lipophilic Surfactant that provides for the con variation and a delayed Tmax, preferably compatible with trolled release of TP and at least the third of which comprises early morning, once-daily dosing. a lipophilic surfactant that further provides for the solubili 0021 FIG. 5 depicts a steady-state pharmacokinetic pro Zation of TP. 0013. In further yet another aspect of the present inven file of the serum concentration of testosterone upon ingestion tion, a method of providing extended release of testosterone of a formulation of TP, which provides a short elimination in vivo is provided, the method comprising solubilizing tes half-life and an early Tmax, preferably compatible with tosterone palmitate (TP) in a lipid mixture comprising two or maximal patient activity soon after waking and twice-daily more lipid components at least the first of which comprises a dosing. hydrophilic Surfactant and at least the second of which com 0022 FIG. 6 depicts a steady-state pharmacokinetic pro prises a lipophilic Surfactant having a melting point of greater file of the serum concentration of testosterone upon ingestion than about 35° C. of a formulation of TP, which provides a relatively short 0014. In still further yet another embodiment of the elimination half-life and a delayed Tmax with maximal activ present invention, a pharmaceutical composition is provided ity about waking time. One of the twice-daily doses is pref comprising testosterone palmitate (TP) and two or more lipid erably scheduled before bedtime. components at least the first of which comprises a hydrophilic 0023 FIG. 7 depicts a steady-state pharmacokinetic pro Surfactant and at least the second of which comprises a lipo philic surfactant, in which the at least first hydrophilic com file of the serum concentration of testosterone upon ingestion ponent or the at least second lipophilic component provides of a formulation of TP, which provides and intermediate for the controlled release of TP. and said lipid components elimination half-life and a Tmax preferably compatible with together provide for the solubilization of TP. In one embodi maximal activity soon afterwalking while reducing the extent ment, the at least first hydrophilic component provides for the of fluctuation to the physiological level with twice-daily dos controlled release of TP. 1ng. 0015. In this respect, before explaining at least one 0024 FIG. 8 depicts a steady-state pharmacokinetic pro embodiment of the invention in detail, it is to be understood file of the serum concentration of testosterone upon ingestion that the invention is not limited in its application to the details of a formulation of TP, which provides a longer elimination of construction and to the arrangements of the components set half-life and a delayed Tmax, preferably compatible with forth in the following description or illustrated in the draw maximal activity about awakening time following bedtime ings. The invention is capable of embodiments in addition to administration. This formulation reduces the extent of fluc those described and of being practiced and carried out in tuation to the physiological levels of testosterone with twice various ways. Also, it is to be understood that the phraseology daily dosing. and terminology employed herein, as well as the abstract, are 0025 FIG. 9 shows dissolution curves of TP from three for the purpose of description and should not be regarded as formulations (9, 23 and 24 the compositions of which are limiting. listed in Table 2) in a phosphate buffered dissolution medium 0016. As such, those skilled in the art will appreciate that incorporating TritonX-100 as a Surfactant in accordance with the conception upon which this disclosure is based may the present invention. readily be utilized as a basis for the designing of other struc 0026 FIG. 10 shows dissolution curves of TP from three tures, methods and systems for carrying out the several pur formulations (47.50, 51 and 54 the compositions of which are poses of the present invention. For example, some embodi listed in Table 3) in a phosphate buffered dissolution medium ments of the invention may combine TP with other active incorporating TritonX-100 as a Surfactant in accordance with drugs, including hormonals, in an oral delivery system that, in the present invention. part, prevents or alleviates symptoms associated with test 0027 FIG. 11 provides the mean steady-state profile of osterone deficiency. It is important, therefore, that the claims be regarded as including such equivalent constructions inso treatment with three regimens for seven days. far as they do not depart from the spirit and scope of the 0028 FIG. 12 shows the mean steady-state serum T and DHT Levels after seven days of BID administration of for present invention. mulation 54. BRIEF DESCRIPTION OF THE DRAWINGS 0029 FIG. 13 provides a simulated mean steady-state pro 0017 FIG. 1 depicts a steady-state pharmacokinetic pro file of formulation 50 with respect to the observed profile for file of the serum concentration of testosterone upon ingestion formulation 54 (both administered BID for seven days). US 2008/0317844 A1 Dec. 25, 2008

0030 FIG. 14 shows representative in vitro dissolution 0039 Anti-depressants: amoxapine, maprotiline HCl, profiles for various TP formulations in phosphate buffer mianserin HCl, nortriptyline HCl, trazodone HCl, trimi (PBS) pramine maleate. 0031 FIG. 15 shows representative in vitro dissolution 0040 Anti-diabetics: acetohexamide, chlorpropamide, profiles for various TP formulations in fed-state simulated glibenclamide, gliclazide, glipizide, tolaZamide, tolbuta intestinal fluid (FeSSIF). mide. 0041 Anti-epileptics: beclamide, carbamazepine, clon DETAILED DESCRIPTION OF THE INVENTION azepam, ethotoin, methoin, methSuximide, methylphenobar 0032. The present invention provides pharmaceutical bitone, oXcarbazepine, paramethadione, phenacemide, phe delivery systems, preferably oral, for hydrophobic drugs. nobarbitone, phenyloin, phensuXimide, primidone, Accordingly, while the instant invention will be described, to Sulthiame, valproic acid. some extent, with reference to oral delivery systems, the 0042 Anti-fungal agents: amphotericin, butoconazole present invention may be suitable for topical and intramus nitrate, clotrimazole, econazole nitrate, fluconazole, flucy cular injection. Further, hydrophobic drugs defined herein tosine, griseofulvin, itraconazole, ketoconazole, miconazole, encompass both those drugs that are inherently hydrophobic natamycin, nystatin, Sulconazole nitrate, terbinafine HCl, ter (i.e., having a log P of at least 2) as well as otherwise hydro conazole, tioconazole, undecenoic acid. philic medicaments that have been rendered hydrophobic 0043 Anti-gout agents: allopurinol, probenecid, Sulphin with Suitable modification (e.g., conjugation to fatty acids pyrazone. and/or lipids). (Log P is the log of the octanol-water or buffer 0044 Anti-hypertensive agents: amlodipine, benidipine, partition coefficient and can be determined by a variety of darodipine, dilitazem HCl, diaZoxide, felodipine, guanabenz methods for those skilled in the art. The higher the value of log acetate, isradipine, minoxidil, nicardipine HCl, nifedipine, P, the greater the lipophilicity and thus lipid solubility of the nimodipine, phenoxybenzamine HCl, praZosin HCl, reser chemical entity in question.) pine, terazosin HC1. 0033. In one embodiment of the present invention, test 0045 Anti-malarials: amodiaquine, chloroquine, chlor osterone and/or esters at the C-17 position of the testosterone proguanil HCl, halofantrine HCl, mefloquine HCl, proguanil molecule, alone or in combination with other active ingredi HCl, pyrimethamine, quinine Sulphate. ents, may be orally delivered using the inventive delivery 004.6 Anti-migraine agents: dihydroergotamine mesylate, system. While many of the embodiments of the present inven ergotamine tartrate, methysergide maleate, pizotifen maleate, tion will be described and exemplified with the palmitic acid Sumatriptan Succinate. ester of testosterone (also referred to as “testosterone palmi 0047 Anti-muscarinic agents: atropine, benzhexol HCl, tate' or “TP), the scope of the present invention should not biperiden, ethopropazine HCl, hyoscyamine, mepenZolate be construed nor limited solely to the delivery of TP or test bromide, oxyphencylcimine HCl, tropicamide. osterone perse. In fact, it should be readily apparent to one of 0048 Anti-neoplastic agents and Immunosuppressants: ordinary skill in the art from the teachings herein that the aminoglutethimide, amsacrine, azathioprine, buSulphan, inventive drug delivery systems and compositions therefrom chlorambucil, cyclosporin, dacarbazine, estramustine, etopo may be suitable for oral delivery of other testosterone esters, side, lomustine, melphalan, mercaptopurine, methotrexate, Such as short-chain (C-C), medium-chain (C7-C) and long-chain (C-C) fatty acid esters, preferably long-chain mitomycin, mitotane, mitoZantrone, procarbazine HCl, fatty acid esters of testosterones and numerous hydrophobic tamoxifen citrate, testolactone. medicaments. Such suitable medicaments, which may befor 0049 Anti-protazoal agents: benznidazole, clioquinol, mulated in accordance with the present invention include, but decoquinate, diiodohydroxyquinoline, diloxanide furoate, should not be limited to, the following: dinitolmide, furzolidone, metronidazole, nimorazole, nitro 0034 Analgesics and anti-inflammatory agents: alox furaZone, omidazole, timidazole. iprin, auranofin, azapropaZone, benorylate, diflunisal, etod 0050 Anti-thyroid agents: carbimazole, propylthiouracil. olac, fenbufen, fenoprofen calcim, flurbiprofen, ibuprofen, 0051 Anxiolytic, sedatives, hypnotics and neuroleptics: indomethacin, ketoprofen, meclofenamic acid, mefenamic alprazolam, amylobarbitone, barbitone, bentazepam, bro acid, nabumetone, naproxen, oxyphenbutaZone, phenylbuta mazepam, bromperidol, brotizolam, butobarbitone, carbro Zone, piroxicam, Sulindac. mal, chlordiazepoxide, chlormethiazole, chlorpromazine, 0035 Anthelmintics: albendazole, bephenium hydrox clobazam, clotiazepam, clozapine, diazepam, droperidol. ynaphthoate, cambendazole, dichlorophen, ivermectin, ethinamate, flunanisone, flunitrazepam, fluopromazine, flu mebendazole, nitaZOXamide, oxamniquine, Oxfendazole, penthixol decanoate, fluiphenazine decanoate, flurazepam, oxantel embonate, praziquantel, pyrantel embonate, thia haloperidol, lorazepam, lormetazepam, medazepam, mep bendazole. robamate, methaqualone, midazolam, nitrazepam, 0036 Anti-arrhythmic agents: amiodarone HCl, disopy oxazepam, pentobarbitone, perphenazine pimozide, prochlo ramide, flecainide acetate, quinidine Sulphate. rperazine, Sulpiride, temazepam, thioridazine, triazolam, 0037 Anti-bacterial agents: benethamine penicillin, cino Zopiclone. Xacin, ciprofloxacin HCl, clarithromycin, clofazimine, clox 0.052 Beta-blockers: acebutolol, alprenolol, atenolol, acillin, demeclocycline, doxycycline, erythromycin, ethiona labetalol, metoprolol, nadolol, oXprenolol, pindolol, propra mide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, nolol. spiramycin, Sulphabenzamide, Sulphadoxine, Sulphamera 0053 Cardiac Inotropic agents: amrinone, digitoxin, Zine, Sulphacetamide, Sulphadiazine, Sulphafurazole, Sulpha digoxin, enoXimone, lanatoside C, medigoxin. methoxazole, Sulphapyridine, tetracycline, trimethoprim. 0054 Corticosteroids: beclomethasone, betamethasone, 0038 Anti-coagulants: dicoumarol, dipyridamole, nicou budesonide, cortisone acetate, desoxymethasone, dexam malone, phenindione. ethasone, fludrocortisone acetate, flunisolide, flucortolone, US 2008/0317844 A1 Dec. 25, 2008 fluticasone propionate, hydrocortisone, methylprednisolone, 0068 According to one aspect of the present invention, prednisolone, prednisone, triamcinolone. each of the components of the delivery system (i.e., the lipo 0.055 Diuretics: acetazolamide, amiloride, bendroflu philic and hydrophilic surfactants) individually have solvent azide, bumetanide, chlorothiazide, chlorthalidone, characteristics and contribute, in part, to solubilizing the ethacrynic acid, frusemide, metolaZone, spironolactone, tri active ingredient. Those lipophilic surfactants that contribute anterene. Substantially to dissolving the drug are defined herein as a 0056 Anti-parkinsonian agents: bromocriptine mesylate, “primary” solvent. Primary solvents can also provide “sus ly Suride maleate. tained-release' or “controlled-release' characteristics to the 0057 Gastro-intestinal agents: bisacodyl, cimetidine, drug delivery system. “Secondary solvents are hydrophilic cisapride, diphenoxylate HCl, domperidone, famotidine, lop surfactants that also solubilize the drug, albeit to a lesser eramide, mesalazine, nizatidine, omeprazole, ondansetron extent than a primary solvent. In addition to dissolving the HCl, ranitidine HCl, sulphasalazine. drug, secondary solvents facilitate the dispersion of the deliv 0058. Histamine H.-Receptor Antagonists: acrivastine, ery system in aqueous media or intestinal fluids and Subse astemizole, cinnarizine, cyclizine, cyproheptadine HCl, quent release of the drug. In cases where the secondary Sol dimenhydrinate, flunarizine HCl, loratadine, meclozine HCl, vent is a high melting point hydrophilic Surfactant, it can also oXatomide, terrenadine. provide for a Sustained drug release, acting synergistically 0059 Lipid regulating agents: bezafibrate, clofibrate, with the lipophilic surfactant. fenofibrate, gemfibrozil, probucol. 0069. A hydrophilic surfactant component may be neces sary to achieve desirable emission of the drug from within the 0060 Nitrates and other anti-anginal agents: amyl nitrate, formulation. That is, a hydrophilic Surfactant may be required glyceryl trinitrate, isosorbide dinitrate, isosorbide mononi to free the drug from within the lipid carrier matrix, or pri trate, pentaerythritol tetranitrate. mary solvent. In this respect, a high HLB Surfactant, such as 0061 Nutritional agents: betacarotene, vitaminA, vitamin Cremophor RH40, can generally suffice. In some formula B. vitamin D, vitamin E, vitamin K. tions incorporating high levels of solubilized TP, the inventors 0062 Opioid analgesics: codeine, dextropropyoxyphene, have observed that in the absence of a high HLB surfactant, diamorphine, dihydrocodeine, meptazinol, methadone, mor there can be substantially no release of the drug from blends phine, nalbuphine, pentazocine. solely comprising lipophilic surfactants. The levels of the 0063 Sex hormones: clomiphene citrate, danazol, ethiny high HLB Surfactant can be adjusted to provide optimum drug loestradiol, medroxyprogesterone acetate, mestranol, meth release without compromising the solubilization of the active yltestosterone, norethisterone, norgestrel, oestradiol, conju ingredient. gated oestrogens, progesterone, synthetic progestins (also 0070 The lipophilic surfactant component, in some referred to as progestogens), Stanozolol, Stiboestrol, tibolone, embodiments, may further comprise a “controlled-release' testosterone, esters of testosterone, including esters of oleic Surfactant. In other words, in addition to being a solvent for acid, linoleic acid, linolenic acid, Stearic acid, myristic acid, the drug, the lipophilic Surfactant may also provide a semi lauric acid, palmitic acid, capric or decanoic acid octanoic or solid and sustained release (SR) matrix. Many semi-solid/SR caprylic acid, pelargonic acid, undecanoic acid, tridecanoic excipients are available to one of ordinary skill in the art, but acid, pentadecanoic acid, and the branched chain, cyclic ana those that additionally are good solvents for the drug are logues of these acids, testosterone analogues such as methyl desirable in the instant invention. Thus, preference should be nortestosterone, and combinations thereof. Synthetic given to semi-solid lipid excipients having high solubilization progestins include, for example, levonorgestrel, levonorg potential for the drug. In one aspect, “controlled-release' estrel butanoate, drospirenone, norethisterone, desogestrel, lipophilic surfactants exhibit a melting point of about 25°C. etonorgestrel and medroxyprogesterone. to about 80°C., preferably about 35° C. to about 65° C., and 0064 Gonadotropin releasing hormone (GnRH) antago more preferably 40° C. to about 60° C. nists that are orally active. (0071. To be sure, however, “controlled-release' surfac 0065. Stimulants: amphetamine, dexamphetamine, tants need not be limited to lipophilic Surfactants alone. dexfenfluramine, fenfluramine, mazindol. Indeed, some hydrophilic Surfactants in compositions of the 0066 Mixtures of hydrophobic drugs may, of course, be instant invention may also provide controlled-release charac used where therapeutically effective. For example, the com teristics in conjunction with a lipophilic Surfactant. bination of testosterone palmitate with an orally active inhibi 0072 Lipophilic surfactants suitable in drug delivery sys tor or Type I or Type II 5C.-reductase or the combination of tems of the present invention include: testosterone palmitate with a synthetic progestin may be pref 0073. Fatty acids (C-C, preferably Co-C, more pref erable in some embodiments. erably C-C), for example, octanoic acid, decanoic acid, 0067 Drug delivery systems of the present invention and undecanoic acid, lauric acid, myristic acid, palmitic acid, compositions comprising same, comprise a hydrophobic Stearic acid, oleic acid, linoleic acid, and linolenic acid. drug or drugs dissolved in a lipophilic Surfactant and a hydro Stearic acid and palmitic acid are preferred. philic Surfactant. Alipophilic Surfactant as defined herein has 0074 Mono- and/or di-glycerides of fatty acids, such as a hydrophilic-lipophilic balance (HLB) less than 10, and pref Imwitor 988 (glyceryl mono-/di-caprylate), Imwitor 742 erably less than 5. A hydrophilic surfactant as defined herein (glyceryl mono-di-caprylate/caprate), Imwitor 308 (glyceryl has an HLB of greater than 10. (HLB is an empirical expres mono-caprylate), Imwitor 191 (glyceryl mono-Stearate), sion for the relationship of the hydrophilic and hydrophobic Softigen 701 (glyceryl mono-/di-ricinoleate), Capmul MCM groups of a Surface active amphiphilic molecule, such as a (glyceryl caprylate/caprate), Capmul MCM(L) (liquid form Surfactant. It is used to index surfactants and its value varies of Capmul MCM), Capmul GMO (glyceryl mono-oleate), from about 1 to about 45. The higher the HLB, the more water Capmul GDL (glyceryl dilaurate), Maisine (glyceryl mono soluble the surfactant.) linoleate), Peceol (glyceryl mono-oleate), Myverol 18-92 US 2008/0317844 A1 Dec. 25, 2008

(distilled monoglycerides from sunflower oil) and Myverol I0085. Any pharmaceutically acceptable hydrophilic sur 18-06 (distilled monoglycerides from hydrogenated soybean factant (i.e., having an HLB value greater than 10) may be oil), Precirol ATO 5 (glyceryl palmitostearate) and Gelucire used in the present invention. Some non-limiting examples 39/01 (semi-synthetic glycerides, i.e., C.s mono-, di- and include: tri-glycerides). The preferred members of this class of lipo I0086 Polyoxyethylene sorbitan fatty acid derivates e.g. philic Surfactants are the partial glycerides of oleic, palmitic Tween 20 (polyoxyethylene (20) monolaureate), Tween 80 and stearic acids and blends thereof. (polyoxyethylene (20) monooleate), Crillet 4 (polyoxyethyl 0075 Acetic, succinic, lactic, citric and/or tartaric esters ene (20) monooleate) and Montanox 40 (polyoxyethylene of mono- and/or di-glycerides of fatty acids, for example, (20) monopalmitate). Tween 80 (Polysorbate 80) is preferred. My vacet 9-45 (distilled acetylated monoglycerides), Miglyol I0087 Castor oil or hydrogenated caster oil ethoxylates 829 (caprylic/capric diglyceryl succinate), Myverol SMG (HLB) 10), e.g. Cremophor EL (polyoxyethylene (35) castor (mono/di-Succinylated monoglycerides), Imwitor 370 (glyc oil), Cremophor RH40 (polyoxyethylene (40) hydrogenated eryl Stearate citrate), Imwitor 375 (glyceryl monostearate/ castor oil), Etocas 40 (polyoxyethylene (40) castor oil), citrate/lactate) and CrodatemT22 (diacetyl tartaric esters of Nikkol HCO-60 (polyoxyethylene (60) hydrogenated castor monoglycerides). oil), Solutol HS-15 (polyethylene glycol 660 hydroxystear 0076 Propylene glycol mono- and/or di-esters of fatty ate), Labrasol (caprylocaproyl macrogol-8 glycerides), C-to acids, for example, Lauroglycol (propylene glycol monolau copherol-polyethylene glycol-1000-succinate (TPGS) and rate), Mirpyl (propylene glycol monomyristate), Captex 200 ascorby1-6 palmitate. Cremophor RH40 is preferred. (propylene glycol dicaprylate/dicaprate), Miglyol 840 (pro I0088 Gelucires, preferably Gelucire 50/13 (PEG mono pylene glycol dicaprylate/dicaprate) and Neobee M-20 (pro and diesters of palmitic and Stearic acids. (In reference to pylene glycol dicaprylate/dicaprate). Gelucires, the first number (i.e., 50) corresponds to the melt 0077. Polyglycerol esters of fatty acids such as Plurol ing point of the material and the second (i.e., 13) to the HLB oleigue (polyglyceryl oleate), Caproll ET (polyglyceryl number.) mixed fatty acids) and Drewpol 10.10.10 (polyglyceryl ole I0089. Fatty acid ethoxylates (HLB>10), e.g. Myri 45 ate). (polyoxyethylene (8) Stearate), Tagat L (polyoxyethylene 0078 Castor oil ethoxylates of low ethoxylate content (30) monolaurate), Marlosol 1820 (polyoxyethylene (20) stearate) and Marlosol OL15 (polyoxyethylene (15) oleate). (HLB<10) such as Etocas 5 (5 moles of ethylene oxide Myri 45 is preferred. reacted with 1 mole of castor oil) and Sandoxylate 5 (5 moles I0090 Alcohol ethoxylates (HLB-10), e.g. Brij 96 (poly of ethylene oxide reacted with 1 mole of castor oil. oxyethylene (10) oleyl ether), Volpo 015 (polyoxyethylene 0079 Acid and ester ethoxylates formed by reacting eth (15) oleyl ether), Marlowet OA30 (polyoxyethylene (30) ylene oxide with fatty acids or glycerol esters of fatty acids oleyl ether) and Marlowet LMA20 (polyoxyethylene (20) (HLB<10) such as Crodet 04 (polyoxyethylene (4) lauric C-C fatty ether). acid), Cithrol 2MS (polyoxyethylene (2) stearic acid), Mar 0091 Polyoxyethylene-polyoxypropylene co-polymers losol 183 (polyoxyethylene (3) stearic acid) and Marlowet and block co-polymers (HLB) 10), that are commercially G12DO (glyceryl 12 EO dioleate). Sorbitan esters of fatty available under the trade name Pluronics or Poloxamers, such acids, for example, Span 20 (sorbitan monolaurate), Crill 1 as Poloxamers 188 and 407 also known as Syperonic PEL44 (Sorbitan monolaurate) and Crill 4 (Sorbitan mono-oleate). (HLB=16) and Syperonic F127 (HLB-22), respectively. 0080 Transesterification products of natural or hydroge 0092 Anionic surfactants e.g. sodium lauryl sulphate, nated vegetable oil triglyceride and a polyalkylene polyol Sodium oleate and Sodium dioctylsulphosuccinate. (HLB<10), e.g. Labrafil M1944CS (polyoxyethylated apricot (0093. Alkylphenol surfactants (HLB-10) e.g. Triton kernel oil), Labrafil M2125CS (polyoxyethylated corn oil) N-101 (polyoxyethylene (9-10) nonylphenol) and Synper and Gelucire 37/06 (polyoxyethylated hydrogenated coco onic NP9 (polyoxyethylene (9) nonylphenol). nut). Labrafil M1944CS is preferred. 0094. Of the hydrophilic surfactants listed above, those I0081 Alcohol ethyoxylates (HLBC10), e.g. Volpo N3 suitable as a “controlled-release' surfactant include, but are (polyoxyethylated (3) oleyl ether), Brij93 (polyoxyethylated not limited to Gelucires of high HLB value, such as Gelucire (2) oleyl ether), Marlowet LA4 (polyoxyethylated (4) lauryl 5Of 13. ether) and 0.095 As mentioned, in one aspect of the present inven 0082 Pluronics, for example, Polyoxyethylene-polyox tion, each of the components of the delivery system (i.e., the ypropylene co-polymers and block co-polymers (HLB<10) lipophilic and hydrophilic surfactants) individually has sol e.g. Symperonic PE L42 (HLB-8) and Symperonic PE L61 vent characteristics and contributes, in part, to solubilizing (HLB-3) the active ingredient. In this way, without being bound by or 0083 Mixtures of suitable lipophilic surfactants, such as limited to theory, the present invention does not require addi those listed above, may be used if desired, and in some tional Solvents, such as additional digestible oils and/or cosol instances are found to be advantageous. For instance, glycerol vents, but these may be optionally included in the inventive palmitate and glycerol Stearate esters alone and in blends are systems and formulations. preferred lipophilic surfactants and controlled-release matri 0096. A digestible oil is defined herein as an oil that is CCS. capable of undergoing de-esterification or hydrolysis in the 0084. Of the lipophilic surfactants listed above, those suit presence of pancreatic lipase in vivo under normal physi able as a “controlled-release' component include, but are not ological conditions. Specifically, digestible oils may be com limited to, Stearic acid, palmitic acid, and their glycerol and plete glycerol triesters of medium chain (C7-C) or long PEG esters, Precirol AT05, Imwitor 191, Myverol 18-06, chain (C-C) fatty acids with low molecular weight (up to Imwitor 370, Imwitor 375, Caprol ET, Cithrol 2MS, Marosol C) mono-, di- or polyhydric alcohols. Some examples of 183, Gelucire 39/01 and combinations thereof. digestible oils for use in this invention thus include: vegetable US 2008/0317844 A1 Dec. 25, 2008

oils (e.g., soybean oil, safflower seed oil, corn oil, olive oil, chain of the fatty acid on T slows the rate of hydrolysis of the castor oil, cottonseed oil, arachis oil, Sunflower seed oil, ester bond thus prolonging the circulation of the TP and coconut oil, palm oil, rapeseed oil, evening primrose oil, consequently T. For example, formulations of the present grape seed oil, wheat germ oil, sesame oil, avocado oil, invention (e.g., formulation nos. 50 and 54 (below)) compris almond, borage, peppermint and apricot kernel oils) and ani ing TP have a Thalf-life of about 8-9 hours. By comparison, mal oils (e.g., fish liver oil, shark oil and mink oil). the half-life for T is about 30 minutes and that of T-unde 0097. As well, optional cosolvents suitable with the canoate is about 1.5 hours. instant invention are, for example, water, short chain mono-, di-, and polyhydric alcohols, such as ethanol, benzyl alcohol, 0102. In other embodiments, formulations of the present glycerol, propylene glycol, propylene carbonate, polyethyl invention may have self-emulsifying properties, forming a ene glycol with an average molecular weight of about 200 to fine emulsion upon dilution with aqueous media or intestinal about 10,000, diethylene glycol monoethyl ether (e.g., Tran fluids in vivo. In other words, the formulations may have high scutol HP), and combinations thereof. Surfactant and lipid content designed for adequate dispersion 0098. Other optional ingredients which may be included upon mixing with an aqueous medium. Qualitative descrip in the compositions of the present invention are those which tion of the self-emulsification property of the inventive for are conventionally used in the oil-based drug delivery sys mulations can be visually observed during the dissolution of tems, e.g. antioxidants such as tocopherol, tocopherol same in vitro. On the other hand, quantitative measurements acetate, ascorbic acid, butylhydroxytoluene, butylhydroxya may be taken of the particle size of the emulsified droplets nisole and propyl gallate; pH stabilizers such as citric acid, using laser light scattering and/or turbidity measurements in tartaric acid, fumaric acid, acetic acid, glycine, arginine, the dissolution medium by UV/VIS spectrophotometer. Any lysine and potassium hydrogen phosphate; thickenerS/sus of these methodologies are available and known to one of pending agents such as hydrogenated vegetable oils, bees ordinary skill in the art. wax, colloidal silicon dioxide, mannitol, gums, celluloses, 0103) The pharmaceutical compositions according to the silicates, bentonite; flavoring agents such as cherry, lemon present invention may be liquid, semi-solid, or Solid at ambi and aniseed flavors; Sweeteners such as aspartame, ent temperatures, but preferably are presented as liquids or acesulfane K. Sucralose, Saccharin and cyclamates; etc. semi-solids. Solid preparations are defined as Solid, pow 0099. The relative proportions of the lipophilic surfactant dered medicaments blended with powdered excipients and and hydrophilic surfactant in the preferred hydrophobic drug directly filled into hard gelatin or cellulose capsule or com carrier system of this invention are, in general, not especially pressed into a tablet. The instant invention, however, prefer critical, save that the concentration of lipophilic and hydro ably comprises a Solid, powdered medicament (e.g., TP) that philic surfactants must be sufficient to solubilize the hydro is solubilized in the presence of the lipid surfactant excipients phobic drug, yet release same both in vitro and in vivo. It (e.g., any combination of the lipophilic and hydrophilic Sur factants noted above). Accordingly, the melting point of the should be noted that in some embodiments of the invention, surfactants used is one factor that can determine whether the one hydrophobic drug may serve as a lipid vehicle for another. resulting composition will be liquid or semi-solid at ambient More specifically, for example, a testosterone ester may serve temperature. Particularly preferred compositions of the as a carrier for testosterone. Even more specifically, TP may present invention are liquid or semi-solid oral unit dosage serve as a lipid vehicle for testosterone. As well, TP may forms, more preferably filled into hard or soft capsules, e.g. serve, in some embodiments, as its own “controlled-release' gelatin or cellulose capsules. The technology for encapsulat vehicle, which may obviate the need for additional “con ing lipid-based pharmaceutical preparations is well known to trolled-release' lipids mentioned above. one of ordinary skill in the art. As the inventive delivery 0100 Generally, the following relative concentrations, by systems and formulations described herein are not limited to weight, are preferred (the percentages are based on the total any one encapsulation method, specific encapsulation tech content of hydrophilic Surfactant and lipophilic Surfactant niques will not be further discussed. (s)): 0104. The drug carrier systems and pharmaceutical prepa Hydrophilic surfactant: 5-60%, more preferably 15-45%, and rations according to the present invention may be prepared by most preferably 30-40% conventional techniques for lipid-based drug carrier systems. Lipophilic surfactant: 10-90%, more preferably 20-80%, and In a typical procedure for the preparation of the preferred most preferably 30-60% carrier systems of this invention, the lipophilic Surfactant is weighed out into a suitable stainless steel vessel and the Lipophilic “controlled-release' surfactant: 1-40%, more hydrophilic Surfactant is then weighed and added to the con preferably 2.5-30%, and most preferably 5-25%. tainer. Mixing of the two components may be effected by use 0101 The concentration of drug in the final pharmaceuti of a homogenizing mixer or other high shear device. If the cal formulation will be that which is required to provide the material is solid at room temperature, Sufficient heat is desired therapeutic effect from the drug concerned, but gen applied to ensure melting and fluidity without chemical erally will lie in the range 0.1% to 50% by weight, preferably decomposition. between about 10% to 30% by weight, and most preferably 0105. The lipophilic “controlled-release surfactant is about 10% and 20% by weight, based on the weight of the then added, if desired, to the two other components in the final composition. However, in many instances, because the stainless steel vessel and mixed using the appropriate equip present compositions may have better bioavailability than ment. The hydrophobic drug is then weighed and added to the known compositions of the drug concerned, the drug concen combined lipid mixture and mixing continued until either a tration may be reduced as compared with the conventional homogenous Solution is prepared. The formulation may be preparations without loss of therapeutic effect. With specific de-aerated before encapsulation in either soft or hard cap reference to testosterone therapy, the present inventors have sules. In some instances the fill formulation may be held at learned that the use of the palmitate ester of T, in particular, is elevated temperature using a suitable jacketed vessel to aid desirable. Indeed, onceabsorbed, the long and fully saturated processing. US 2008/0317844 A1 Dec. 25, 2008

0106 Returning now to the delivery of testosterone, in one and wt. percentage) are based on 800 mg fill weight per 00 embodiment of the present invention, drug delivery systems hard gelatin capsule. However, at testosterone-ester amounts of the present invention may be suitable for testosterone less than about 100 mg/capsule, the formulations may be therapy. Testosterone is the main endogenous androgen in proportionally adjusted for smaller total fill weights that men. Leydig cells in the testes produce approximately 7 mg of would permit use of Smaller hard gelatin capsules (e.g., '0' testosterone each day resulting in serum concentrations rang S17). ing from about 300 to about 1100 ng/dL. Women also syn ifi As well, it should be apparent to one of ordinary thesize testosterone in both the ovary and adrenal gland, but skill in the art that many, if not all, of the surfactants within a the amount is about one-tenth that observed in eugonadal category (e.g., lipophilic, hydrophilic, etc.) may be men. The majority (about 98%) of circulating testosterone is exchanged with another Surfactant from the same category. bound to sex hormone binding globulin and is biologically Thus, while Table 1 lists formulations comprising Labrafil active only when released to the free form. The term “free” is M1944CS (HLB=3) and Precirol ATO5 (HLB=2), one of thus defined as not being bound to or confined within, for ordinary skill in the art should recognize other lipophilic example, biomolecules, cells and/or lipid matrices of the Surfactants (e.g., those listed above) may be suitable as well. inventive formulations described herein. Generally, “free” Similarly, while Table 1 lists formulations comprising Cre medicaments described herein refer to medicament that is mophor RH40 (HLB=13) and Labrasol (HLB=14), one of accessible to metabolic enzymes circulating in serum. ordinary skill in the art should recognize other hydrophilic 0107 While the present invention should not be limited to Surfactants (e.g., those listed above) may be Suitable. the delivery of testosterone or any particular ester thereof. TP has been found to offer unique chemical and physical char TABLE 1 acteristics that make its use preferable in Some embodiments. Labrafil Precirol Cremophor The present inventors have learned that the palmitic acid ester D T or Tester M1944CS ATOS RH4O Labrasol of testosterone, in particular, can yield Superior bioavailabil A. 400 O9.68 66.49 223.83 ity to that found with other equivalent esters (e.g., testoster SO.00% 13.71% 8.31% 27.98% one undecanoate (TU)). Without being held to or bound by B 360 20.64 73.14 246.21 theory, it is believed that TP is superior, in part, to other 45.00% 15.08% 9.14% 30.78% testosterone esters, because it has a particularly high log P C 32O 31.61 79.79 268.60 compared to similar analogs. (The log Pfor TP is greater than 40.00% 16.45% 9.97% 33.57% D 28O 42.58 86.44 290.98 9 compared to a log P for TU of about 6.5) 35.00% 17.82% O.80% 36.37% 0108 Consequently, TP absorbed into the bloodstream E 240 53.55 93.09 313.36 may passively diffuse into red blood cells (RBCs) circulating 30.00% 19.19% 1.64% 39.17% in the blood. Specifically, because palmitic acid is both a 228.32 56.75 95.03 3.19.9 28.54% 19.59% 1.88% 39.99% significant component of the RBC membrane and has been G 2OO 64.52 99.74 335.75 shown to be transported across this membrane, TP is better 25.00% 20.56% 2.47% 41.97% Suited to be in an equilibrium with and pass said membrane. H 160 75.48 106.39 358.13 In this manner, some portion of the total concentration of free 20.00% 21.94% 3.30% 44.77% TP at any given time may be found within RBCs. Further, 120 86.45 113.04 380.51 15.00% 23.31% 4.13% 47.56% when confined to a RBC, any TP therein is shielded from the 8O 97.42 119.69 402.90 esterases found in the serum. As the conversion of TP to 10.00% 24.68% 4.96% S.O.36% testosterone is a direct consequence of esterase activity, K 40 208.39 126.33 425.28 greater inaccessibility to the esterases is expected to prolong S.OO% 26.05% 5.79% 53.16% the half-life of TP. For this reason, it is believed that the 2O 213.87 129.66 436.47 2.50% 26.73% 6.21% 54.56% residence time ofTP in the blood is greater than that would be M 400 199.97 66.62 13340 expected from other saturated esters of shorter hydrocarbon SO.00% 25.00% 8.33% 16.68% chain-length. N 360 219.97 73.29 146.74 0109 What is more, the use of TP. in contrast to that for 45.00% 27.50% 9.16% 18.34% O 32O 239.97 79.95 160.08 other orally administered testosterone esters, does not appear 40.00% 30.00% 9.99% 20.01% to dramatically elevate serum dihydrotestosterone (“DHT) P 28O 259.96 86.61 173.42 above physiological levels, which are typically about /10th 35.00% 32.50% O.83% 21.68% that of testosterone (i.e., about 30 to 100 ng/dL) in eugonadal Q 240 279.96 93.27 186.76 men. Testosterone interacts with respective androgen recep 30.00% 35.00% 1.66% 23.35% tors either directly or following its conversion to DHT via the R 228.32 285.8 95.22 19066 28.54% 35.739% 1.90% 23.83% action of 5C-reductase. DHT is a more potent androgen than S 2OO 299.96 99.94 2001O testosterone and its elevated levels are thought by some sci 25.00% 37.49% 2.49% 25.01% entists to increase the risk of prostate cancer. Elevated levels T 160 319.96 106.60 21345 of DHT are a noted problem with the administration of, for 20.00% 39.99% 3.32% 26.68% example, TU. In this way, TP provides yet another unexpected U 120 339.95 113.26 226.79 15.00% 42.49% 4.16% 28.35% advantage over other testosterone esters. V 8O 359.95 11992 240.13 0110 Specific embodiments of the instant invention will 10.00% 44.99% 4.99% 30.02% now be described in non-limiting examples. Table 1 provides W 40 379.95 126.59 253.47 composition details of various formulations of testosterone S.OO% 47.49% S.82% 31.68% X 2O 389.95 129.92 260.14 (T) or testosterone-esters (T-esters), in accordance with the 2.50% 48.74% 6.24% 32.52% teachings of the instant invention. For calculation purposes, 1 AA 400 109.79 66. SS 149.72 73.94 mg of T is equivalent to: 1.39 mg T-enanthate, 1.58 mg SO.00% 13.72% 8.32% 18.72% 9.24% T-undecanoate: 1.43 mg T-cypionate, and 1.83 mg T-palmi BB 360 120.77 73.21 164.69 81.33 tate. TP is a preferred T-ester in some of the formulations 45.00% 15.10% 9.15% 20.59% 10.17% listed below. The compositions details of Table 1 (mg/capsule US 2008/0317844 A1 Dec. 25, 2008

TABLE 1-continued TABLE 1-continued

Labrafil Precirol Cremophor Labrafil Precirol Cremophor Tor Tester M1944CS ATOS RH4O Labrasol ID T or Tester M1944CS ATOS RH4O Labrasol

32O 131.75 79.87 179.66 88.72 QQ 240 11427 132.26 313.47 40.00% 16.47% 9.98% 22.46% 1.09% 30.00% 4.28%. 16.53% 39.18% 28O 142.73 86.52 194.64 96.12 RR 228.32 116.65 135.02 32O.O1 35.00% 17.84% O.82% 24.33% 2.01% 28.54% 4.58%. 16.88% 40.00% 240 153.70 209.61 O3.51 SS 2OO 122.43 141.71 335.86 30.00% 19.21% 26.20% 2.94% 25.00% 5.30%. 17.71% 41.98% 228.32 156.91 213.98 05.67 TT 160 130.59 151.16 358.25 28.54% 19.61% 26.75% 3.21% 20.00% 6.32%. 18.89% 44.78% 2OO 164.68 224.58 O.90 UU 120 138.75 160.60 380.64 25.00% 20.59% 28.07% 3.86% 15.00% 7.34%. 20.08% 47.58% 160 175.66 239.55 8.30 VV 8O 146.91 170.05 403.04 20.00% 21.96% 29.94% 4.79% 10.00% 8.36%. 21.26% S.O.38% 120 186.64 254.52 25.69 WW 40 155.08 179.50 425.43 15.00% 23.33% 31.82% 5.719, S.OO% 9.38%. 22.44% 53.18% 8O 197.62 269.50 33.09 XX 2O 159.16 18422 436.62 10.00% 24.70% 33.69% 6.64% 2.50% 9.89%. 23.03% 54.58% KK 40 208.60 284.47 40.48 S.00% 26.07% 35.56% 7.56% LL 2O 214.09 291.95 0. 44.18 0. 0112 Table 2 provides composition details of various TP 2.50% 26.76% 36.49% 8.02% formulations in accordance with the teachings of the instant MM 400 81.62 223.91 invention and FIG. 9 provides in vitro dissolution of select SO.00% 10.20% 27.99% formulations therein. TP may be synthesized through esteri 360 89.78 246.30 fication of testosterone with palmitoyl chloride in an acetone/ 45.00% 11.22% 30.79% idine mixture. T lmi de is purified b OO 32O 97.94 268.69 pyridine mixture. Testosterone palmitate crude 1s purified by 40.00% 12.24% 33.59% filtration, crystallized from a methanol/methylene chloride PP 28O 106.10 291.08 mixture and washed with methanol. When necessary, recrys 35.00% 13.26% 36.39% tallization can be done from heptane, followed by washing with methanol.

TABLE 2

Composition details (mg capsule and wt. percentage)* Filwt

No. TP LBR PRC5 OA Peceol TPGS SO CRH4O L'sol M'tol (mg)**

228.32 285.84 S7 570 (40.0) (50.0) (10.0) 228.32 57 228 57 570 (40.0) (10.0) (40.0) (10.0) 228.32 171 114 57 570 (40.0) (30.0) (20.0) (10.0) 228.32 171 114 57 570 (40.0) (30.0) (20.0) (10.0) 228.32 114 57 171 570 (40.0) (20.0) (10.0) (30.0) 228.32 476 95.2 800 (28.5) (59.5) (11.9) 228.32 95.2 380.8 95.2 800 (28.5) (11.9) (47.6) (11.9) 228.32 1904 95.2 285.6 800 (28.5) (23.8) (11.9) (35.7) 228.32 285.84 95.2 190.56 800 (28.5) (35.7) (11.9) (23.8) 10 228.32 190.56 190.56 190.56 800 (28.5) (23.8) (23.8) (23.8) 11 228.32 190.56 95.2 190.56 95.2 800 (28.5) (23.8) (11.9) (23.8) (11.9) 12 228.32 190.56 190.56 95.2 95.2 800 (28.5) (23.8) (23.8) (11.9) (11.9) 13 228.32 190.56 190.56 95.2 95.2 800 (28.5) (23.8) (23.8) (11.9) (11.9) 14 228.32 285 95.2 95.2 95.2 800 (28.5) (35.7) (11.9) (11.9) (11.9) US 2008/0317844 A1 Dec. 25, 2008

TABLE 2-continued F. Composition details (ng capsule and wt. percentage) Filwt No. TP LBR PRC5 OA Peceol TPGS SO CRH4O L'sol M'tol (mg)** 1S 228.32 285.84 20.O 265.6 800 (28.5) (35.7) (2.50) (33.2) 16 228.32 285.84 20.O 40.O 225.6 800 (28.5) (35.7) (2.50) (5.00) (28.2) 17 228.32 285.84 80.0 2OS.6 800 (28.5) (35.7) (10.0) (25.7) 18 228.32 95.20 190.56 28S.6 800 (28.5) (11.9) (23.8) (35.7) 19 228.32 133.08 88.672 450 (50.73) (29.57) (19.7) 20 228.32 285.84 20O28 85.72 800 (28.5) (35.7) (25.0) (10.7) 21 228.32 285.84 95.2 190.67 800 (28.5) (35.7) (11.9) (23.8) 22 228.32 240.33 65.7 16O.22 105.74 800 (28.5) (30.0) (8.2) (20.0) (13.2) 23 228.32 157.02 95.2 32O45 800 (28.5) (19.6) (11.9) (40.0) 24 228.32 157.02 95.2 214.4 105.74 800 (28.5) (19.6) (11.9) (26.8) (13.2) 2S 228.32 157.02 65.6 349.6 800 (28.5) (19.6) (8.2) (43.7) 26 228.32 157.02 4O.O 375.2 800 (28.5) (19.6) (5.0) (46.9) 57 182.6S 229.3S 20.O 368.O 800 (22.83) (28.7) (2.5) (46.0) S8 12O.O S2O.O 20.O 14O.O 800 (15.0) (65.0) (2.5) (17.5) *TP:Testosterone palmitate; LBR: Labrafil M1944CS: PRC5: Precirol ATO5; OA: Refined Oleic acid; SO: Refined Soybean oil; TPGS: D-C-tocopheryl PEG1000 succinate; CRH 40: Cremophor RH40; L’sol: Labrasol; Mitol: Manni tol **Filled into size “O'” capsule (570 mg) or “00 capsule (800 mg)

0113 A preferred formulation of TP in accordance with hour period, a concentration of TP of less than about 23 the present invention is: percent by weight. In some embodiment, a weight percentage of less than about 20 is preferred, more preferably a weight percentage of less than about 18, and most preferably a weight percentage of less than about 15. Without being bound Component mg capsule %, ww by or limited to theory, it is believed that TP at levels greater Testosterone palmitate 228.32 28.5 than about 23 weight percent may, in fact, retard its own Cremophor (R) RH40 320.45 40.O release. For example, formulations according to the instant Labrafil (R) M1944 CS 157.02 19.6 invention comprising less than about 23 weight percent TP Precirol (RATO 5 95.20 11.9 can release 50-70% of the drug at 1 hour and 80 to near 100% Total: 800 1OO.O at 2 hours. On the other hand, formulations according to the instant invention comprising greater than about 23 weight 0114. In some embodiments, it may be desirable to reduce percent TP release less than 5% of the drug at 1 hr and less the absolute concentration of testosterone and/or an ester than 70% at 6 hours. thereof in order to promote a relatively faster release of the 0115 Table 3 provides composition details of various TP testosterone and/or ester from within the lipid vehicle. That is, formulations, that in some cases, are at TP concentrations it has been found, Surprisingly, that reducing the concentra lower than those in Table 2 and in accordance with the teach tion of TP. may in Some cases, confer quicker release kinetics. ings of the instant invention. FIG. 10 provides in vitro disso For example, for significant release of TP within about a two lution of select Table 3 formulations.

TABLE 3 Composition (ng capsule and weight% FI Cremophor Oleic Capmul Tween Precirol Gelucire Wt. F. No. TP Labrasol RH4O Acid MCM(L) 8O ATOS 39.01 (mg) 27 32O.O 24O.O 22O.O 2O.O 800 (40.0%) (30.0%) (27.5%) (2.5%) 28 364.O 16O.O 8O 176.O 2O.O 800 (45.5%) (20.0%) (10.0%) (22.0%) (2.5%) US 2008/0317844 A1 Dec. 25, 2008

TABLE 3-continued Composition (ng capsule and weight% FI Cremophor Oleic Capmul Tween Precirol Gelucire Wt. F. No. TP Labrasol RH4O Acid MCM(L) 80 ATOS 39/01 (mg) 29 32O.O 16O.O 3OO.O 2O.O 800 (40%) (20%) (37.5%) (2.5%) 30, 34 12O.O 68O.O 800 (15.0%) (85.0%) 31, 35 12O.O S6O.O 12O.O 800 (15.0%) (70.0%) (15.0%) 32 228.0 296.O 8O.O 176.O 2O.O 800 (28.5%) (37.0%) (10.0%) (22.0%) (2.5%) 33 228.0 24O.O 312.O 2O.O 800 (28.5%) (30.0%) (39.0%) (2.5%) 36 2O.O 3OO.O 12O.O 24O.O 2O.O 800 (15%) (37.5%) (15.0%) (30.0%) (2.5%) 37 2O.O 3OO.O 36O.O 2O.O 800 (15%) (37.5%) (45.0%) (2.5%) 38 76.O 624.O 800 (22.0%) (78.0% 39 228.0 572.0 800 (28.5%) (71.5%) 40 76.O SO4.O 12O.O 800 (22.0%) (63.0%) (15.0%) 41 76.O 12O.O SO4.O 800 (22.0%) (15%) (63.0%) 42 76.O 12O.O SO4.O 800 (22.0%) (15.0%) (63.0%) 43 2O.O 68O.O 800 (15%)15% (85%)85% 44 2O.O 340.O 32O.O 2O.O 800 (15%) (42.5%) (40.0%) (2.5%) 45 2O.O 68O.O 800 (15%) (85%) 46 2O.O 68O.O 800 (15%) (85%) 47 2O.O 66O.O 2O.O 800 (15%) (82.5%) (2.5%) 48 76.O 12O.O SO4.O 800 (22.0%) (15.0%) (63.0%) 49 2O.O 408.O 272.O 800 (15.0%) (51%) (34%) 50 2O.O 37048 246.88 800 (15%) (46.31) (30.86%) 51 2O.O 14O.O S2O.O 2O.O 800 (15%) (17.5%) (65.0%) (2.5%) 52 82.65 97.36 S2O.O 800 (22.83%) (12.17%) (65.0%) 53 82.65 97.36 208.O 312.O 800 (22.83%) (12.17%) (26%) (39%) S4 2O.O 2O4.O 476.0 800 (15%) (25.5%) (59.5%) 55 82.65 185.21 432.15 800 (22.83%) (23.15%) (54.02%) 56 82.65 185.21 81.28 800 (22.83%) (67.01%) (10.16%) 59 2O.O 32O.O 340.O 2O.O 800 (15%) (40%) (42.5%) (2.5%)

0116 Formulation numbers 50, 51 and 54 are preferred EXAMPLE embodiments. As well, while a variety of solvents may be useful in the formulations presented in Table 3, preferred 0117 Formulations 50 and 54 were administered to 6 solvents may have the following characteristics: C-C fatty patients; number 50 was administered once-daily (“QD”) in acids and/or their glycerol-, propylene glycol-, polyethylene the form of two capsules per dose (100 mg T equivalents/ capsule) and number 54 was administered once- and twice glycol, Sorbitan-mono-fcliesters alone and in mixtures. Pre daily (“BID) in the form of three capsules per dose (66 mg T ferred fatty acids and esters are Cs-Cs. Saturated and unsat equivalents/capsule). The mean steady-state profiles after 7 urated. In addition, the solvents include, fatty acid esters with days of treatment with one of the three, respective, regimens lower alcohols, such as ethyl oleate, ethyllinoleate, isopropyl are shown in FIG. 11. The pharmacokinetic profile for for myristate, isopropylpalmitate, isopropyloleate and isopropy mulation 54 BID was relatively uniform over the entire 24hr llinoleate. period and had a trough of the mean profile about 70% of the US 2008/0317844 A1 Dec. 25, 2008 11 peak of the mean profile. Additional data from formulation 54 blood stream. In other words, the fatty acid ester may com include: petitively inhibit esterases that would otherwise metabolize 0118 Average serum T increase from baseline of 275 TP. Table 4 provides effective amounts of inhibitors of test ng/dL osterone ester metabolism. Examples of other esters or com 0119 Mean serum T levels at lower end of normal binations thereof include botanical extracts or benign esters range, i.e., about 325 ng/dL. used as food additives (e.g., propylparben, octylacetate, and I0120 Relatively fast release (T. of about 1 hour) ethylacetate). I0121 Estimated terminal half-life ofT at steady-state of 0.126 Other components that can modulate TP absorption approximately 8-9 hours include “natural and synthetic inhibitors of 5C.-reductase, 0.122 Consistent dose-related elevation in serum T which is present in enterocytes and catalyze the conversion of baseline levels over the 7-day treatment period T to DHT. Complete or partial inhibition of this conversion I0123 Average steady-state serum DHT level of 114 may both increase and Sustain increases serum levels of T ng/dL (FIG. 12) after oral dosing with TP while concomitantly reducing 0.124. A simulation of the pharmacokinetic profile of for serum DHT levels. Borage oil, which contains a significant mulation 50 administered BID was performed and compared amount of the 5C.-reductase inhibitor gamma-linoleic acid to the observed profile for formulation 54 administered BID. (GLA), is an example of a “natural modulator of TP metabo The simulation predicts about a 384 ng/dL increase in C. lism. Other than within borage oil, of course, GLA could be over the 24-hour period for formulation 50 over formulation directly added as a separate component of TP formulations 54 (FIG. 13). described herein. Many natural inhibitors of 5C.-reductase are 0.125. In other embodiments of the present invention, known in the art (e.g., epigallocatechin gallate, a catechin methods and compositions for modulating (i.e., Sustaining) derived primarily from green tea and saw palmetto extract the rate of available serum testosterone by incorporating com from berries of the Serenoa repens species), all of which may ponent(s) that may biochemically modulate (1) TP absorp be suitable in the present invention. Non-limiting examples of tion, (2) TP metabolism to T, and/or (3) metabolism of T to synthetic 5C.-reductase inhibitors suitable in the present DHT. For example, the inclusion of medium to long chain invention include finasteride and dutasteride. fatty acid esters can enhance TP absorption. Without being I0127. In addition to 5C.-reductase inhibitors, the present held to or bound by theory, the present inventors believe that invention contemplates the use of inhibitors of T metabolism the use of effective amounts fatty acid esters, particularly via other mechanisms. One such point of inhibition may be palmitate esters such as ascorby1-palmitate, retinyl-palmitate, the cytochrome P450 isozyme CYP3A4 that is present in Sorbitan-palmitate and blends thereof may establish compe enterocytes and in liver cells and thus capable of metabolizing tition between said ester and TP for endogenous esterase testosterone. Accordingly, formulations of the present inven activity. Indeed, it is believed that testosterone ester metabo tion, in some embodiments, include peppermint oil, which is lism, generally, may be retarded with the administration of an known to contain factors capable of inhibiting CYP3A4. effective amount of an ester of a medium or long chain fatty I0128 Table 4 provides composition details of various TP acid (e.g., esters of oleic acid, linoleic acid, linolenic acid, formulations comprising ingredients to modulate TP absorp Stearic acid, myristic acid, lauric acid, palmitic acid, capric or tion (i.e., ascorbyl-palmitate, borage oil and peppermint oil). decanoic acid octanoic or caprylic acid, pelargonic acid, FIGS. 14 and 15 show representative in vitro dissolution undecanoic acid, tridecanoic acid, pentadecanoic acid, and profiles for select TP formulations therein in either phosphate the branched chain, cyclic analogues of these acids). In this buffer (PBS) or fed-state simulated intestinal fluid (FeSSIF), way, more TP may stave offhydrolysis in the gut and enter the respectively.

TABLE 4 Composition 96 wiw (mg/'00" capsule)' FI F. Ascorby|- Cremophor Cremophor Oleic Borage Peppermint Wt. No. TP Palmitate RH4O EL Acid Peceol Oil Oil (mg)?

62 3O.O 2.5 67.5 800 (240) (20) (540) 62A 1S.O 2.5 82.5 800 (120) (20) (660) 63 3O.O S.O 6S.O 800 (240) (40) (520) 63A 22.9 S.O 12.2 6O.O 800 (183) (40) (97) (480) 64 1S.O 1S.O 70.O 800 (120) (120) (560) 64A 1S.O 1O.O 2SO SO.O 800 (120) (80) (200) (400) 65 22.9 2SO S2.0 800 (183) (200) (417) 66 1S.O 42.5 42.5 800 (120) (340) (340) 67 1S.O 3O.O 55.0 800 (120) (240) (440) 68 22.9 2O.O 45.O 12.0 800 (183) (160) (360) (96) US 2008/0317844 A1 Dec. 25, 2008 12

TABLE 4-continued Composition% w/w (mg/'00" capsule)' FI F. Ascorby|- Cremophor Cremophor Oleic Borage Peppermint Wt. No. TP Palmitate RH4O EL Acid Peceol Oil Oil (mg)’

69 22.9 53.0 19.0 800 (183) (424) (152) 70 22.9 1O.O 2S.O 22.1 1O.O 1O.O 800 (183) (80) (200) (177) (80) (80) 7OB 22.9 2.5 2O.O 39.7 1O.O S.O 800 (183) (20) (160) (318) (80) (40) 71 1S.O 1O.O 2S.O 3O.O 1O.O 1O.O 800 (120) (80) (200) (240) (80) (80) 71A 1O.O 2.5 2O.O 52.5 1O.O S.O 800 (80) (20) (160) (420) (80) (40) 71B 1S.O 2.5 2O.O 47.5 1O.O S.O 800 (120) (20) (160) (380) (80) (40) 72 1S.O 6O.O 2SO 800 (120) (480) (200) 73 1S.O 6O.O 2SO 800 (120) (480) (200) "Milligram weights rounded to nearest whole number ^+1 mg

0129. In yet another embodiment of the present invention, Labrafil M1944CS). On the other had, to achieve a delayed drug delivery systems disclosed herein may also be suitable T, the percentage of "controlled-release' lipophilic Sur for ameliorating some of the side-effects of certain strategies factant in composition can be increased. FIGS.9 and 10 show for male contraception. For example, progestin-based male in vitro dissolution curves of TP from three formulations, contraception Substantially suppresses luteinizing hormone respectively, in a phosphate buffered dissolution medium (LH) and follicle-stimulating hormone (FSH), and thereby incorporating TritonX-100 as a surfactant in accordance with Suppresses spermatogenesis, resulting in clinical azoosper the present invention. mia (defined as less than about 1 million sperm/ml semen for 0.133 Without being bound by or limited to theory, it is 2 consecutive months). However, administration of believed that the inventive formulations described herein, in progestins also has the undesirable side-effect of significantly one aspect, enhance absorption of a medicament therein by reducing steady-state serum testosterone levels. the intestinal lymphatic system. In this way, drug delivery 0130. In such situations, for example, it may be preferable systems of the present invention can provide extended release to provide preparations of progestin concomitantly with tes formulations that can deliver testosterone into the serum over tosterone or a testosterone derivative (e.g., TP). More prefer several hours. The serum half-life of testosterone in men is ably, a pharmaceutical preparation according to the invention considered to be in the range of 10 to 100 minutes, with the is provided, comprising progestin in an amount Sufficient to upper range for testosterone administered in a form (i.e., TU) substantially suppress LH and FSH production in combi that favors lymphatic absorption. However, oral dosages of nation with testosterone. In some embodiments, the pharma the present invention can be taken by a patient in need of ceutical preparation is for once-daily, oral delivery. testosterone therapy once every about twelve hours to main 0131 Drug delivery systems, in one aspect of the present tain desirable levels of serum testosterone. In a more pre invention, afford the flexibility to achieve desirable pharma ferred embodiment, oral dosages are taken by a patient in cokinetic profiles. Specifically, the formulations can be tai need of testosterone therapy once every about twenty four lored to deliver medicament in a relatively early peak serum hours. In general, “desirable' testosterone levels are those concentration (T) or one that appears later. See FIGS. 1, 3, levels found in a human Subject characterized as not having 5 and 7 versus FIGS. 2, 4, 6 and 8, respectively. Similarly, the testosterone deficiency. formulations may be tailored to have a relative steep or wide 0.134. While the invention has been described in connec drop in drug serum concentration upon obtaining T. See tion with specific embodiments thereof, it will be understood FIGS. 1, 3, 5 and 7 versus FIGS. 2, 4, 6 and 8, respectively. that it is capable of further modifications and this application Accordingly, pharmaceutical preparations of the instant is intended to cover any variations, uses, or alterations of the invention may be administered once-daily, twice-daily, or in invention following. In general, the principles of the inven multiple doses per day, depending on, for example, patient tion and including Such departures from the present disclo preference and convenience. Sure as come within known or customary practice within the 0.132. One way in which the formulations may be modified art to which the invention pertains and as may be applied to to affect these changes is to calibrate the ratio of lipophilic the essential features hereinbefore set forth and as follows in surfactants. The magnitude and timing of the T, for the scope of the appended claims. example, can be affected by not only the type of lipids used, 1-35. (canceled) but also the ratios thereof. For example, to obtain a relatively 36. A pharmaceutical composition comprising: early T, or fast release of the medicament from the deliv (a) testosterone ester comprising testosterone enanthate ery system, the concentration of the “controlled-release' (TE), testosterone undecanoate (TU), or both; lipophilic surfactant (e.g., Precirol) may be reduced relative (b) and two or more lipid components at least the first of to the concentration of the other lipophilic Solvents (e.g., which comprises a hydrophilic Surfactant and at least the US 2008/0317844 A1 Dec. 25, 2008

second of which comprises a lipophilic Surfactant, said 55. The pharmaceutical composition of claim 36 which lipid components together providing for the solubiliza comprises from about 10 to about 50 percent by weight of the tion of the testosterone ester. testOSterOne ester. 37. The pharmaceutical composition of claim 36 which 56. The pharmaceutical composition of claim 55 which comprises at least three lipid components at least the first of comprises from about 10 to about 35 percent by weight of the which comprises a hydrophilic Surfactant and at least the testOSterOne ester. second and third of which comprise a lipophilic Surfactant 57. The pharmaceutical composition of claim 36 filled into each providing for the solubilization of the testosterone ester. a hard or soft gelatin capsule. 38. The pharmaceutical composition of claim 37 which 58. A method of preventing or alleviating the symptoms of further comprises a second lipid-soluble therapeutic agent. testosterone deficiency in a mammalian Subject comprising 39. The pharmaceutical composition of claim 38 in which administering to the mammalian Subject an effective amount the second lipid-soluble therapeutic agent comprises a syn of testosterone enanthate (TE) and/or (TU) solubilized in two thetic progestin, an inhibitor of type-I and/or type II 5C-re or more lipid components, such that the administration of said ductase, finasteride, dutasteride or combinations thereof. solubilized TE and/or TU raises the mammalian subject's 40. The pharmaceutical composition of claim 36 in which average steady state serum level of total testosterone to within the at least first lipid component exhibits an HLB of 10 to 45. those levels found in mammalian Subjects having no testoster 41. The pharmaceutical composition of claim 40 in which one deficiency and providing at least some relief from Such the at least first lipid component is Cremophor EL, Cremo symptoms. phor RH 40, Etocas 35, Etocas 40 and combinations thereof. 59. The method of claim 58 in which the TE and/or TU is 42. The pharmaceutical composition of claim 36 in which solubilized in at least three lipid components. the at least first lipid component is glycerol and PEG esters 60. The method of claim 58 in which the solubilized TE thereof. 43. The pharmaceutical composition of claim 42 in which and/or TU is administered orally. the at least first lipid component is Cremophor RH 40. 61. The method of claim 58 in which the mammalian 44. The pharmaceutical composition of claim 36 in which Subject is a human male or human female. the at least second lipid component exhibits an HLB of less 62. The method of claim 61 in which the human male's than 10. average steady state serum level of total testosterone is raised 45. The pharmaceutical composition of claim 44 in which to fall within a range of about 300 ng/dl to about 1100 ng/dl. the at least second lipid component exhibits an HLB of less 63. The method of claim 58 which further comprises than 5. administering an amount of a synthetic progestin sufficient to 46. The pharmaceutical composition of claim 45 in which Substantially inhibit gonadotropin release in said mammalian the at least second lipid component exhibits an HLB of less Subject. than or equal to 2. 64. A method of providing extended release of testosterone 47. The pharmaceutical composition of claim 46 in which in vivo comprising solubilizing testosterone enanthate (TE) the at least second lipid component is a glyceryl palmitostear and/or (TU) in a lipid mixture comprising two or more lipid ate, palmitosterate, borage oil, peppermint oil, oleic acid and components at least the first of which comprises a hydrophilic blends thereof. Surfactant and at least the second of which comprises a lipo 48. The pharmaceutical composition of claim 47 in which philic Surfactant having a melting point of greater than about the at least second lipid component is aborage oil, pepper 30° C. mint oil, oleic acid and blends thereof. 65. A method of inhibiting the hydrolysis of an ester of 49. The pharmaceutical composition of claim 48 in which testosterone in a mammal comprising co-administering to the at least third lipid component is aborage oil, peppermint said mammal along with a medium or long chain fatty acid oil, oleic acid and blends thereof. ester of testosterone an effective inhibitory amount of a 50. The pharmaceutical composition of claim 38 compris medium or long chain fatty acid ester. ing Cremophor RH40, borage oil, oleic acid, and peppermint 66. The method of claim 65 in which the medium or long oil. chain ester of testosterone is selected from the group consist 51. The pharmaceutical composition of claim 37 further ing of testosterone palmitate, testosterone Stearate, testoster comprising an antioxidant. one myristate, testosterone laurate, testosterone caprate, tes 52. The pharmaceutical composition of claim 51 in which tosterone decanoate, testosterone enanthate, testosterone the antioxidant is tocopherol, tocopherol acetate, ascorbic octanoate, testosterone caprylate, testosterone pelargonate, acid, butylhydroxytoluene, butylhydroxyanisole, propyl gal testosterone undecanoate, testosterone tridecanoate and test late, or combinations thereof. osterone pentadecanoate. 53. The pharmaceutical composition of claim 37 further 67. The method of claim 66 in which the medium or long comprising a medium to long chain fatty acid ester. chain fatty acid moiety of the ester and the testosterone ester 54. The pharmaceutical composition of claim 53 wherein are the same. the medium to long chain fatty acid ester is ascorbyl-palmi tate, retinyl-palmitate, Sorbitan-palmitate and blends thereof.