USOO8828428B1

(12) United States Patent (10) Patent No.: US 8,828,428 B1 Dudley et al. (45) Date of Patent: Sep. 9, 2014

(54) PHARMACEUTICAL DELIVERY SYSTEMS 6,267,985 B1 7/2001 Chen et al. FOR HYDROPHOBC DRUGS AND 6,294,192 B1 9, 2001 Patel et al. 6,309.663 B1 10/2001 Patel et al. COMPOSITIONS COMPRISING SAME 6,383,471 B1 5, 2002 Chen et al. 6,451,339 B2 9, 2002 Patel et al. (71) Applicant: Clarus Therapeutics, Inc., Northbrook, 6,458,383 B2 10/2002 Chen et al. IL (US) 6,569.463 B2 5/2003 Patel et al. 6,652,880 B1 1 1/2003 Aylwin et al. 6,665,880 B2 12/2003 Poppe (72) Inventors: Robert E. Dudley, Rosemary Beach, FL 6,761,903 B2 7/2004 Chen et al. (US); Panayiotis P. Constantinides, 6,923,988 B2 8, 2005 Patel et al. Gurnee, IL (US) 6,982,281 B1 1/2006 Chen et al. 7,025,979 B2 4/2006 Nieschlag et al. (73) Assignee: Clarus Therapeutics, Inc., Northbrook, 7,374,779 B2 5/2008 Chen et al. 8,367,103 B2 2/2013 Bardani IL (US) 2001/0018069 A1 8/2001 Johnson et al. 2002.0068693 A1 6/2002 Jeng et al. (*) Notice: Subject to any disclaimer, the term of this 2003/0022875 A1 1/2003 Wilson et al. patent is extended or adjusted under 35 2003/0104.048 A1 6/2003 Patel et al. U.S.C. 154(b) by 0 days. 2003. O180352 A1 9, 2003 Patel et al. 2003. O186892 A1 10/2003 Taneja 2003/0235595 A1 12/2003 Chen et al. (21) Appl. No.: 14/254,545 2003/0236236 A1 12/2003 Chen et al. 2004.0002445 A1 1/2004 Taneja (22) Filed: Apr. 16, 2014 2004/01 15287 A1 6/2004 Chen et al. 2004/O127476 A1 7/2004 Kershman et al. 2005, 0096.296 A1 5/2005 Fikstad et al. Related U.S. Application Data 2005, 0096365 A1 5/2005 Fikstad et al. 2005/0171193 A1 8, 2005 Chen et al. (63) Continuation of application No. 13/553,586, filed on 2005/0176692 A1 8/2005 Amory et al. Jul. 19, 2012, which is a continuation of application 2005/02872O3 A1 12/2005 Nijs De et al. No. 1 1/911,446, filed as application No. PCT/US2006/014207 on Apr. 14, 2006, now Pat. No. (Continued) 8,241,664. FOREIGN PATENT DOCUMENTS (60) Provisional application No. 60/671,454, filed on Apr. 15, 2005, provisional application No. 60/721,971, EP 0904.064 B1 10, 2001 filed on Sep. 30, 2005. GB 1264677 2, 1972 (Continued) (51) Int. Cl. OTHER PUBLICATIONS A6 IK9/48 (2006.01) A6 IK3I/568 (2006.01) Bergman JACS 71 p.3372 1949, New Series of Esters.* A6IP5/26 (2006.01) Noguchi, T. et al. “The effect of drug lipophilicity and lipid vehicles A6 IK 47/26 (2006.01) on the lymphatic absorption of various testosterone.” International A6 IK 47/12 (2006.01) Journal of Pharmaceutics, 24 (1985) 173-184. A6 IK 47/4 (2006.01) MacGregor, KJ, et al., “Influence of lipolysis on drug absorption from (52) U.S. Cl. the gastro-intestinal tract.” Advanced Drug Delivery Reviews 25 CPC ...... A6 IK3I/568 (2013.01); A61 K47/26 (1997) 33-46. (2013.01); A61 K47/12 (2013.01); A61 K47/14 Constantinides, P. “Lipid Microemulsions for Improving Drug Dis (2013.01) solution and Oral Absorption: Physical and Bioopharmaceutical USPC ...... 424/456; 514/170: 514/171; 514/179 Aspects.” Pharmaceutical Research, 1995, pp. 1561-1572, vol. 12, (58) Field of Classification Search No. 11. CPC. A61K 31/573; A61K 31/32: A61K9/1075; (Continued) A61K 2300700 See application file for complete search history. Primary Examiner — Suzanne Ziska Assistant Examiner — Thurman Wheeler (56) References Cited (74) Attorney, Agent, or Firm — Dennis A. Bennett; Brock U.S. PATENT DOCUMENTS Levin 3,164,520 A 1, 1965 Huber (57) ABSTRACT 3,266,991 A 8, 1966 Wettstein et al. 4,147,783 A 4, 1979 van der Vies A drug delivery system for oral administration of hydropho 4,572,915 A 2f1986 Crooks bic drugs with enhanced and extended absorption and 4,719,239 A 1, 1988 Muller et al. improved pharmacokinetics is provided. In one embodiment, 5,342,625 A 8, 1994 Hauer et al. formulations comprising testosterone and testosterone esters, 5,645,856 A 7/1997 Lacy et al. 5,891,469 A 4/1999 AmSelem e.g., testosterone palmitate, are disclosed. Methods of treat 6,013,665 A 1/2000 DeMichele et al. ing a hormone deficiency or effecting male contraception 6,096.338 A 8/2000 Lacy et al. with the inventive formulations are also provided. 6, 160,007 A 12/2000 DeMichele et al. 6,248,363 B1 6, 2001 Patel et al. 4 Claims, 15 Drawing Sheets US 8,828,428 B1 Page 2

(56) References Cited OTHER PUBLICATIONS Cantrill J. et al., (1984) Which Testosterone Replacement Therapy?, U.S. PATENT DOCUMENTS Clinical Endocrinology, 21 pp. 97-107. Tenover, JL. The -Deficient Aging Male: Current Treat 2006,0003002 A1 1, 2006 Fikstad et al. ment Options, Reviews in Urology, 2003, vol. 5, Suppl 1, S22-S28. 2006, OO34937 A1 2, 2006 Patel et al. US Patent Publication No. US20120322780A1, downloaded Jun. 27, 2007/0232548 A1 10, 2007 Taneja 2013. 2008.0020053 A1 1, 2008 Persson et al. US Patent Publication No. US2013/0052263 A1, downloaded May 2008/0217692 A1 9, 2008 Anderson et al. 28, 2013. 2008/0317844 A1 12, 2008 Dudley et al. International Search Report and Written Opinion mailed Dec. 1, 2008/0317850 A1 12, 2008 Hewitt et al. 2010, in International Application No. PCT/US2010/030788. 2009, OO74859 A1 3, 2009 Patel et al. S.Yu. Kalinchenko Testosteron-korolgormonov Igormon korolei. 2010, O136105 A1 6, 2010 Chen et al. The Journal "Sex and Life”, 2004, pp. 12-22 I online retrieved on 2010.0137271 A1 6, 2010 Chen et al. Mar. 26, 2010 13:27). Retrieved from the Internet: URL:http://www. 2010/0173882 A1 T/2010 Giliyar et al. laZmed.ru/interesting/gublications/testosteron.html. (partial transla 2011/0039814 A1 2, 2011 Huatan et al. tion only). 2011/O142945 A1 6, 2011 Chen et al. A.T. Burbello et al., Sovremennye lekarstvennyesredstva S-Pb 2012/0135069 A1 5, 2012 Keck et al. “Neva', 2004, p. 567. (partial translation only). Addo et al., “Non-polar extracts of serum from males contain covert 2012/0135074 A1 5, 2012 Giliyar et al. radioimmunoassayable testosterone.” on line (abstract, database 2012fO244215 A1 9, 2012 Giliyar et al. PubMed PMID: 2588302) found Nov. 19, 2009)), Sep. 1989, pp. 2012,0322780 A1 12, 2012 Giliyar et al. 257-269, vol. 54, No. 3. 2013,0045271 A1 2, 2013 Dadey et al. Tso, et al. “Intestinal Absorption and Lymphatic Transport of a High 2013,0052263 A1 2, 2013 Fikstad et al. y-Linolenic Acid Canola Oil in Lymph Fistula Sprague-Dawley 2013/0225544 A1 8, 2013 Nachaegari et al. Rats'. American Society for Nutritional Sciences, 2002, pp. 218-221. Graham-Smith-et a “The OXford Reterence-book on Clinical Phar FOREIGN PATENT DOCUMENTS macology and Pharmacotherapy'. M. Meditsina Publishers, 2000, pp. 25, 136-137 (partial translation). GB 2228198 A 8, 1990 WO 92.18147 10, 1992 Maisey et al., “Clinical Efficacy of in WO 2, 1993 Male Hypogonadism.”Clinical Endocrinology, 1981, pp. 625-629, WO 94.08610 4f1994 vol. 14. ck WO WO9524893 3, 1995 ...... A61K9/48 Submitted Journal of Andrology, Mar. 23, 2012, Yin A. et al., Dietary WO 97.40823 11, 1997 Fat Modulates Testosterone Pharmacokinetics of a New Self-Emul WO OO59482 A1 10, 2000 sifying Formulation of Oral Testosterone Undercanoate in WO 00:59512 A1 10, 2000 Hypogonadal Men. WO 201112.9812 A1 10, 2001 Yin A. et al., (2012) Reexamination of Pharmacokinetics of Oral WO O101960 A1 11, 2001 Testosterone Undecanoatein Hypogonadal Men with a New Self WO 2005081742 A1 9, 2005 Emulsifying Formulation, Journal of Andrology, vol. 33, No. 2. WO 2006O13369 A2 2, 2006 Andriol.R TESTOCAPSTM Consumer Medicine Information, Sep. WO 2006113505 A2 10, 2006 2003. WO 20061-19498 A1 11, 2006 WO 2007O18943 A1 2, 2007 Wacher, V.J. et al. Peppermint Oil Enhances Cyclosporine Oral WO 2010O81032 A1 T 2010 Bioavailability in Rats: Comparison With D-a-Tocopheryl Poly(eth WO 2011082384 A2 T 2011 ylene glycol 1000) Succinate (TPGS) and ; J. Pharm. WO 2012O79092 A1 6, 2012 Sci., vol. 91, No. 1. pp. 77-90. WO 2012075081 A2 T 2012 WO 20120922O2 A1 T 2012 * cited by examiner U.S. Patent Sep. 9, 2014 Sheet 1 of 15 US 8,828,428 B1

FIGURE 1

es iNgf Normal Range s s s war.

S t S. s Lower Limit of Nortal range

72 76 80 84 88 92 96 100 104 108 112 116 120 124 128 132 136 14, 144 Time (hr) U.S. Patent Sep. 9, 2014 Sheet 2 of 15 US 8,828,428 B1

FIGURE 2

m 9. C s sur 9 O () " s as E d Lower Limit of NermaTRange

O 72 76 8O 84 88 92 96 100 104 108 112 116 120 124 128 132 136 140 144 Time (hr) U.S. Patent Sep. 9, 2014 Sheet 3 of 15 US 8,828,428 B1

FIGURE 3

al Upper Limit of Normal Range es s 1 e r

s

s SE E Lowerint of Nortararge t

72 76 80 84 88 92 96 100 104 O3 112 16 120 24, 28 32 138 40 44 Time (hr) U.S. Patent Sep. 9, 2014 Sheet 4 of 15 US 8,828,428 B1

FIGURE 4

Upper Limit of Normal Range

s e s c s sa t

s

(s E Lower Limit of Normal Range

72 76 80 84 88 92 96 100 104 108 112 116 120 124 128 132 136 14O 44 Time (hr) U.S. Patent Sep. 9, 2014 Sheet 5 Of 15 US 8,828,428 B1

FIGURE 5

y ope limit of Norma - 9. 1 o we

s D

s s E

O 72 is 80 84 88 92 96 100 104, 18 12 11s 120 124 128 132 36 14O 144 Time (hr) U.S. Patent Sep. 9, 2014 Sheet 6 of 15 US 8,828,428 B1

FIGURE 6

m - 3. 1 C C wa t O r c wn

O) Lower Limit of Normal Range

72 76 BC 84 88 92 96 OO 104 108 112 16 120 124 128 132 36 40 144 Time (hr) U.S. Patent Sep. 9, 2014 Sheet 7 Of 15 US 8,828,428 B1

FIGURE 7

es Upper Limit of Normal Range s 1 S.

C c w s s E LowerLimit of Normal Range

O 72 76 8O 84 88 92 96 100 104 108 12 16 120 124 128 132 136 140 144 Time (hr) U.S. Patent Sep. 9, 2014 Sheet 8 of 15 US 8,828,428 B1

FIGURE 8

Upper Lin it of Normal Range

h - g

aar 5

wind

E 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) U.S. Patent Sep. 9, 2014 Sheet 9 Of 15 US 8,828,428 B1

FIGURE 9

120 -e- Formulation if 9 o-E-Formulation #23 - A - Formulation #24 8

60

40

2 U.S. Patent Sep. 9, 2014 Sheet 10 of 15 US 8,828,428 B1

FIGURE 10

120

100

8O

50

40 -0- Formulation it 47 -E. Formulation if 50 20 - A - Formulation 51 -e- Formulation 54

1. 2 3 A. 5 Time (Hours) U.S. Patent Sep. 9, 2014 Sheet 11 of 15 US 8,828,428 B1

FIGURE 11

O 2 4. 6 8 10 12 14 16 18 20 22 24 Time (hr) U.S. Patent Sep. 9, 2014 Sheet 12 of 15 US 8,828,428 B1

FIGURE 12

400 m-alum-m-m-m-m-m-m-m------

350

300 S. S 3.

E E. S 1 O O s

-E-DHT

Time (hr) U.S. Patent Sep. 9, 2014 Sheet 13 of 15 US 8,828,428 B1

FIGURE 3

-e- is -E-5OBO Sn

Time (hr) U.S. Patent Sep. 9, 2014 Sheet 14 of 15 US 8,828,428 B1

FIGURE 14

60 -- 62A -A-64A

-e- 7 -- 71 40

-P-7A re-71B

Time (Hours) U.S. Patent Sep. 9, 2014 Sheet 15 of 15 US 8,828,428 B1

FIGURE 15

8 S

|

1. --m---- -6-62A -A-64A -3-70 -- 71 -- 71A -g- 7.3

O 1 2 A. S 8 Time (Hours) US 8,828,428 B1 1. 2 PHARMACEUTICAL DELVERY SYSTEMS tate (TP), or a testosterone ester thereof, and two or more lipid FOR HYDROPHOBC DRUGS AND components at least the first of which comprises a hydrophilic COMPOSITIONS COMPRISING SAME Surfactant and at least the second of which comprises a lipo philic surfactant that provides for the controlled release of TP. CLAIM OF PRIORITY said lipid components together providing for the solubiliza tion of TP. The pharmaceutical composition may further com This application is a continuation of U.S. non-provisional prise at least three lipid components at least the first of which application Ser. No. 13/553,586, filed Jul.19, 2012, which is comprises a hydrophilic Surfactant, at least the second of a continuation application of U.S. non-provisional applica which comprises a lipophilic surfactant that provides for the tion Ser. No. 1 1/911,446, now U.S. Pat. No. 8,241,664, issued Aug. 14, 2012, which is a national phase application of PCT/ 10 controlled release of TP and at least the third of which com US06/14207, filed Apr. 14, 2006, which claims priority to prises a lipophilic surfactant that further provides for the U.S. provisional application nos. 60/671,454 filed Apr. 15, solubilization of TP. As well, the pharmaceutical composition 2005 and 60/721,971 filed Sep. 30, 2005, the disclosures of may further comprise a second lipid-soluble therapeutic which are incorporated by reference herein in their entireties. agent, such as a synthetic progestin. Formulations comprising 15 same may be preferably in the form of an orally active male FIELD OF THE INVENTION contraceptive. The first lipid component may exhibit an HLB of 10 to 45, The present invention relates generally to pharmaceutical preferably 10 to 30, and more preferably 10 to 20. The second delivery systems of hydrophobic drugs and compositions lipid component may exhibit an HLB of less than about 10, comprising same. More particularly, the present invention preferably less than about 7, and more preferably less than relates to pharmaceutical compositions comprising testoster about 5. Further, the second lipid component may exhibit a one and esters thereof with enhanced and extended absorp melting point in the range of about 25°C. to about 80°C., tion and pharmacokinetics. preferably about 35° C. to about 65°C., and more preferably about 40°C. to about 60°C. The second lipid component may BACKGROUND OF THE INVENTION 25 be chosen from the group consisting of Stearic acid, , glycerol and PEG esters thereof. Precirol ATO 5 and Many pharmaceutically active compounds intended for Gelucires. oral administration are poorly soluble in water providing a In some embodiments, the lipophilic surfactant further challenge to formulate these drugs in a drug delivery system comprises a “sustained or controlled-release' surfactant that exhibits the desirable pharmacokinetic profiles in vivo. 30 which may be chosen from the group consisting of Stearic Poor oral bioavailability may lead to ineffective therapy, the acid, palmitic acid, glycerol and PEG esters thereof. Precirol need for higher dosing and/or undesirable side effects. As AT05, Imwitor 191, Myverol 18-06, Imwitor 370, Imwitor well, pharmaceutical preparations with relatively short half 375, Caprol ET, Cithrol 2MS, Marosol 183 and combinations lives require frequent dosing at the expense of patient incon thereof. The hydrophilic surfactant may be a poloxyl deriva Venience and higher therapy costs. 35 tive of castor oil. Commercially available products of this Sex hormones (e.g., testosterone and its esters) are margin class are Supplied under the tradenames, Cremophor or Eto ally water Soluble, and attempts have been made to increase cas and include, Cremophor EL and RH 40 and Etocas 35 and their bioavailability, particularly when taken orally. However, 40. Chemophor, RI-140 or Etocas 40 are preferred. administration of testosterone, per se, presents additional Compositions of the present invention may comprise, challenges. Indeed, while testosterone given by mouth is 40 based on weight, 10-70% a lipophilic surfactant; 1-40% a essentially completely absorbed into the portal circulation, controlled release surfactant; and 5-60% a hydrophilic sur because of extensive first-pass hepatic metabolism, the serum factant; and preferably 30-50% alipophilic surfactant; 5-25% concentration of testosterone following this route of admin a controlled release surfactant; and 30-40% a hydrophilic istration is low unless very large doses are administered. To surfactant. The compositions further comprise about 5 to overcome this problem, attempts have been made to alkylate 45 about 50 percent, by weight, testosterone palmitate, prefer testosterone at the C-17 position (e.g., with a methyl group to ably, about 20 to about 40 percent, by weight, testosterone form ) thereby reducing metabolism by palmitate. The inventive pharmaceutical compositions may the liver. Unfortunately, however, mere alkylation of test also comprise one or more cosolvents and/or filled into a hard osterone has not yielded desirable bioavailability and has or soft gelatin capsule. been associated with potentially serious hepatotoxicity. 50 In another aspect of the present invention, a method of Other attempts have managed to increase the transient bio preventing or alleviating the symptoms of testosterone defi availability of testosterone and its derivatives with lipophilic ciency in a mammalian Subject is provided comprising Solvents and Surfactants. Nonetheless, even in cases where administering to the mammalian Subject an effective amount bioavailability was enhanced, the delivery systems failed to oftestosterone palmitate (TP) solubilized in two or more lipid maintain desirable serum concentrations over an extended 55 components, such that the administration of said solubilized period of time. TP raises the mammalian subjects steady state serum level of Accordingly, there is a need for a drug delivery system that testosterone to within those levels found in mammalian sub can provide enhanced bioavailability of hydrophobic drugs in jects having no testosterone deficiency and providing at least vivo. In addition, with respect to testosteronetherapy, there is Some relief from Such symptoms. In human males, the admin a need for an oral drug delivery system that may provide 60 istering is preferably once or twice daily and the mammals enhanced bioavailability of testosterone and/or an ester steady state serum level of testosterone is raised to fall within thereof in vivo over an extended period of time. a range of about 300 ng/dl to about 1100 ng/dl. With human females, a similar dosing schedule (with a lower daily TP SUMMARY OF THE INVENTION dose) is preferred to achieve serum testosterone levels of 65 approximately 10 to 100 ng/dl. In some embodiments, the In one embodiment of the present invention, a pharmaceu method may raise the mammal’s steady state serum level of tical composition is provided comprising testosterone palmi testosterone by 150%, 200%, 300% or 400%. The method US 8,828,428 B1 3 4 may further comprise administering an amount of a synthetic mulation of TP, which maximizes diurnal variation while progestin Sufficient to inhibit release in said producing an early Tmax, preferably compatible with early mammalian Subject and produce severe oligospermia or morning, once-daily dosing. aZospermia. FIG.2 depicts a steady-state pharmacokinetic profile of the serum concentration of testosterone upon ingestion of a for In yet another aspect of the present invention, a method of 5 mulation of TP which maximizes diurnal variation while delivering steady-state serum levels of testosterone effective producing a late Tmax, preferably compatible with night to provide at least Some relief from Symptoms of testosterone time, once-daily dosing. deficiency is provided comprising solubilizing testosterone FIG.3 depicts a steady-state pharmacokinetic profile of the palmitate (TP) in two or more lipid components at least the serum concentration of testosterone upon ingestion of a for first of which comprises a hydrophilic Surfactant and at least 10 mulation of TP which provides physiological diurnal varia the second of which comprises a lipophilic Surfactant that tion and an early Tmax, preferably compatible with early provides for the controlled release ofTP and administering an morning, once-daily dosing. effective amount of the solubilized TP to a subject suffering FIG. 4 depicts a steady-state pharmacokinetic profile of the from the symptoms of testosterone deficiency. The method serum concentration of testosterone upon ingestion of a for 15 mulation of TP, which provides physiological diurnal varia can further comprise solubilizing TP in at least three lipid tion and a delayed Tmax, preferably compatible with early components at least the first of which comprises a hydrophilic morning, once-daily dosing. Surfactant, at least the second of which comprises a lipophilic FIG.5 depicts a steady-state pharmacokinetic profile of the surfactant that provides for the controlled release ofTP and at serum concentration of testosterone upon ingestion of a for least the third of which comprises a lipophilic surfactant that mulation of TP, which provides a short elimination half-life further provides for the solubilization of TP. and an early Tmax, preferably compatible with maximal In further yet another aspect of the present invention, a patient activity soon after waking and twice-daily dosing. method of providing extended release of testosterone in vivo FIG. 6 depicts a steady-state pharmacokinetic profile of the is provided, the method comprising solubilizing testosterone serum concentration of testosterone upon ingestion of a for palmitate (TP) in a lipid mixture comprising two or more lipid 25 mulation of TP, which provides a relatively short elimination half-life and a delayed Tmax with maximal activity about components at least the first of which comprises a hydrophilic waking time. One of the twice-daily doses is preferably Surfactant and at least the second of which comprises a lipo scheduled before bedtime. philic Surfactant having a melting point of greater than about FIG.7 depicts a steady-state pharmacokinetic profile of the 35o C. serum concentration of testosterone upon ingestion of a for In still further yet another embodiment of the present 30 mulation of TP, which provides and intermediate elimination invention, a pharmaceutical composition is provided com half-life and a Tmax preferably compatible with maximal prising testosterone palmitate (TP) and two or more lipid activity soon after walking while reducing the extent of fluc components at least the first of which comprises a hydrophilic tuation to the physiological level with twice-daily dosing. Surfactant and at least the second of which comprises a lipo FIG.8 depicts a steady-state pharmacokinetic profile of the philic surfactant, in which the at least first hydrophilic com 35 serum concentration of testosterone upon ingestion of a for ponent or the at least second lipophilic component provides mulation of TP, which provides a longer elimination half-life for the controlled release of TP. and said lipid components and a delayed Tmax, preferably compatible with maximal together provide for the solubilization of TP. In one embodi activity about awakening time following bedtime administra ment, the at least first hydrophilic component provides for the tion. This formulation reduces the extent of fluctuation to the controlled release of TP. 40 physiological levels of testosterone with twice-daily dosing. In this respect, before explaining at least one embodiment FIG. 9 shows dissolution curves of TP from three formu of the invention in detail, it is to be understood that the lations (9, 23 and 24 the compositions of which are listed in invention is not limited in its application to the details of Table 2) in a phosphate buffered dissolution medium incor construction and to the arrangements of the components set porating TritonX-100 as a surfactant in accordance with the 45 present invention. forth in the following description or illustrated in the draw FIG. 10 shows dissolution curves of TP from three formu ings. The invention is capable of embodiments in addition to lations (47.50, 51 and 54 the compositions of which are listed those described and of being practiced and carried out in in Table 3) in a phosphate buffered dissolution medium incor various ways. Also, it is to be understood that the phraseology porating TritonX-100 as a surfactant in accordance with the and terminology employed herein, as well as the abstract, are present invention. for the purpose of description and should not be regarded as 50 FIG.11 provides the mean steady-state profile of treatment limiting. with three regimens for seven days. As such, those skilled in the art will appreciate that the FIG. 12 shows the mean steady-state serum T and DHT conception upon which this disclosure is based may readily Levels after seven days of BID administration of formulation be utilized as a basis for the designing of other structures, 54. methods and systems for carrying out the several purposes of 55 FIG. 13 provides a simulated mean steady-state profile of the present invention. For example, Some embodiments of the formulation 50 with respect to the observed profile for for invention may combine TP with other active drugs, including mulation 54 (both administered BID for seven days). hormonals, in an oral delivery system that, in part, prevents or FIG. 14 shows representative in vitro dissolution profiles alleviates symptoms associated with testosterone deficiency. for various TP formulations in phosphate buffer (PBS) It is important, therefore, that the claims be regarded as 60 FIG. 15 shows representative in vitro dissolution profiles including Such equivalent constructions insofar as they do not for various TP formulations in fed-state simulated intestinal depart from the spirit and scope of the present invention. fluid (FeSSIF). BRIEF DESCRIPTION OF THE DRAWINGS DETAILED DESCRIPTION OF THE INVENTION 65 FIG.1 depicts a steady-state pharmacokinetic profile of the The present invention provides pharmaceutical delivery serum concentration of testosterone upon ingestion of a for systems, preferably oral, for hydrophobic drugs. Accord US 8,828,428 B1 5 6 ingly, while the instant invention will be described, to some mycin, nystatin, Sulconazole nitrate, terbinafine HCl, ter extent, with reference to oral delivery systems, the present conazole, tioconazole, undecenoic acid. invention may be Suitable for topical and intramuscular injec Anti-gout agents: allopurinol, probenecid, Sulphin-pyra tion. Further, hydrophobic drugs defined herein encompass ZO. both those drugs that are inherently hydrophobic (i.e., having Anti-hypertensive agents: amlodipine, benidipine, dar a log P of at least 2) as well as otherwise hydrophilic medi odipine, dilitazem HCl, diaZOxide, felodipine, guanabenz caments that have been rendered hydrophobic with suitable acetate, isradipine, , nicardipine HCl, nifedipine, modification (e.g., conjugation to fatty acids and/or lipids). nimodipine, phenoxybenzamine HCl, praZosin HCl, reser (Log P is the log of the octanol-water or buffer partition pine, HC1. coefficient and can be determined by a variety of methods for 10 Anti-malarials: amodiaquine, chloroquine, chlorproguanil those skilled in the art. The higher the value of log P, the HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, greater the lipophilicity and thus lipid solubility of the chemi pyrimethamine, quinine Sulphate. cal entity in question.) Anti-migraine agents: dihydroergotamine mesylate, In one embodiment of the present invention, testosterone 15 ergotamine tartrate, methysergide maleate, pizotifen maleate, and/or esters at the C-17 position of the testosterone mol Sumatriptan Succinate. ecule, alone or in combination with other active ingredients, Anti-muscarinic agents: atropine, benzhexol HCl, may be orally delivered using the inventive delivery system. biperiden, ethopropazine HCl, hyoscyamine, mepenZolate While many of the embodiments of the present invention will bromide, oxyphencylcimine HCl, tropicamide. be described and exemplified with the palmitic acid ester of Anti-neoplastic agents and Immunosuppressants: amino testosterone (also referred to as “testosterone palmitate' or glutethimide, amsacrine, azathioprine, buSulphan, chloram “TP), the scope of the present invention should not be con bucil, cyclosporin, dacarbazine, estramustine, etoposide, strued nor limited solely to the delivery of TP or testosterone lomustine, melphalan, mercaptopurine, methotrexate, mito perse. In fact, it should be readily apparent to one of ordinary mycin, mitotane, mitoZantrone, procarbazine HCl, skill in the art from the teachings herein that the inventive 25 citrate, testolactone. drug delivery systems and compositions therefrom may be Anti-protazoal agents: benznidazole, clioquinol, deco suitable for oral delivery of other testosterone esters, such as quinate, diiodohydroxyquinoline, diloxanide furoate, dini short-chain (C-C), medium-chain (C7-C) and long-chain tolmide, furzolidone, metronidazole, nimorazole, nitrofura (C-C) fatty acid esters, preferably long-chain fatty acid Zone, ornidazole, tinidazole. esters of testosterones and numerous hydrophobic medica 30 Anti-thyroid agents: carbimazole, propylthiouracil. ments. Such suitable medicaments, which may beformulated Anxiolytic, sedatives, hypnotics and neuroleptics: alpra in accordance with the present invention include, but should not be limited to, the following: Zolam, amylobarbitone, barbitone, bentazepam, bro Analgesics and anti-inflammatory agents: aloxiprin, aura mazepam, bromperidol, brotizolam, butobarbitone, carbro nofin, azapropaZone, benorylate, diflunisal, etodolac, fen 35 mal, chlordiazepoxide, chlormethiazole, , bufen, fenoprofen calcim, flurbiprofen, ibuprofen, clobazam, clotiazepam, clozapine, diazepam, droperidol. indomethacin, ketoprofen, meclofenamic acid, mefenamic ethinamate, flunanisone, flunitrazepam, fluopromazine, flu acid, nabumetone, naproxen, oxyphenbutaZone, phenylbuta penthixol decanoate, fluiphenazine decanoate, flurazepam, Zone, piroxicam, Sulindac. , lorazepam, lormetazepam, medazepam, mep Anthelmintics: albendazole, bephenium hydroxynaph 40 robamate, methaqualone, midazolam, nitrazepam, thoate, cambendazole, dichlorophen, ivermectin, mebenda oxazepam, pentobarbitone, perphenazine pimozide, prochlo Zole, nitaZOXamide, oxamniquine, Oxfendazole, oxantel rperazine, , temazepam, thioridazine, triazolam, embonate, praziquantel, pyrantel embonate, thiabendazole. Zopiclone. Anti-arrhythmic agents: amiodarone HCl, disopyramide, Beta-blockers: acebutolol, alprenolol, atenolol, labetalol, flecainide acetate, quinidine Sulphate. 45 metoprolol, nadolol, oXprenolol, pindolol, propranolol. Anti-bacterial agents: benethamine penicillin, cinoxacin, Cardiac Inotropic agents: amrinone, digitoxin, digoxin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, enoXimone, lanatoside C, medigoxin. demeclocycline, doxycycline, erythromycin, ethionamide, Corticosteroids: beclomethasone, betamethasone, budes imipenem, nalidixic acid, nitrofurantoin, rifampicin, spira onide, cortisone acetate, desoxymethasone, dexamethasone, mycin, Sulphabenzamide, Sulphadoxine, Sulphamerazine, 50 fludrocortisone acetate, flunisolide, flucortolone, fluticasone Sulphacetamide, Sulphadiazine, Sulphafurazole, Sulpha propionate, hydrocortisone, methylprednisolone, predniso methoxazole, Sulphapyridine, tetracycline, trimethoprim. lone, prednisone, triamcinolone. Anti-coagulants: dicoumarol, dipyridamole, nicoumalone, Diuretics: acetazolamide, amiloride, bendrofluazide, phenindione. bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, Anti-depressants: amoxapine, maprotiline HCl, mianserin 55 frusemide, metolaZone, , triamterene. HCl, nortriptyline HCl, trazodone HCl, trimipramine male Anti-parkinsonian agents: bromocriptine mesylate, ate. ly Suride maleate. Anti-diabetics: acetohexamide, chlorpropamide, glib Gastro-intestinal agents: bisacodyl, , cisapride, enclamide, gliclazide, glipizide, tolaZamide, tolbutamide. diphenoxylate HCl, , famotidine, loperamide, Anti-epileptics: beclamide, carbamazepine, clonazepam, 60 mesalazine, nizatidine, omeprazole, ondansetron HCl, raniti ethotoin, methoin, methSuximide, methylphenobarbitone, dine HCl, sulphasalazine. oXcarbazepine, paramethadione, phenacemide, phenobarbi Histamine H.-Receptor Antagonists: acrivastine, astemi tone, phenytoin, phensuXimide, primidone, Sulthiame, Valp Zole, cinnarizine, cyclizine, HCl, dimenhy roic acid. drinate, flunarizine HCl, loratadine, meclozine HCl, oxato Anti-fungal agents: amphotericin, butoconazole nitrate, 65 mide, terrenadine. clotrimazole, econazole nitrate, fluconazole, flucytosine, Lipid regulating agents: beZafibrate, clofibrate, fenofi griseofulvin, itraconazole, ketoconazole, miconazole, nata brate, gemfibrozil, probucol. US 8,828,428 B1 7 8 Nitrates and other anti-anginal agents: amyl nitrate, glyc mophor RH40, can generally suffice. In some formulations eryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, incorporating high levels of solubilized TP, the inventors have pentaerythritol tetranitrate. observed that in the absence of a high HLB surfactant, there Nutritional agents: betacarotene, A, vitamin B, can be substantially no release of the drug from blends solely , , . comprising lipophilic surfactants. The levels of the high HLB Opioid analgesics: codeine, dextropropyoxyphene, Surfactant can be adjusted to provide optimum drug release diamorphine, dihydrocodeine, meptazinol, methadone, mor without compromising the solubilization of the active ingre phine, nalbuphine, pentazocine. dient. Sex hormones: clomiphene citrate, , ethinyloestra The lipophilic Surfactant component, in some embodi diol, medroxyprogesterone acetate, mestranol, methyltest 10 osterone, , , oestradiol, conjugated ments, may further comprise a “controlled-release' surfac oestrogens, progesterone, synthetic progestins (also referred tant. In other words, in addition to being a solvent for the drug, to as ), , Stiboestrol, , test the lipophilic Surfactant may also provide a semi-solid and osterone, esters of testosterone, including esters of oleic acid, sustained release (SR) matrix. Many semi-solid/SR excipi linoleic acid, linolenic acid, Stearic acid, myristic acid, lauric 15 ents are available to one of ordinary skill in the art, but those acid, palmitic acid, capric or decanoic acid octanoic or that additionally are good solvents for the drug are desirable caprylic acid, pelargonic acid, undecanoic acid, tridecanoic in the instant invention. Thus, preference should be given to acid, pentadecanoic acid, and the branched chain, cyclic ana semi-solid lipid excipients having high solubilization poten logues of these acids, testosterone analogues such as methyl tial for the drug. In one aspect, “controlled-release' lipophilic nortestosterone, and combinations thereof. Synthetic surfactants exhibit a melting point of about 25°C. to about progestins include, for example, , levonorg 80° C., preferably about 35° C. to about 65° C., and more estrel butanoate, , norethisterone, , preferably 40° C. to about 60° C. etonorgestrel and medroxyprogesterone. To be sure, however, "controlled-release' surfactants need Gonadotropin releasing hormone (GnRH) antagonists that not be limited to lipophilic Surfactants alone. Indeed, some are orally active. 25 hydrophilic Surfactants in compositions of the instant inven Stimulants: amphetamine, dexamphetamine, dexfenflu tion may also provide controlled-release characteristics in ramine, fenfluramine, mazindol. conjunction with a lipophilic Surfactant. Mixtures of hydrophobic drugs may, of course, be used Lipophilic Surfactants Suitable in drug delivery systems of where therapeutically effective. For example, the combina the present invention include: tion of testosterone palmitate with an orally active inhibitor or 30 Fatty acids (C-C, preferably Co-C, more preferably Type I or Type II 5C.-reductase or the combination of test Cia-C24), for example, octanoic acid, decanoic acid, unde osterone palmitate with a synthetic progestin may be prefer canoic acid, lauric acid, myristic acid, palmitic acid, stearic able in some embodiments. acid, oleic acid, linoleic acid, and linolenic acid. Stearic acid Drug delivery systems of the present invention and com and palmitic acid are preferred. positions comprising same, comprise a hydrophobic drug or 35 Mono- and/or di-glycerides offatty acids, such as Imwitor drugs dissolved in a lipophilic Surfactant and a hydrophilic 988 (glyceryl mono-fcdi-caprylate), Imwitor 742 (glyceryl Surfactant. A lipophilic Surfactant as defined herein has a mono-di-caprylate/caprate), Imwitor 308 (glyceryl mono-ca hydrophilic-lipophilic balance (HLB) less than 10, and pref prylate), Imwitor 191 (glyceryl mono-stearate), Softigen 701 erably less than 5. A hydrophilic surfactant as defined herein (glyceryl mono-/di-ricinoleate), Capmul MCM (glyceryl has an HLB of greater than 10. (HLB is an empirical expres 40 caprylate/caprate), Capmul MCM(L) (liquid form of Capmul sion for the relationship of the hydrophilic and hydrophobic MCM), Capmul GMO (glyceryl mono-oleate), Capmul GDL groups of a Surface active amphiphilic molecule, such as a (glyceryl dilaurate), Maisine (glyceryl mono-linoleate), Surfactant. It is used to index surfactants and its value varies Peceol (glyceryl mono-oleate), Myverol 18-92 (distilled from about 1 to about 45. The higher the HLB, the more water monoglycerides from sunflower oil) and Myverol 18-06 (dis soluble the surfactant.) 45 tilled monoglycerides from hydrogenated Soyabean oil), Pre According to one aspect of the present invention, each of cirol ATO 5 (glyceryl palmitostearate) and Gelucire 39/01 the components of the delivery system (i.e., the lipophilic and (semi-synthetic glycerides, i.e., C.s mono-, di- and tri hydrophilic surfactants) individually have solvent character glycerides). The preferred members of this class of lipophilic istics and contribute, in part, to solubilizing the active ingre Surfactants are the partial glycerides of oleic, palmitic and dient. Those lipophilic surfactants that contribute substan 50 stearic acids and blends thereof. tially to dissolving the drug are defined herein as a “primary Acetic, Succinic, lactic, citric and/or tartaric esters of solvent. Primary solvents can also provide “sustained-re mono- and/or di-glycerides of fatty acids, for example, lease' or “controlled-release' characteristics to the drug My vacet 9-45 (distilled acetylated monoglycerides), Miglyol delivery system. “Secondary' solvents are hydrophilic sur 829 (caprylic/capric diglyceryl succinate), Myverol SMG factants that also solubilize the drug, albeit to a lesser extent 55 (mono/di-Succinylated monoglycerides), Imwitor 370 (glyc than a primary solvent. In addition to dissolving the drug, eryl Stearate citrate), Imwitor 375 (glyceryl monostearate/ secondary solvents facilitate the dispersion of the delivery citrate/lactate) and Crodatem T22 (diacetyl tartaric esters of system in aqueous media or intestinal fluids and Subsequent monoglycerides). release of the drug. In cases where the secondary solvent is a Propylene glycol mono- and/or di-esters offatty acids, for high melting point hydrophilic Surfactant, it can also provide 60 example, Lauroglycol (propylene glycol monolaurate), for a Sustained drug release, acting synergistically with the Mirpyl (propylene glycol monomyristate), Captex 200 (pro lipophilic Surfactant. pylene glycol dicaprylate/dicaprate), Miglyol 840 (propylene A hydrophilic Surfactant component may be necessary to glycol dicaprylate/dicaprate) and Neobee M-20 (propylene achieve desirable emission of the drug from within the for glycol dicaprylate/dicaprate). mulation. That is, a hydrophilic Surfactant may be required to 65 Polyglycerol esters of fatty acids such as Plurol oleidue free the drug from within the lipid carrier matrix, or primary (polyglyceryl oleate), Caproll ET (polyglyceryl mixed fatty Solvent. In this respect, a high HLB Surfactant, such as Cre acids) and Drewpol 10.10.10 (polyglyceryl oleate). US 8,828,428 B1 9 10 Castor oil ethoxylates of low ethoxylate content (HLB<10) Polyoxyethylene-polyoxypropylene co-polymers and such as Etocas 5 (5 moles of ethylene oxide reacted with 1 block co-polymers (HLB-10), that are commercially avail mole of castor oil) and Sandoxylate 5 (5 moles of ethylene able under the trade name Pluronics or Poloxamers, such as oxide reacted with 1 mole of castor oil. Poloxamers 188 and 407 also known as Syperonic PE L44 Acid and ester ethoxylates formed by reacting ethylene (HLB=16) and Syperonic F127 (HLB-22), respectively. oxide with fatty acids or glycerol esters of fatty acids Anionic Surfactants e.g. lauryl Sulphate, Sodium (HLB<10) such as Crodet 04 (polyoxyethylene (4) lauric oleate and sodium dioctylsulphosuccinate. acid), Cithrol 2MS (polyoxyethylene (2) stearic acid), Mar Alkylphenol surfactants (HLB-10) e.g. Triton N-101 losol 183 (polyoxyethylene (3) stearic acid) and Marlowet (polyoxyethylene (9-10) nonylphenol) and Symperonic NP9 G12DO (glyceryl 12 EO dioleate). Sorbitan esters of fatty 10 (polyoxyethylene (9) nonylphenol). acids, for example, Span 20 (sorbitan monolaurate), Crill 1 Of the hydrophilic surfactants listed above, those suitable (Sorbitan monolaurate) and Crill 4 (Sorbitan mono-oleate). as a “controlled-release' surfactant include, but are not lim Transesterification products of natural or hydrogenated ited to Gelucires of high HLB value, such as Gelucire 50/13. Vegetable oil triglyceride and a polyalkylene polyol As mentioned, in one aspect of the present invention, each (HLB<10), e.g. Labrafil M1944CS (polyoxyethylated apricot 15 of the components of the delivery system (i.e., the lipophilic kernel oil), Labrafil M2125CS (polyoxyethylated corn oil) and hydrophilic Surfactants) individually has solvent charac and Gelucire 37/06 (polyoxyethylated hydrogenated coco teristics and contributes, in part, to solubilizing the active nut). Labrafil M1944CS is preferred. ingredient. In this way, without being bound by or limited to Alcohol ethyoxylates (HLB<10), e.g. Volpo N3 (polyoxy theory, the present invention does not require additional Sol ethylated (3) oleyl ether), Brij93 (polyoxyethylated (2) oleyl vents, such as additional digestible oils and/or cosolvents, but ether), Marlowet LA4 (polyoxyethylated (4) lauryl ether) and these may be optionally included in the inventive systems and Pluronics, for example, Polyoxyethylene-polyoxypropy formulations. lene co-polymers and block co-polymers (HLB<10) e.g. Syn A digestible oil is defined herein as an oil that is capable of peronic PE L42 (HLB=8) and Symperonic PEL61 (HLB-3) undergoing de-esterification or hydrolysis in the presence of Mixtures of suitable lipophilic surfactants, such as those 25 pancreatic lipase in vivo under normal physiological condi listed above, may be used if desired, and in some instances are tions. Specifically, digestible oils may be complete glycerol found to be advantageous. For instance, glycerol palmitate triesters of medium chain (C7-C) or long chain (C-C) and glycerol Stearate esters alone and in blends are preferred fatty acids with low molecular weight (up to C) mono-, di- or lipophilic Surfactants and controlled-release matrices. polyhydric alcohols. Some examples of digestible oils for use Of the lipophilic surfactants listed above, those suitable as 30 in this invention thus include: vegetable oils (e.g., soybean a “controlled-release' component include, but are not limited oil, safflower seed oil, corn oil, olive oil, castor oil, cottonseed to, stearic acid, palmitic acid, and their glycerol and PEG oil, arachis oil, Sunflower seed oil, coconut oil, palm oil, esters, Precirol AT05, Imwitor 191, Myverol 18-06, Imwitor rapeseed oil, evening primrose oil, grape seed oil, wheat germ 370, Imwitor 375, Caprol. ET, Cithrol 2MS, Marosol 183, oil, Sesame oil, avocado oil, almond, borage, peppermint and Gelucire 39/01 and combinations thereof. 35 apricot kernel oils) and animal oils (e.g., fish liver oil, shark Any pharmaceutically acceptable hydrophilic Surfactant oil and mink oil). (i.e., having an HLB value greater than 10) may be used in the As well, optional cosolvents suitable with the instant present invention. Some non-limiting examples include: invention are, for example, water, short chain mono-, di-, and Polyoxyethylene sorbitan fatty acid derivates e.g. Tween polyhydric alcohols. Such as ethanol, benzyl alcohol, glyc 20 (polyoxyethylene (20) monolaureate), Tween 80 (poly 40 erol, propylene glycol, propylene carbonate, polyethylene oxyethylene (20) monooleate), Crillet 4 (polyoxyethylene glycol with an average molecular weight of about 200 to (20) monooleate) and Montanox 40 (polyoxyethylene (20) about 10,000, diethylene glycol monoethyl ether (e.g., Tran monopalmitate). Tween 80 (Polysorbate 80) is preferred. scutol HP), and combinations thereof. Castor oil or hydrogenated caster oil ethoxylates Other optional ingredients which may be included in the (HLB-10), e.g. Cremophor EL (polyoxyethylene (35) castor 45 compositions of the present invention are those which are oil), Cremophor RH40 (polyoxyethylene (40) hydrogenated conventionally used in the oil-based drug delivery systems, castor oil), Etocas 40 (polyoxyethylene (40) castor oil), Nild e.g. antioxidants such as tocopherol, tocopherol acetate, col HCO-60 (polyoxyethylene (60) hydrogenated castor oil), ascorbic acid, butylhydroxytoluene, butylhydroxyanisole Solutol HS-15 (polyethylene glycol 660 hydroxystearate), and propyl gallate; pH stabilizers such as citric acid, tartaric Labrasol (caprylocaproyl macrogol-8 glycerides), C-toco 50 acid, fumaric acid, acetic acid, glycine, arginine, lysine and pherol-polyethylene glycol-1000-succinate (TPGS) and hydrogen phosphate; thickeners/Suspending ascorby1-6 palmitate. Cremophor RH40 is preferred. agents such as hydrogenated vegetable oils, beeswax, colloi Gelucires, preferably Gelucire 50/13 (PEG mono- and dal silicon dioxide, mannitol, gums, celluloses, silicates, ben diesters of palmitic and stearic acids. (In reference to Gelu tonite, flavoring agents such as cherry, lemon and aniseed cires, the first number (i.e., 50) corresponds to the melting 55 flavors; Sweeteners such as aspartame, acesulfane K. Sucral point of the material and the second (i.e., 13) to the HLB ose, Saccharin and cyclamates; etc. number.) The relative proportions of the lipophilic surfactant and Fatty acid ethoxylates (HLB-10), e.g. Myri 45 (polyoxy hydrophilic surfactant in the preferred hydrophobic drug car ethylene (8) stearate), Tagat L (polyoxyethylene (30) mono rier system of this invention are, in general, not especially laurate), Marlosol 1820 (polyoxyethylene (20) stearate) and 60 critical, save that the concentration of lipophilic and hydro Marlosol OL15 (polyoxyethylene (15) oleate). Myri 45 is philic surfactants must be sufficient to solubilize the hydro preferred. phobic drug, yet release same both in vitro and in vivo. It Alcohol ethoxylates (HLB-10), e.g. Brij 96 (polyoxyeth should be noted that in some embodiments of the invention, ylene (10) oleyl ether), Volpo 015 (polyoxyethylene (15) one hydrophobic drug may serve as a lipid vehicle for another. oleyl ether), Marlowet OA30 (polyoxyethylene (30) oleyl 65 More specifically, for example, a testosterone ester may serve ether) and Marlowet LMA20 (polyoxyethylene (20) C-C, as a carrier for testosterone. Even more specifically, TP may fatty ether). serve as a lipid vehicle for testosterone. As well, TP may US 8,828,428 B1 11 12 serve, in some embodiments, as its own “controlled-release' described herein are not limited to any one encapsulation vehicle, which may obviate the need for additional “con method, specific encapsulation techniques will not be further trolled-release' lipids mentioned above. discussed. Generally, the following relative concentrations, by The drug carrier systems and pharmaceutical preparations weight, are preferred (the percentages are based on the total according to the present invention may be prepared by con content of hydrophilic surfactant and lipophilic ventional techniques for lipid-based drug carrier systems. In Surfactant(s)): a typical procedure for the preparation of the preferred carrier Hydrophilic surfactant: 5-60%, more preferably 15-45%. systems of this invention, the lipophilic Surfactant is weighed and most preferably 30-40% Lipophilic surfactant: 10-90%. out into a suitable stainless steel vessel and the hydrophilic 10 Surfactant is then weighed and added to the container. Mixing more preferably 20-80%, and most preferably 30-60% Lipo of the two components may be effected by use of a homog philic “controlled-release' surfactant: 1-40%, more prefer enizing mixer or other high shear device. If the material is ably 2.5-30%, and most preferably 5-25%. Solid at room temperature, Sufficient heat is applied to ensure The concentration of drug in the final pharmaceutical for metling and fluidity without chemical decomposition. mulation will be that which is required to provide the desired 15 The lipophilic “controlled-release' surfactant is then therapeutic effect from the drug concerned, but generally will added, if desired, to the two other components in the stainless lie in the range 0.1% to 50% by weight, preferably between steel vessel and mixed using the appropriate equipment. The about 10% to 30% by weight, and most preferably about 10% hydrophobic drug is then weighed and added to the combined and 20% by weight, based on the weight of the final compo lipid mixture and mixing continued until either a homog sition. However, in many instances, because the present com enous solution is prepared. The formulation may be de-aer positions may have better bioavailability than known compo ated before encapsulation in either soft or hard capsules. In sitions of the drug concerned, the drug concentration may be some instances the fill formulation may be held at elevated reduced as compared with the conventional preparations temperature using a Suitablejacketed vessel to aid processing. without loss of therapeutic effect. With specific reference to Returning now to the delivery of testosterone, in one testosterone therapy, the present inventors have learned that 25 embodiment of the present invention, drug delivery systems the use of the palmitate ester of T. in particular, is desirable. of the present invention may be suitable for testosterone Indeed, once absorbed, the long and fully Saturated chain of therapy. Testosterone is the main endogenous androgen in the fatty acid on T slows the rate of hydrolysis of the ester men. Leydig cells in the testes produce approximately 7 mg of bond thus prolonging the circulation of the TP and conse testosterone each day resulting in serum concentrations rang quently T. For example, formulations of the present invention 30 ing from about 300 to about 1100 ng/dL. Women also syn (e.g., formulation nos. 50 and 54 (below)) comprising TP thesize testosterone in both the ovary and adrenal gland, but have a T half-life of about 8-9 hours. By comparison, the the amount is about one-tenth that observed in eugonadal half-life for T is about 30 minutes and that of T-undecanoate men. The majority (about 98%) of circulating testosterone is is about 1.5 hours. bound to sex hormone binding globulin and is biologically In other embodiments, formulations of the present inven 35 active only when released to the free form. The term “free” is tion may have self-emulsifying properties, forming a fine thus defined as not being bound to or confined within, for emulsion upon dilution with aqueous media or intestinal flu example, biomolecules, cells and/or lipid matrices of the ids in vivo. In other words, the formulations may have high inventive formulations described herein. Generally, “free” Surfactant and lipid content designed for adequate dispersion medicaments described herein refer to medicament that is upon mixing with an aqueous medium. Qualitative descrip 40 accessible to metabolic enzymes circulating in serum. tion of the self-emulsification property of the inventive for While the present invention should not be limited to the mulations can be visually observed during the dissolution of delivery of testosterone or any particular ester thereof, TPhas same in vitro. On the other hand, quantitative measurements been found to offer unique chemical and physical character may be taken of the particle size of the emulsified droplets istics that make its use preferable in some embodiments. The using laser light scattering and/or turbidity measurements in 45 present inventors have learned that the palmitic acid ester of the dissolution medium by UV/VIS spectrophotometer. Any testosterone, in particular, can yield Superior bioavailability of these methodologies are available and known to one of to that found with other equivalent esters (e.g., testosterone ordinary skill in the art. undecanoate (TU). Without being held to or bound by theory, The pharmaceutical compositions according to the present it is believed that TP is superior, in part, to other testosterone invention may be liquid, semi-solid, or Solid at ambient tem 50 esters, because it has a particularly high log P compared to peratures, but preferably are presented as liquids or semi similar analogs. (The log Pfor TP is greater than 9 compared solids. Solid preparations are defined as solid, powdered to a log P for TU of about 6.5) medicaments blended with powdered excipients and directly Consequently, TP absorbed into the bloodstream may pas filled into hardgelatin or cellulose capsule or compressed into sively diffuse into red blood cells (RBCs) circulating in the a tablet. The instant invention, however, preferably comprises 55 blood. Specifically, because palmitic acid is both a significant a solid, powdered medicament (e.g., TP) that is solubilized in component of the RBC membrane and has been shown to be the presence of the lipid surfactant excipients (e.g., any com transported across this membrane, TP is better suited to be in bination of the lipophilic and hydrophilic surfactants noted an equilibrium with and pass said membrane. In this manner, above). Accordingly, the melting point of the Surfactants used some portion of the total concentration of free TPat any given is one factor that can determine whether the resulting com 60 time may be found within RBCs. Further, when confined to a position will be liquid or semi-solid at ambient temperature. RBC, any TP therein is shielded from the esterases found in Particularly preferred compositions of the present invention the serum. As the conversion of TP to testosterone is a direct are liquid or semi-solid oral unit dosage forms, more prefer consequence of esterase activity, greater inaccessibility to the ably filled into hard or Soft capsules, e.g. gelatin or cellulose esterases is expected to prolong the half-life of TP. For this capsules. The technology for encapsulating lipid-based phar 65 reason, it is believed that the residence time of TP in the blood maceutical preparations is well known to one of ordinary skill is greater than that would be expected from other saturated in the art. As the inventive delivery systems and formulations esters of shorter hydrocarbon chain-length. US 8,828,428 B1 13 14 What is more, the use of TP in contrast to that for other TABLE 1-continued orally administered testosterone esters, does not appear to dramatically elevate serum (“DHT) Labrafil Precirol Cremophor above physiological levels, which are typically about /10th ID T or Tester M1944CS ATOS RH4O Labrasol that of testosterone (i.e., about 30 to 100 ng/dL) in eugonadal 5 N 360 219.97 73.29 146.74 45.00% 27.50% 9.16% 18.34% men. Testosterone interacts with respective androgen recep O 32O 239.97 79.95 160.08 tors either directly or following its conversion to DHT via the 40.00% 30.00% 9.99% 20.01% action of 5C-reductase. DHT is a more potent androgen than P 28O 259.96 86.61 173.42 testosterone and its elevated levels are thought by some sci 35.00% 32.50% O.83% 21.68% 10 Q 240 279.96 93.27 186.76 entists to increase the risk of cancer. Elevated levels 30.00% 35.00% 1.66% 23.35% of DHT are a noted problem with the administration of, for R 228.32 285.8 95.22 19066 example, TU. In this way, TP provides yet another unexpected 28.54% 35.739% 1.90% 23.83% S 2OO 299.96 99.94 2001O advantage over other testosterone esters. 25.00% 37.49% 2.49% 25.01% Specific embodiments of the instant invention will now be 15 T 160 319.96 106.60 21345 described in non-limiting examples. Table 1 provides com 20.00% 39.99% 3.32% 26.68% U 120 339.95 113.26 226.79 position details of various formulations of testosterone (T) or 15.00% 42.49% 4.16% 28.35% testosterone-esters (T-esters), in accordance with the teach V 8O 359.95 11992 240.13 ings of the instant invention. For calculation purposes, 1 mg 10.00% 44.99% 4.99% 30.02% W 40 379.95 126.59 253.47 of T is equivalent to: 1.39 mg Tenanthate; 1.58 mg T-unde S.OO% 47.49% S.82% 31.68% canoate, 1.43 mg T-cypionate, and 1.83 mg T-palmitate. TP is X 2O 389.95 129.92 260.14 a preferred T-ester in some of the formulations listed below. 2.50% 48.74% 6.24% 32.52% AA 400 O9.79 66. SS 149.72 73.94 The compositions details of Table 1 (mg/capsule and wt. SO.00% 13.72% 8.32% 18.72% 9.24% percentage) are based on 800 mg fill weight per 00 hard BB 360 20.77 73.21 164.69 81.33 gelatin capsule. However, at testosterone-ester amounts less 25 45.00% 15.10% 9.15% 20.59% O.17% than about 100 mg/capsule, the formulations may be propor CC 32O 31.75 79.87 179.66 88.72 40.00% 16.47% 9.98% 22.46% 1.09% tionally adjusted for smaller total fill weights that would DD 28O 42.73 86.52 194.64 96.12 permit use of Smaller hard gelatin capsules (e.g., '0' size). 35.00% 17.84% O.82% 24.33% 2.01% As well, it should be apparent to one of ordinary skill in the EE 240 53.70 93.18 209.61 103.51 art that many, if not all, of the Surfactants within a category 30 30.00% 19.21% 1.65% 26.20% 2.94% FF 228.32 56.91 95.12 213.98 105.67 (e.g., lipophilic, hydrophilic, etc.) may be exchanged with 28.54% 19.61% 1.89% 26.75% 3.21% another surfactant from the same category. Thus, while Table GG 2OO 64.68 99.83 224.58 110.90 1 lists formulations comprising Labrafil M1944CS (HLB-3) 25.00% 20.59% 2.48% 28.07% 3.86% and Precirol ATO5 (HLB=2), one of ordinary skill in the art HH 160 75.66 O6.49 239.55 118.30 35 20.00% 21.96% 3.31% 29.94% 4.79% should recognize other lipophilic Surfactants (e.g., those I 120 86.64 3.14 254.52 125.69 listed above) may be suitable as well. Similarly, while Table 1 15.00% 23.33% 4.14% 31.82% 5.719, lists formulations comprising Cremophor RH40 (HLB=13) J 8O 97.62 9.8O 269.50 133.09 and Labrasol (HLB=14), one of ordinary skill in the art 10.00% 24.70% 4.97% 33.69% 6.64% KK 40 208.60 26.45 284.47 140.48 should recognize other hydrophilic Surfactants (e.g., those S.OO% 26.07% 5.81% 35.56% 7.56% listed above) may be suitable. 40 LL 2O 214.09 29.78 291.95 144.18 2.50% 26.76% 6.22% 36.49% 8.02% TABLE 1. MM 400 81.62 94.47 223.91 SO.00% O.20% 1.81% 27.99% Labrafil Precirol Cremophor NN 360 89.78 O3.92 246.30 ID T or Tester M1944CS ATOS RH4O Labrasol 45.00% 1.22% 2.99% 30.79% 45 OO 32O 97.94 3.37 268.69 A. 400 O9.68 66.49 223.83 40.00% 2.24% 4.17% 33.59% SO.00% 13.71% 8.31% 27.98% PP 28O O6.10 2281 291.08 B 360 20.64 73.14 246.21 35.00% 3.26% 5.359 36.39% 45.00% 15.08% 9.14% 30.78% QQ 240 4.27 32.26 313.47 C 32O 31.61 79.79 268.60 30.00% 4.28% 6.53% 39.18% 40.00% 16.45% 9.97% 33.57% 50 RR 228.32 6.65 35.02 32O.O1 D 28O 42.58 86.44 290.98 28.54% 4.58% 6.88% 40.00% 35.00% 17.82% O.80% 36.37% SS 2OO 22.43 41.71 335.86 E 240 53.55 93.09 313.36 25.00% 5.30% 7.719, 41.98% 30.00% 19.19% 1.64% 39.17% TT 160 30.59 51.16 358.25 F 228.32 56.75 95.03 3.19.9 20.00% 6.32% 8.89% 44.78% 28.54% 19.59% 1.88% 39.99% 55 UU 120 38.75 60.60 380.64 G 2OO 64.52 99.74 335.75 15.00% 7.34% 20.08% 47.58% 25.00% 20.56% 2.47% 41.97% VV 8O 46.91 70.05 403.04 H 160 75.48 106.39 358.13 10.00% 8.36% 21.26% S.O.38% 20.00% 21.94% 3.30% 44.77% WW 40 55.08 79.50 425.43 I 120 86.45 113.04 380.51 S.OO% 9.38% 22.44% 53.18% 15.00% 23.31% 4.13% 47.56% XX 2O 59.16 84.22 436.62 J 8O 97.42 119.69 402.90 60 2.50% 9.89% 23.03% 54.58% 10.00% 24.68% 4.96% S.O.36% K 40 208.39 126.33 425.28 S.00% 26.05% 5.79% 53.16% Table 2 provides composition details of various TP formu L 2O 213.87 129.66 436.47 2.50% 26.73% 6.21% 54.56% lations in accordance with the teachings of the instant inven M 400 199.97 66.62 13340 65 tion and FIG. 9 provides in vitro dissolution of select formu SO.00% 25.00% 8.33% 16.68% lations therein. TP may be synthesized throughesterification oftestosterone with palmitoyl chloride in an acetone/pyridine US 8,828,428 B1 15 16 mixture. Testosterone palmitate crude is purified by filtration, washed with methanol. When necessary, recrystallization can crystallized from a methanol/methylene chloride mixture and be done from heptane, followed by washing with methanol. TABLE 2

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

No. TP LBR PRCS OA Peceo TPGS SO CRH40 LSol Mitol (mg)**

1 228.32 285.84 Sf 570 (40.0) (50.0) (10.0) 2 228.32 57 228 57 570 (40.0) (10.0) (40.0) (10.0) 3 228.32 171 114 57 570 (40.0) (30.0) (20.0) (10.0) 4 228.32 171 114 57 570 (40.0) (30.0) (20.0) (10.0) S 228.32 114 57 171 570 (40.0) (20.0) (10.0) (30.0) 6 228.32 476 95.2 800 (28.5) (59.5) (11.9) 7 228.32 95.2 380.8 95.2 800 (28.5) (11.9) (47.6) (11.9) 8 228.32 1904 95.2 285.6 800 (28.5) (23.8) (11.9) (35.7) 9 228.32 285.84 95.2 190.56 800 (28.5) (35.7) (11.9) (23.8) O 228.32 190.56 190.56 190.56 800 (28.5) (23.8) (23.8) (23.8) 1 228.32 190.56 95.2 190.56 95.2 800 (28.5) (23.8) (11.9) (23.8) (11.9) 2 228.32 190S6 190.56 95.2 95.2 800 (28.5) (23.8) (23.8) (11.9) (11.9) 3 228.32 190S6 190.56 95.2 95.2 800 (28.5) (23.8) (23.8) (11.9) (11.9) 4 228.32 285 95.2 95.2 95.2 800 (28.5) (35.7) (11.9) (11.9) (11.9) S 228.32 285.84 20.O 265.6 800 (28.5) (35.7) (2.50) (33.2) 6 228.32 285.84 20.0 40.O 225.6 800 (28.5) (35.7) (2.50) (5.00) (28.2) 7 228.32 285.84 8O.O 205.6 800 (28.5) (35.7) (10.0) (25.7) 8 228.32 95.20 190.56 285.6 800 (28.5) (11.9) (23.8) (35.7) 9 228.32 133.08 88.672 450 (50.73) (29.57) (19.7) 20 228.32 285.84 200.28 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 16022 105.74 800 (28.5) (30.0) (8.2) (20.0) (13.2) 23 228.32 157.02 95.2 320.45 800 (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 368.0 800 (22.83) (28.7) (2.5) (46.0) S8 120.0 S2O.O 2O.O 14O.O 800 (15.0) (65.0) (2.5) (17.5)

*TP:Testosterone palmitate; LBR: Labrafil M1944CS; PRC5: PrecirolaTO5; OA: Refined Oleic acid; SO: Refined Soybean oil; TPGS: D-O-tocopheryl PEG1000 succinate; CRH 40: Cremophor RH40; L’sol: Labrasol; Mitol: Mannitol **Filled into size “0” capsule (570 mg) or “00'capsule (800 mg) US 8,828,428 B1 17 18 A preferred formulation of TP in accordance with the period, a concentration of TP of less than about 23 percent by present invention is: weight. In some embodiment, a weight percentage of less than about 20 is preferred, more preferably a weight percent age of less than about 18, and most preferably a weight Component mg capsule %, ww 5 percentage of less than about 15. Without being bound by or Testosterone palmitate 228.32 28.5 limited to theory, 1t 1S believed that TP at levels greater than Cremophor (R) RH40 320.45 40.O about 23 weight percent may, in fact, retard its own release. Labrafil (R) M1944 CS 157.02 19.6 For example, formulations according to the instant invention Precirol (RATO 5 95.20 11.9 comprising less than about 23 weight percent TP can release Total: 800 1OOO 10 50-70% of the drug at 1 hour and 80 to near 100% at 2 hours. On the other hand, formulations according to the instant invention comprising greater than about 23 weight percent TP In some embodiments, it may be desirable to reduce the release less than 5% of the drug at 1 hr and less than 70% at 6 absolute concentration of testosterone and/or an ester thereof hours. in order to promote a relatively faster release of the testoster- 15 Table 3 provides composition details of various TP formu one and/or ester from within the lipid vehicle. That is, it has lations, that in Some cases, are at TP concentrations lower been found, Surprisingly, that reducing the concentration of than those in Table 2 and in accordance with the teachings of TP may in Some cases, confer quicker release kinetics. For the instant invention. FIG. 10 provides in vitro dissolution of example, for significant release ofTP within about a two hour select Table 3 formulations. TABLE 3 Composition (mg/capsule and wellht 96)" FI F. Cremophor Oleic Capmul Tween Precirol Gelucire Wt. 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%) 29 32O.O 16O.O 3OO.O 2O.O 800 (40%) (20%) (37.5%) (2.5%) 30, 34 120.0 68O.O 800 (15.0%) (85.0%) 31, 35 120.0 S600 12O.O 800 (15.0%) (70.0%) (15.0%) 32 228.0 296.O 80.0 176.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 12O.O 3OO.O 12O.O 24O.O 2O.O 800 (15%) (37.5%) (15.0%) (30.0%) (2.5%) 37 12O.O 3OO.O 36O.O 2O.O 800 (15%) (37.5%) (45.0%) (2.5%) 38 176.O 624.O 800 (22.0%) (78.0% 39 228.0 572.0 800 (28.5%) (71.5%) 40 176.O SO4.O 12O.O 800 (22.0%) (63.0%) (15.0%) 41 176.O 12O.O SO4.O 800 (22.0%) (15%) (63.0%) 42 176.O 12O.O SO4.O 800 (22.0%) (15.0%) (63.0%) 43 12O.O 68O.O 800 (15%) (85%) 44 12O.O 340.O 32O.O 2O.O 800 (15%) (42.5%) (40.0%) (2.5%) 45 12O.O 68O.O 800 (15%) (85%) 46 12O.O 68O.O 800 (15%) (85%) 47 12O.O 66O.O 2O.O 800 (15%) (82.5%) (2.5%) 48 176.O 12O.O SO4.O 800 (22.0%) (15.0%) (63.0%) 49 12O.O 408.O 272.O 800 (15.0%) (51%) (34%) SO 12O.O 370.48 246.88 800 (15%) (46.31) (30.86%) S1 12O.O 14O.O S2O.O 2O.O 800 (15%) (17.5%) (65.0%) (2.5%) S2 18265 97.36 S2O.O 800 (22.83%) (12.17%) (65.0%) S3 18265 97.36 2O8.0 312.O 800 (22.83%) (12.17%) (26%) (39%) US 8,828,428 B1

TABLE 3-continued Composition (mg/capsule and wellht 96)" FI F. Cremophor Oleic Capmul Tween Precirol Gelucire Wt. No. TP Labrasol RH4O Acid MCM(L) 8O ATOS 39/01 (mg) S4 12O.O 2O4.O 476.0 800 (15%) (25.5%) (59.5%) 55 18265 185.21 432.15 800 (22.83%) (23.15%) (54.02%) 56 18265 185.21 81.28 800 (22.83%) (67.01%) (10.16%) 59 12O.O 32O.O 340.O 2O.O 800 (15%) (40%) (42.5%) (2.5%)

Formulation numbers 50, 51 and 54 are preferred embodi 15 palmitate and blends thereof may establish competition ments. As well, while a variety of solvents may be useful in between said ester and TP for endogenous esterase activity. the formulations presented in Table 3, preferred solvents may Indeed, it is believed that testosterone ester metabolism, gen have the following characteristics: C-C fatty acids and/or erally, may be retarded with the administration of an effective their glycerol-, propylene glycol-, polyethylene glycol, Sor amount of an ester of a medium or long chain fatty acid (e.g., bitan-mono-fcliesters alone and in mixtures. Preferred fatty esters of oleic acid, linoleic acid, linolenic acid, Stearic acid, acids and esters are Cs-Cs. Saturated and unsaturated. In myristic acid, lauric acid, palmitic acid, capric or decanoic addition, the solvents include, fatty acid esters with lower acid octanoic or caprylic acid, pelargonic acid, undecanoic alcohols, such as ethyl oleate, ethyl linoleate, isopropyl acid, tridecanoic acid, pentadecanoic acid, and the branched myristate, isopropylpalmitate, isopropyloleate and isopropy 25 chain, cyclic analogues of these acids). In this way, more TP llinoleate. may stave offhydrolysis in the gut and enter the blood stream. In other words, the fatty acid ester may competitively inhibit EXAMPLE esterases that would otherwise metabolize TP. Table 4 pro vides effective amounts of inhibitors of testosterone ester Formulations 50 and 54 were administered to 6 patients: 30 number 50 was administered once-daily (“OD) in the form metabolism. Examples of other esters or combinations of two capsules per dose (100 mg Tequivalents/capsule) and thereof include botanical extracts or benign esters used as number 54 was administered once- and twice-daily (“BID') food additives (e.g., propylparben, octylacetate, and ethylac in the form of three capsules per dose (66 mg Tequivalents/ etate). capsule). The mean steady-state profiles after 7 days of treat 35 Other components that can modulate TP absorption ment with one of the three, respective, regimens are shown in include “natural and synthetic inhibitors of 5C.-reductase, FIG. 11. The pharmacokinetic profile for formulation 54 BID which is present in enterocytes and catalyze the conversion of was relatively uniform over the entire 24hr period and had a T to DHT. Complete or partial inhibition of this conversion trough of the mean profile about 70% of the peak of the mean may both increase and Sustain increases serum levels of T profile. Additional data from formulation 54 include: 40 after oral dosing with TP while concomitantly reducing Average serum T increase from baseline of 275 ng/dL serum DHT levels. Borage oil, which contains a significant Mean serum T levels at lower end of normal range, i.e., amount of the 5C.-reductase inhibitor gamma-linoleic acid about 325 ng/dL. (GLA), is an example of a “natural modulator of TP metabo Relatively fast release (T. of about 1 hour) lism. Other than within borage oil, of course, GLA could be Estimated terminal half-life ofT at steady-state of approxi 45 directly added as a separate component of TP formulations mately 8-9 hours described herein. Many natural inhibitors of 5C.-reductase are Consistent dose-related elevation in serum T baseline lev known in the art (e.g., epigallocatechin gallate, a catechin els over the 7-day treatment period derived primarily from green tea and saw palmetto extract Average steady-state serum DHT level of 114 ng/dL (FIG. from berries of the repens species), all of which may 12) 50 be suitable in the present invention. Non-limiting examples of A simulation of the pharmacokinetic profile of formulation synthetic 5C.-reductase inhibitors suitable in the present 50 administered BID was performed and compared to the invention include and . observed profile for formulation 54 administered BID. The In addition to 5C.-reductase inhibitors, the present inven simulation predicts about a 384 ng/dL increase in Cover the tion contemplates the use of inhibitors of T metabolism via 24-hour period for formulation 50 over formulation 54 (FIG. 55 other mechanisms. One such point of inhibition may be the 13). cytochrome P450 isozyme CYP3A4 that is present in entero h other embodiments of the present invention, methods cytes and in liver cells and thus capable of metabolizing and compositions for modulating (i.e., Sustaining) the rate of testosterone. Accordingly, formulations of the present inven available serum testosterone by incorporating component(s) tion, in some embodiments, include peppermint oil, which is that may biochemically modulate (1) TP absorption, (2) TP 60 known to contain factors capable of inhibiting CYP3A4. Table 4 provides composition details of various TP formu metabolism to T, and/or (3) metabolism of T to DHT. For lations comprising ingredients to modulate TP absorption example, the inclusion of medium to long chain fatty acid (i.e., ascorby1-palmitate, borage oil and peppermint oil). esters can enhance TP absorption. Without being held to or FIGS. 14 and 15 show representative in vitro dissolution bound by theory, the present inventors believe that the use of 65 profiles for select TP formulations therein in either phosphate effective amounts fatty acid esters, particularly palmitate buffer (PBS) or fed-state simulated intestinal fluid (FeSSIF), esters such as ascorbyl-palmitate, retinyl-palmitate, Sorbitan respectively. US 8,828,428 B1 21 22 TABLE 4 Composition% w/w (mg "00" capsuleCapsule)' FI F. Ascorby|- Cremophor Cremophor Oleic Borage Peppermint Wt. No. TP Palmitate RH4O EL Acid Peceol Oil Oil (mg)?

62. 30.0 2.5 67.5 800 (240) (20) (540) 62A 15.O 2.5 82.5 800 (120) (20) (660) 63 3O.O S.O 6S.O 800 (240) (40) (520) 63 A 229 S.O 12.2 6O.O 800 (183) (40) (97) (480) 64 S.O 1S.O 7O.O 800 (120) (120) (560) 64A 15.O 1O.O 2SO SO.O 800 (120) (80) (200) (400) 6S 22.9 2SO S2O 800 (183) (200) (417) 66 S.O 42.5 42.5 800 (120) (340) (340) 67 S.O 3O.O 55.0 800 (120) (240) (440) 68 22.9 2O.O 45.0 12.O 800 (183) (160) (360) (96) 69 22.9 53.0 19.0 800 (183) (424) (152) 70 22.9 1O.O 2SO 22.1 1O.O 1O.O 800 (183) (80) (200) (177) (80) (80) 7 OB 22.9 2.5 2O.O 39.7 1O.O S.O 800 (183) (20) (160) (318) (80) (40) 71 S.O 1O.O 2SO 3O.O 1O.O 1O.O 800 (120) (80) (200) (240) (80) (80) 71A, 10.0 2.5 2O.O 52.5 1O.O S.O 800 (80) (20) (160) (420) (80) (40) 71B 15.O 2.5 2O.O 47.5 1O.O S.O 800 (120) (20) (160) (380) (80) (40) 72 S.O 6O.O 2SO 800 (120) (480) (200) 73 S.O 6O.O 2SO 800 (120) (480) (200) 'Milligram weights rounded to nearest whole number *::1 ng

In yet another embodiment of the present invention, drug Accordingly, pharmaceutical preparations of the instant delivery systems disclosed herein may also be suitable for 40 invention may be administered once-daily, twice-daily, or in ameliorating some of the side-effects of certain strategies for multiple doses per day, depending on, for example, patient male contraception. For example, progestin-based male con preference and convenience. traception Substantially Suppresses luteinizing hormone (LH) One way in which the formulations may be modified to and follicle-stimulating hormone (FSH), and thereby sup 45 affect these changes is to calibrate the ratio of lipophilic presses spermatogenesis, resulting in clinical azoospermia Surfactants. The magnitude and timing of the T, for (defined as less than about 1 million sperm/ml semen for 2 example, can be affected by not only the type of lipids used, consecutive months). However, administration of progestins but also the ratios thereof. For example, to obtain a relatively also has the undesirable side-effect of significantly reducing early T or fast release of the medicament from the deliv steady-state serum testosterone levels. 50 ery system, the concentration of the “controlled-release' In Such situations, for example, it may be preferable to lipophilic surfactant (e.g., Precirol) may be reduced relative provide preparations of progestin concomitantly with test to the concentration of the other lipophilic Solvents (e.g., osterone or a testosterone derivative (e.g., TP). More prefer Labrafil M1944CS). On the other had, to achieve a delayed ably, a pharmaceutical preparation according to the invention T, the percentage of “controlled-release' lipophilic Sur is provided, comprising progestin in an amount Sufficient to 55 factant in composition can be increased. FIGS.9 and 10 show substantially suppress LH and FSH production in combi in vitro dissolution curves of TP from three formulations, nation with testosterone. In some embodiments, the pharma respectively, in a phosphate buffered dissolution medium ceutical preparation is for once-daily, oral delivery. incorporating TritonX-100 as a Surfactant in accordance with Drug delivery systems, in one aspect of the present inven the present invention. tion, afford the flexibility to achieve desirable pharmacoki 60 Without being bound by or limited to theory, it is believed netic profiles. Specifically, the formulations can be tailored to that the inventive formulations described herein, in one deliver medicament in a relatively early peak serum concen aspect, enhance absorption of a medicament therein by the tration (T) or one that appears later. See FIGS. 1, 3, 5 and intestinal lymphatic system. In this way, drug delivery sys 7 versus FIGS. 2, 4, 6 and 8, respectively. Similarly, the tems of the present invention can provide extended release formulations may be tailored to have a relative steep or wide 65 formulations that can deliver testosterone into the serum over drop in drug serum concentration upon obtaining T. See several hours. The serum half-life of testosterone in men is FIGS. 1, 3, 5 and 7 versus FIGS. 2, 4, 6 and 8, respectively. considered to be in the range of 10 to 100 minutes, with the US 8,828,428 B1 23 24 upper range for testosterone administered in a form (i.e., TU) The invention claimed is: that favors lymphatic absorption. However, oral dosages of 1. An oral pharmaceutical composition comprising (1) a the present invention can be taken by a patient in need of testosterone ester chosen from ; test testosterone therapy once every about twelve hours to main osterone undecanoate; , and testoster tain desirable levels of serum testosterone. In a more pre one palmitate, (2) a lipophilic Surfactant chosen from mono ferred embodiment, oral dosages are taken by a patient in and/or di-glycerides of fatty acids, (3) Cremophor RH40 need of testosterone therapy once every about twenty four (polyoxyl 40 hydrogenated castor oil), and (4) a polyethylene hours. In general, “desirable' testosterone levels are those glycol with an average molecular weight of about 200 to levels found in a human Subject characterized as not having about 10,000 g/mol, wherein said composition is free of etha testosterone deficiency. 10 While the invention has been described in connection with nol. specific embodiments thereof, it will be understood that it is 2. The pharmaceutical composition of claim 1 wherein the capable of further modifications and this application is testosterone ester is testosterone undecanoate. intended to cover any variations, uses, or alterations of the 3. The composition as recited in claim 1 wherein said mono invention following. In general, the principles of the inven 15 and/or di-glycerides of fatty acids is chosen from Precirol tion and including Such departures from the present disclo ATO 5 (glyceryl palmitostearate) and Maisine (glyceryl Sure as come within known or customary practice within the mono-linoleate). art to which the invention pertains and as may be applied to 4. The composition as recited in claim 1, wherein said the essential features hereinbefore set forth and as follows in composition contains 10% to 20% w/w of testosterone ester. the scope of the appended claims. k k k k k