( 12 ) United States Patent ( 10 ) Patent No .: US 10,792,292 B2 Sharp Et Al

US010792292B2

( 12 ) United States Patent ( 10 ) Patent No .: US 10,792,292 B2 Sharp et al . ( 45 ) Date of Patent : Oct. 6 , 2020

( 54 ) ABIRATERONE PRODRUGS 9,353,145 B2 5/2016 Derrien et al . 9,359,395 B2 6/2016 Casebier 9,889,144 B2 2/2018 Murphy et al . ( 71 ) Applicant: PROPELLA THERAPEUTICS , INC . , 9,937,259 B2 4/2018 Sun Pittsboro , NC ( US ) 10,087,212 B2 10/2018 Xing et al. 10,292,990 B2 5/2019 Nemeth et al . ( 72 ) Inventors: Matthew J. Sharp , Apex, NC (US ); 2009/0124587 Al 5/2009 Auerbach et al . William R. Moore , Jr., Pittsboro , NC 2011/0129423 A1 6/2011 Frincke 2011/0312916 A1 12/2011 Casebier ( US ) 2014/0011992 Al 1/2014 Perez Encabo et al . 2015/0337003 A1 11/2015 Koziol et al . ( 73 ) Assignee : Propella Therapeutics , Inc. , Pittsboro , 2019/0040098 A1 2/2019 Wang et al . NC (US ) 2019/0151458 A1 5/2019 Ciufolini et al . 2019/0315797 Al 10/2019 Sun et al . ( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154 ( b ) by 0 days. WO WO - 2013158644 A2 10/2013 WO WO - 2013159225 A1 10/2013 ( 21 ) Appl . No .: 16 / 808,912 WO WO - 2014009434 A1 1/2014 WO WO2014111815 A2 * 7/2014 A61K 31/58 ( 22 ) Filed : Mar. 4 , 2020 WO WO - 2014145813 Al 9/2014 WO WO - 2015038649 Al 3/2015 ( 65 ) Prior Publication Data WO WO - 2015134464 A2 9/2015 WO WO - 2015143004 Al 9/2015 US 2020/0281945 A1 Sep. 10 , 2020 WO WO - 2016044701 A1 3/2016 WO WO - 2016050116 A1 4/2016 Related U.S. Application Data WO WO - 2016082792 Al 6/2016 ( 60 ) Provisional application No. 62 / 814,568 , filed on Mar. OTHER PUBLICATIONS 6 , 2019 , provisional application No. 62 / 849,259 , filed on May 17 , 2019 . Zytiga® ( abiraterone acetate) tablets Prescribing Information , the Food and Drug Administration , 2018 . ( 51 ) Int . Ci . Larsen , S. W. and Larsen , C. , “ Critical Factors Influencing the In A61K 31/58 ( 2006.01 ) Vivo Performance of Long - acting Lipophilic Solutions— Impact on A61K 9/00 In Vitro Release Method Design , ” AAPS J. , 11 ( 4 ) : 762-770 ( 2009 ) . ( 2006.01 ) Minto, C. F. , et al . , “ Pharmacokinetics and Pharmacodynamics of A61K 47744 ( 2017.01 ) Nandrolone Esters in Oil Vehicle : Effects of Ester , Injection Site and A61K 47/14 ( 2017.01 ) Injection Volume, " J Pharmacol Exp Ther . , 281 ( 1 ) : 93-102 ( 1997 ) . CO7D 213/02 ( 2006.01 ) Tanaka , T. , et al . , “ Intramuscular Absorption of Drugs from Oily ( 52 ) U.S. CI . Solutions in the Rat, ” Chem Pharm Bull . , 22 ( 6 ) : 1275-1284 ( 1974 ) . CPC A61K 31/58 ( 2013.01 ) ; A61K 9/0019 ( 2013.01 ) ; A61K 47/14 ( 2013.01 ) ; A61K 47/44 * cited by examiner ( 2013.01 ) ( 58 ) Field of Classification Search Primary Examiner Zinna Northington Davis None ( 74 ) Attorney, Agent, or Firm — Nixon & Vanderhye P.C. See application file for complete search history . ( 57 ) ABSTRACT Sustained - release abiraterone prodrug formulations, meth ( 56 ) References Cited ods , and kits for parenteral administration to a subject having a sex hormone -dependent benign or malignant dis U.S. PATENT DOCUMENTS order such as prostate cancer , a syndrome due to androgen 5,604,213 A 2/1997 Barrie et al . excess , and / or a syndrome due to glucocorticoid excess such 5,618,807 A 4/1997 Barrie et al . as hypercortisolemia . 8,338,588 B2 12/2012 Hunt 8,822,438 B2 9/2014 Auerbach et al. 30 Claims , 28 Drawing Sheets U.S. Patent Oct. 6 , 2020 Sheet 1 of 28 US 10,792,292 B2

FIG . 1

Mean Concentration ( ng/ mL )

hr)Time(

168 Suspension OilSolution TweenSuspensionbuffer0.1%, SuspensionTweenbuffer,0.1% PhosphateAbirateronein AbirateroneinCastorOil PhosphateAcetateinAbiraterone AbirateroneAcetateinCastor U.S. Patent Oct. 6 , 2020 Sheet 2 of 28 US 10,792,292 B2

FIG . 2 Mean Abiraterone Concentration ( ng /mL ) 1000

144 216 hr)Time( 288 360 432

BenzylBenzoate BenzylAlcohol IM-CastorOil IM-CastorOjiwith50% U.S. Patent Oct. 6 , 2020 Sheet 3 of 28 US 10,792,292 B2

FIG . 3

100000

10000 MeanConcentration(ng/mL) Abiraterone Acetate Abiraterone

Time (hr )

FIG . 4

1000

MeanConcentration(ng/mL) Abiraterone Acetate Abiraterone

0 6 . 8 Time ( Days) U.S. Patent Oct. 6 , 2020 Sheet 4 of 28 US 10,792,292 B2

FIG . 5

10000

MeanConcentration(ng/mL) Abiraterne Decanoate

N-- 6 Time ( h )

FIG . 6 .

MeanConcentration(ng/mL) Aviratcrone Propionate

Time ( h ) U.S. Patent Oct. 6 , 2020 Sheet 5 of 28 US 10,792,292 B2

FIG.7

MeanPlasmaConcentration(ng/mL)

Aviraterona Decanoate

24 32 56 64 . Time ( day )

FIG . 8

MeanPlasmaConcentration(ng/mL)

Abiraterone Decanoate

0,1 32 Time ( day ) U.S. Patent Oct. 6 , 2020 Sheet 6 of 28 US 10,792,292 B2

FIG . 9

MeanPlasmaConcentration(ng/mL)

Abiraterone Propionate

0 36 Time ( day )

FIG . 10

MeanPlasmaConcentration(ng/mL)

Abiraterone Propionate

12 24 36 Time ( day ) U.S. Patent Oct. 6 , 2020 Sheet 7 of 28 US 10,792,292 B2

FIG . 11A

Predicted Cmin AMMW

336 672 1008 1344 1680 2016 2352 2688 3024 3360 3696 4032 Time ( h )

FIG . 11B

30 Predicted Cinin

20 Concentration(ng/mL) 15MW 336 672 108 1344 1680 2016 2352 2688 3024 3360 3696 1032 Time ( h ) U.S. Patent Oct. 6 , 2020 Sheet 8 of 28 US 10,792,292 B2

FIG . 11C

80 Predicted Cinin 70 60 Concentration(ng/mL)

30 20 N 336 672 1008 1344 1680 2016 2352 2688 302 3360 3696 4032 Time ( h )

FIG . 11D -Predicted Cnin 120

100

Concentration(ng/mL) 60

336 672 1008 1344 1680 2016 2352 2688 3024 3360 3696 4032 Time ( h ) U.S. Patent Oct. 6 , 2020 Sheet 9 of 28 US 10,792,292 B2

FIG . 12A

. U.S. Patent Oct. 6 , 2020 Sheet 10 of 28 US 10,792,292 B2

FIG . 12B U.S. Patent Oct. 6 , 2020 Sheet 11 of 28 US 10,792,292 B2

FIG . 12C

60 U.S. Patent Oct. 6 , 2020 Sheet 12 of 28 US 10,792,292 B2

FIG . 13A Plot of AbiDec Solubility in Corn Oil vs % Benzyl Alcohol and % Benzyl Benzoate

Sample Solubility ( mg / ml )

Benzyl Benzoate [ % ] 5 Benzyl Alcohol [ % ] U.S. Patent Oct. 6 , 2020 Sheet 13 of 28 US 10,792,292 B2

FIG . 13B Benzyl Alcohol [ % ]

0 2 6 8 10 0

10 BenzylBenzoate[%] and[BenzylBenzoate]CornOilvs(AlcoholDecanoateSolubilityinContourPlotofAbiraterone

180210 150180 12090 [mg/mL] >210 150120 Solubility Sample 90 U.S. Patent Oct. 6 , 2020 Sheet 14 of 28 US 10,792,292 B2

FIG . 13C

w Peanut Olofon Cottonseed oil bores foresen Migivol 812 0.0800

0.0200

FIG . 13D

Miglyot 812

cambianocon VI

20 % BENZYI . ALCOHOL U.S. Patent Oct. 6 , 2020 Sheet 15 of 28 US 10,792,292 B2

FIG . 13E

Peanut ou www Cottonseed 01 Melyol 812 120.0

* U.S. Patent Oct. 6 , 2020 Sheet 16 of 28 US 10,792,292 B2

FIG . 14A

Mean Plasma Concentration ( ng /mL )

0.1 1 10 100 1000 10000

12 (4)au

24 7

OmAbirateroneDecanoate Abiraterone Analyte U.S. Patent Oct. 6 , 2020 Sheet 17 of 28 US 10,792,292 B2

FIG . 14B Mean Plasma Concentration ( ng / mL )

0.1. 10 100

21 AnalyteAAbiraterone

DoseDaysPost)Time-( 28 35 O DecanoateAbirateroneO

56 U.S. Patent Oct. 6 , 2020 Sheet 18 of 28 US 10,792,292 B2

FIG . 14C

Geometric Mean ( + SD ) Change from Baseline ( Ratio )

0.01 0.1 3 10 100 10001000

7 T

PostDoseDays-)Time( 28

Testosterone- Progesterone- OCortisol Steroid U.S. Patent Oct. 6 , 2020 Sheet 19 of 28 US 10,792,292 B2

FIG . 14D

Cholesterol

CYPIAL Androgens CYP17 CYP17 176 - HSDI Pregnenolone come 17a -Hydroxy wwwwwww you Dehydroepiandrosterone 5 - Androstenediol 17a - hydroxylase pregnenolone C17,20 - lyase 17B - HSD2

3B -HSD 3B -HSD 3B - HSD 3B -HSD

CYP17 CYP17 17B - HSO3 / 5 Progesterone mo 170x - l- lydroxy Xum Androstenedione Testosterone 17a - hydroxylase progesterone C17,20 - yase 17B -HSD2

CYP21 CYP21 Sa - Reductase 50 - Reductase CYPI1B1 / 2 17B -HSD3 /5 Corticosterone 11 - Deoxycortisol 50 - Androstanedione Dihydrotestosterone 17B -HSD2

CYPTIB2 CYPIBI Estrogens 17B - HSDI Aldosterone Cortisol Estrone Estradiol CYPI9A 17B -HSD2 CYPI9AL Mineralocorticoids Glucocorticoids U.S. Patent Oct. 6 , 2020 Sheet 20 of 28 US 10,792,292 B2

FIG . 14E

Mean Plasma Concentration ( ng / mL )

0:01 0.1 10 100

21. Analyte 28 AAbiraterone Dose)DaysPost-Time( 35 42 DecanoateAbirateroneO 49

:56

70 U.S. Patent Oct. 6 , 2020 Sheet 21 of 28 US 10,792,292 B2

FIG . 14F

S UME DAYS ! FIG . 15A 10000

1000

MeanPlasmaConcentration(ng/mL) 100 Analyte A Abiraterone 10 o Abiraterone Decanoate

0 4 . 12 16 20 24 Time (h ) U.S. Patent Oct. 6 , 2020 Sheet 22 of 28 US 10,792,292 B2

FIG . 15B Mean Plasma Concentration ( ng / mL ) 0.01 10 100

14 A Analyte 21 AbirateroneA Dose)PostDays-Time( 28 35 DecanoateAbirateroneo

56 U.S. Patent Oct. 6 , 2020 Sheet 23 of 28 US 10,792,292 B2

FIG . 15C Mean Plasma Concentration ( ng / mL )

0.01 0.1 10 100

14.

Dose)Post-DaysTime( 35 Analyte?AbirateroneOAbirateroneDecanoate

70 U.S. Patent Oct. 6 , 2020 Sheet 24 of 28 US 10,792,292 B2

FIG . 16A

Orats Odogs omonkeys Apredicted Man

y = 13.997X0.8097 100

SSA7)(

1 100 Body weight ( kg ) U.S. Patent Oct. 6 , 2020 Sheet 25 of 28 US 10,792,292 B2

FIG . 16B

0.018 0.016 0.014 0.012 Concentration(ng/mL) 0.01 0.008 0.006 0.004 0.002

0 . 0 48 96 192 240 288 336 384 432 480 528 576 624 672 Time ( h )

FIG . 16C

336 672 1008 1344 1680 2016 2352 2688 3024 3360 3696 4032 IMWTime ( h ) U.S. Patent Oct. 6 , 2020 Sheet 26 of 28 US 10,792,292 B2

FIG . 16D

Concentration(ng/mL) 20

10 5 M. 336 672 1008 1344 1680 2016 2352 2688 3024 3360 3696 4032 M, Time ( h ) U.S. Patent Oct. 6 , 2020 Sheet 27 of 28 US 10,792,292 B2

FIG . 17A

MeanConcentration(ng/mL) Abiraterone Isocaproate

12 20 24 Time (h )

FIG . 17B

MeanPlasmaConcentration(ng/mL)

Abiraterie Isocaproate

0.1 21 28 35 Time (day ) U.S. Patent Oct. 6 , 2020 Sheet 28 of 28 US 10,792,292 B2

FIG . 17C

MeanPlasmaConcentration(ng/mL)

Abiraterone Decanoate

14 28 12 Time (day )

FIG . 17D

1000

MeanPlasmaConcentration(ng/mL) Isacaproule Decanoate

14 28 35 Time ( day ) US 10,792,292 B2 1 2 ABIRATERONE PRODRUGS Indeed , Zytiga tablets ( 250 mg ) are approved in the United States in combination with prednisone for the treatment of This application claims the benefit of U.S. Provisional patients with metastatic castration resistant prostate cancer Application Nos . 62 / 814,568 , filed Mar. 6 , 2019 , and and patients with metastatic castration - sensitive prostate 62 / 849,259 , filed May 17 , 2019 , the content of each of which 5 cancer. The prescribing information provided with Zytigar is incorporated herein by reference in its entirety . recommends oral administration of 1,000 mg ( 4x250 mg The present disclosure relates generally to novel prodrugs tablets ) once daily in combination with prednisone ( 5 mg ) of abiraterone and long -acting , depot- based parenteral for administered orally twice daily for castration resistant pros mulations of abiraterone prodrugs. The disclosure is subject tate cancer patients or once daily for castration sensitive to a wide range of applications , such as for intramuscular 10 prostate cancer patients. In Europe, the use of Zytiga® is ( IM ) injection to a patient suffering from an androgen or approved in combination with either prednisone or predni estrogen hormone -dependent benign or malignant disorder , solone . including various cancers ( such as prostate cancer , bladder Because the administration of abiraterone acetate with cancer, hepatocellular carcinoma, lung cancer , breast cancer , food increases the absorption of abiraterone acetate ( and, and ovarian cancer, etc. ), and for the treatment of non- 15 therefore , has the potential to result in increased and highly oncologic syndromes due to the overproduction of andro variable exposures , which can potentially cause various side gens ( including both classical and nonclassical congenital effects including cardiovascular side effects and / or hepato adrenal hyperplasia, endometriosis, polycystic ovary syn toxicity etc. ) , the prodrug should be consumed on an empty drome precocious puberty, hirsutism , etc. ) or due to the stomach at least one hour before , or two hours after, a meal . overproduction of glucocorticoids, typically cortisol in con- 20 Indeed , the prescribing information for Zytiga® states it ditions such as Cushing's syndrome or Cushing's disease . must be taken on an empty stomach , and no food should be consumed for at least two hours before oral dosing and at BACKGROUND least one hour after oral dosing . The prescribing information explains that for a daily oral Abiraterone ( (3B ) -17- (pyridin - 3 - yl) androsta - 5 , 16 - dien- 25 dose of 1,000 mg of Zytiga® in patients with metastatic 3 - ol ; CAS # : 154229-19-3 ) ; Formula : C24Hz , NO ; Mol . castration - resistant prostate cancer , abiraterone's steady Weight: 349.5 g /mol ) is an inhibitor of CYP17A1 (which is state Cmar values were 226 + 178 ng /mL ( mean + SD ) and its a member of the cytochrome P450 superfamily of enzymes area under the curve ( AUC ) values were 1173 690 ng.hr/ that catalyze the synthesis of cholesterol, steroids and other mL (mean : SD ). A single - dose ( 1,000 mg ) cross - over study lipids and are involved in drug metabolism ) . CYP17A1 has 30 of Zytiga® in healthy subjects found that systemic exposure both 17a -hydroxylase activity and 17,20 - lyase activity . Abi of abiraterone was increased when Zytiga® was adminis raterone potently and selectively inhibits both CYP17A1 tered with food . Specifically, abiraterone's Cmax and AUC 17a -hydroxylase and 17,20 - lyase enzyme activities . The values were approximately 7- and 5 - fold higher, respec 17a -hydroxylase activity of CYP17A1 is required for the tively , when Zytiga® was administered with a low - fat meal generation of glucocorticoids such as cortisol . However, 35 ( 7 % fat , 300 calories) and approximately 17- and 10 - fold both the hydroxylase and 17,20 - lyase activities of CYP17A1 higher, respectively, when Zytiga was administered with a are required for the production of androgenic ( e.g. , andros high - fat meal ( 57 % fat, 825 calories ). tenedione , testosterone , and dihydrotestosterone) and estro The currently approved solid dosage oral form of the genic ( estrone , estradiol. estratriol) steroids through the prodrug abiraterone acetate has several disadvantages. For conversion of 17a -hydroxypregnenolone to the sex steroid 40 example, it has very low bioavailability that necessitates a precursor, dehydroepiandrosterone, see FIG . 14D . Thus , large daily pill burden for patients ( 4x250 mg tablets once abiraterone interferes with the synthesis of androgens and daily ) . In addition , it causes highly variable blood levels in estrogens in the gonads ( primarily in the testes and overies) patients due to the combination of low bioavailability and a and extra - gonadally ( e.g. , in the adrenals and in the tumors large food effect. Further, as abiraterone is rapidly cleared , themselves ). 45 this approved dosing regimen results in a daily Cmin of Though abiraterone itself is poorly absorbed , it can be abiraterone , which is believed to be associated with a loss of administered orally as an abiraterone acetate prodrug. Abi therapeutic effect in metastatic castration resistant prostate raterone acetate is also poorly absorbed , but can be con cancer patients. verted to abiraterone in the gut, which is poorly absorbed Non - oral modes of administration ( for example , parent into the bloodstream following the cleavage of the acetate 50 eral routes ) have been explored for other classes of drugs. prodrug. Abiraterone acetate ( (3B ) -17-( 3 - Pyridyl) androsta However, to date , there are no sustained - release injectable 5 , acetate ; CAS # 154229-18-2 ) is approved in the United prodrug formulations of abiraterone. States for treatment of castration resistant or castration sensitive prostate cancer under the brand name Zytiga® . SUMMARY Abiraterone acetate is now also available globally . 55 It is known that orally - administered abiraterone acetate is In various embodiments, the present disclosure provides not absorbed by the gastrointestinal tract ( and is not detected novel abiraterone prodrugs, long - acting abiraterone prodrug in blood plasma ) . Instead , it has been shown that abiraterone formulations, and methods of using the same , for example , acetate is hydrolyzed to abiraterone in the intraluminal in treating a subject having a sex hormone -dependent benign environment resulting in generation of abiraterone super- 60 or malignant disorder and / or a syndrome due to androgen saturation , which is responsible for creating the strong and / or glucocorticoid excess . Typically, the novel abirater driving force for abiraterone absorption ( Stappaerts et al . , one prodrugs herein can be a fatty acid ester of abiraterone, Eur. J. Pharmaceutics Biopharmaceutics 90 : 1 , 2015 ) . which upon cleavage, releases abiraterone and a safe and Because abiraterone blocks the normal physiologic pro degradable fatty acid component. As detailed herein , com duction of steroids by the adrenal glands , its prodrug for- 65 pared to oral abiraterone acetate formulation , the novel mulation is commonly prescribed with administration of a abiraterone prodrugs and formulations disclosed herein are low dose of a steroid to prevent adrenal insufficiency. a breakthrough in that they provide increased bioavailability, US 10,792,292 B2 3 4 elimination of the food effect, reduced pill burden , less frequent dosing frequency , and sustained effective blood Formula II plasma levels of abiraterone, e.g. , continuous plasma expo sures above daily Cmin levels observed for oral administra tion of abiraterone acetate , for example, for at least one 5 week , typically, for at least two weeks following adminis tration of the abiraterone prodrug formulation . Further, pharmacokinetics and pharmacodynamics studies of repre T sentative abiraterone prodrugs herein , such as abiraterone decanoate or abiraterone isocaproate, demonstrate that the 10 novel abiraterone prodrugs and formulations disclosed herein are suitable for dosing once a week , once a month , or R2 even less frequently, for treating a subject having a sex hormone - dependent benign or malignant disorder, a syn- 15 wherein R2 is defined herein . In some embodiments, the drome due to androgen excess and / or a syndrome due to abiraterone prodrug formulation can be formulated for intra glucocorticoid excess described herein . This feature alone muscular injection , intradermal injection , or subcutaneous represents a significant improvement over the currently injection . In some embodiments, the compound of Formula marketed Zytiga tablets , which require a large daily pill II or pharmaceutically acceptable salt thereof can be present burden for patients ( 4x250 mg tablets once daily ) . 20 in the formulation at a concentration of about 25 mg /ml to Some embodiments of the present disclosure are directed about 500 mg/ ml . to novel abiraterone prodrugs. In some embodiments, the Typically, upon administration of a formulation ( e.g. , the abiraterone prodrug can be a compound of Formula I , or a abiraterone prodrug formulation herein ), a therapeutic blood pharmaceutically acceptable salt thereof: plasma concentration of abiraterone is achieved and persists 25 for at least one week , e.g. , at least two weeks and up to four or more weeks . In one aspect , the therapeutic blood plasma concentration of abiraterone is at least 1 ng /ml , e.g. , at least 1 ng /ml , at least 2 ng /ml , at least 4 ng /ml , or at least 8 ng /ml , following parenteral administration of the prodrug formu Formula I 30 lation . In some embodiments , the therapeutic blood plasma concentration of abiraterone can also be about 0.5 ng /ml or higher. Parenteral administration can be via IM injection, intradermal injection , or subcutaneous injection . In one aspect , the formulation is suitable for treatment of sex 35 hormone -dependent benign or malignant disorders such as androgen - dependent disorders and estrogen -dependent dis orders, such as androgen - dependent or estrogen -dependent cancers . The sex hormone -dependent benign or malignant disorders can include prostate cancer and breast cancer . R ! 40 Prostate cancer can include castration resistant prostate cancer and castration sensitive prostate cancer . In some du embodiments , the sex hormone - dependent benign or malig wherein Rl is defined herein . nant disorders can include various cancers such as ovarian cancer , bladder cancer , hepatocellular carcinoma, lung can In one representative embodiment, an abiraterone prodrug 45 cer, etc. Inhibition of CYP17A1 is expected to reduce formulation is provided for parenteral administration to a androgen and glucocorticoid ( e.g. , cortisole ) overproduc subject having a sex hormone -dependent benign or malig tion . The abiraterone prodrug formulation herein is not nant disorder, a syndrome due to androgen excess , and / or a limited to the treatment of oncologic conditions described syndrome due to glucocorticoid ( e.g. , cortisol) excess . In herein , but can also be used for the treatment of non one aspect , the formulation includes a lipophilic - ester form 50 oncologic syndromes due to androgen and glucocorticoid ( e.g. , cortisole ) excess . In one aspect , the formulation is of abiraterone and one or more pharmaceutically acceptable suitable for treatment of non - oncologic syndromes due to carriers, diluents , or excipients ( such that, for example, the androgen excess , such as endometriosis, polycystic ovary prodrug formulation is present as a solution or suspension in syndrome, congenital adrenal hyperplasia ( e.g. , classical or a pharmaceutically acceptable oil , such as an oil of vegetable 55 nonclassical congenital adrenal hyperplasia ), precocious origin or a synthetic oil including synthetic mono- or di puberty, hirsutism , etc. , and / or syndromes due to glucocor glycerides of fatty acid ; for example, the prodrug formula ticoid ( e.g. , cortisole ) excess such as Cushing's syndrome or tion can be present as a solution or suspension in vegetable Cushing's disease . oil and other co - solvents and excipients ). In certain repre The parenteral formulations fulfill a long - felt and unmet sentative embodiments, the lipophilic - ester form of abirater- 60 need by providing an alternative to oral formulations that suffer from ( 1 ) low bioavailability, ( 2 ) interactions with one can be an acetate , propionate , butanoate , valerate, ingested food , ( 3 ) delivery of highly variable blood levels of caproate , enanthate, cypionate , isocaproate , buciclate, parent drug with the possibility of reduced efficacy and cyclohexanecarboxylate , phenyl propionate , decanoate or increased side effects, ( 4 ) requirement of daily dosing and undecanoate . In some embodiments, the abiraterone prodrug 65 high pill burden , and ( 5 ) poor patient compliance due to formulation can include a compound of Formula II , or a required abstinence from food within hours of administra pharmaceutically acceptable salt thereof: tion , high pill burden , and the need for complementary daily US 10,792,292 B2 5 6 administration of prednisone or prednisolone with a con cyclohexanecarboxylate, phenyl propionate , decanoate or flicting dosing schedule as it is to be taken with food . undecanoate . Upon administration of a formulation to a One object of the present disclosure is to provide a subject in need thereof, a therapeutic blood plasma concen method for inhibiting CYP17A1 activity such as inhibiting tration of abiraterone is achieved and persists for at least one 17a - hydroxylase activity and 17,20 - lyase activity, by par- 5 week , e.g. , at least two weeks and up to four or more weeks . enterally administering to a subject in need thereof an In one aspect , the therapeutic blood plasma concentration of effective dose of at least one abiraterone prodrug formula abiraterone is at least 1 ng /ml , e.g. , at least 1 ng/ ml , at least tion . In some embodiments, the subject suffers from a sex 2 ng /ml , at least 4 ng /ml , or at least 8 ng/ ml , following hormone - dependent benign or malignant disorder, a syn parenteral administration of the prodrug formulation . In drome due to androgen excess , and /or a syndrome due to 10 some embodiments, the therapeutic blood plasma concen glucocorticoid excess such as hypercortisolemia as tration of abiraterone can also be about 0.5 ng /ml or higher. described herein . Parenteral administration can be via IM injection , intrader One object of the present disclosure is to provide a mal injection , or subcutaneous injection . In certain embodi method for reducing the level of glucocorticoids ( e.g. , ments, the method can include once -monthly administration cortisol) by parenterally administering to a subject in need 15 of at least one abiraterone prodrug formulation . In one thereof an effective dose of at least one abiraterone prodrug aspect , at least one abiraterone prodrug formulation can be formulation . In some embodiments , the subject suffers from administered in a divided dose . In another representative a syndrome due to glucocorticoid excess , such as due to embodiment, at least one abiraterone prodrug formulation hypercortisolemia as described herein . In some embodi can be administered simultaneously with one or more dif ments, the subject suffers from Cushing's syndrome disor- 20 ferent prodrug formulations and / or at least one other drug or ders or Cushing's disease . agent ( for example , another cancer chemotherapeutic drug, One object of the present disclosure is to provide a hormone replacement drug, or hormone ablation drug ). In method for reducing the level of androgens ( e.g. , testoster certain aspects , at least one abiraterone prodrug formulation one and / or dihydrotestosterone) and / or estrogens by paren can be administered before at least one other drug or agent. terally administering to a subject in need thereof an effective 25 Alternatively, at least one abiraterone prodrug formulation dose of at least one abiraterone prodrug formulation . In can be administered after at least one other drug or agent. In some embodiments , the subject suffers from a syndrome due other representative embodiments, more than one adminis to androgen excess , such as classical or nonclassical con tration of one or more formulations can be performed over genital adrenal hyperplasia , endometriosis, polycystic ovary the course of several days, weeks , months , or years to syndrome precocious puberty, hirsutism , etc. In some 30 provide initial and continual treatment of a sex hormone embodiments , the subject suffers from an androgen and / or dependent benign or malignant disorder ( such as prostate estrogen associated cancer, such as prostate cancer or breast cancer ), a syndrome due to androgen excess , and / or a cancer . syndrome due to glucocorticoid excess such as hypercorti Another object is to provide a method for treating a sex solemia . In other representative embodiments , at least one hormone -dependent benign or malignant disorder, a syn- 35 abiraterone prodrug formulation can contain at least two drome due to androgen excess , and / or a syndrome due to different lipophilic - ester forms of abiraterone and the for glucocorticoid excess such as hypercortisolemia , by paren mulation can be administered simultaneously with one or terally administering to a subject in need of such treatment more different prodrug formulations and / or at least one other an effective dose of at least one abiraterone prodrug formu drug or agent ( for example, another cancer chemotherapeu lation . In one representative embodiment, the method is for 40 tic drug, hormone replacement drug, or hormone ablation treating a sex hormone - dependent benign or malignant dis drug ). In certain aspects , at least one abiraterone prodrug order, which is an androgen - dependent disorder or an estro formulation can contain at least two different lipophilic - ester gen -dependent disorder, such as an androgen - dependent forms of abiraterone and the formulation can be adminis cancer or an estrogen - dependent cancer. The sex hormone tered before at least one other drug or agent. Alternatively, dependent benign or malignant disorder can include prostate 45 at least one abiraterone prodrug formulation can contain at cancer or breast cancer. Prostate cancer can include castra least two different lipophilic - ester forms of abiraterone and tion resistant prostate cancer and castration sensitive pros the formulation can be administered after at least one other tate cancer . In some embodiments, the sex hormone -depen drug or agent. In other representative embodiments, more dent benign or malignant disorder can also include ovarian than one administration of one or more formulations con cancer, bladder cancer , hepatocellular carcinoma, lung can- 50 taining at least two different lipophilic - ester forms of abi cer , etc. In one representative embodiment, the method is for raterone can be performed over the course of several days , treating a non - oncologic syndrome due to androgen excess , weeks, months , or years to provide initial and continual such as endometriosis, polycystic ovary syndrome, congeni treatment of a sex hormone -dependent benign or malignant tal adrenal hyperplasia ( e.g. , classical or nonclassical con disorder ( such as prostate cancer ), a syndrome due to genital adrenal hyperplasia ), precocious puberty , hirsutism , 55 androgen excess , and / or a syndrome due to glucocorticoid etc. , and / or a syndrome due to glucocorticoid ( e.g. , corti excess such as hypercortisolemia . The lipophilic -ester forms sole ) excess such as Cushing's syndrome or Cushing's of abiraterone can be chosen from among , for example, an disease . acetate , propionate, butanoate , valerate , caproate, enanthate , In some embodiments , the abiraterone prodrug formula cypionate, isocaproate, buciclate , cyclohexanecarboxylate , tion can include at least one compound of Formula I or II , 60 phenyl propionate, decanoate or undecanoate . or a pharmaceutically acceptable salt thereof . In one aspect , Another object is to provide a kit for treating a subject the formulation includes a lipophilic - ester form of abirater with a sex hormone - dependent benign or malignant disorder one and one or more pharmaceutically acceptable carriers, ( such as prostate cancer ), a syndrome due to androgen diluents, or excipients. In certain representative embodi excess , and / or a syndrome due to glucocorticoid excess such ments, the lipophilic - ester form of abiraterone can be , for 65 as hypercortisolemia . In a representative embodiment, the example , an acetate , propionate , butanoate , valerate , kit includes a container such as a vial , an ampule , or a caproate, enanthate, cypionate , isocaproate, buciclate , preloaded syringe , containing one or more formulations . In US 10,792,292 B2 7 8 another representative embodiment, the kit includes a con the formula — ( CH2) n CH3, wherein n is an integer tainer such as a vial , an ampule , or a preloaded syringe, selected from 6 , 7 , 8 , 9 , 10 , 11 , or 12 , containing one or more formulations and at least one other [ 4 ] the compound of [ 1 ] , or a pharmaceutically acceptable drug or agent capable of enhancing the efficacy of the salt thereof, wherein Rl is an alkyl having the formula formulation ( s ) or decreasing an undesirable side effect( s ) of 5 (CH2 ) , CH , or the formulation ( s ). In other representative embodiments, the kit includes a container such as a vial , an ampule , or a preloaded syringe containing one or more formulations and at least one other drug or agent capable of enhancing the efficacy of the formulation ( s ) or decreasing an undesirable 10 side effect (s ) of the formulations. It is understood that the formulations can contain one lipophilic - ester form of abi raterone or two or more different lipophilic - ester forms of abiraterone. A person skilled in the art would understand that [ 5 ] a pharmaceutical composition comprising the com kits and packages can be prepared including one , all , or any 15 pound of any one of [ 1 ] - [ 4 ] , or a pharmaceutically combination of a formulation , diluent, buffer, adjuvant, acceptable salt thereof, and a pharmaceutically accept pharmaceutically -acceptable carrier, and at least one other able carrier; drug or agent capable of enhancing the efficacy of a formu [ 6 ] a pharmaceutical composition comprising abiraterone lation or decreasing an undesirable side effect of a formu decanoate having the formula of: lation . 20 Another object is to provide a method for preparing an abiraterone decanoate formulation suitable for parenteral administration to a subject having a sex hormone - dependent benign or malignant disorder, a syndrome due to androgen excess , and / or a syndrome due to glucocorticoid excess such 25 as hypercortisolemia . These and other objects can be achieved in certain embodiments. In some embodiments, the disclosure provides : [ 1 ] a compound of Formula I , or a pharmaceutically 30 acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, Formula I [ 7 ] the pharmaceutical composition of [ 5 ] or [ 6 ] , formu 35 lated for intramuscular injection , intradermal injection , or subcutaneous injection, [ 8 ] the pharmaceutical composition of any one of [ 5 ] - [ 7 ] , wherein the pharmaceutically acceptable carrier com prises a pharmaceutically acceptable oil and optionally 40 a further pharmaceutically acceptable solvent, H [ 9 ] the pharmaceutical composition of [ 8 ] , wherein the pharmaceutically acceptable oil comprises a triglycer ide ( e.g. , long and / or medium chain triglycerides ), and the further pharmaceutically acceptable solvent, if pres R1 45 ent, comprises an alcohol, ester, and / or acid solvent, [ 10 ] the pharmaceutical composition of any one of [ 8 ] - [ 9 ] , wherein R is R10,0 - R10 , or NHR 10! wherein the pharmaceutically acceptable oil is selected wherein R10 is selected from : from vegetable oil , castor oil , corn oil , sesame oil , a C7-30 alkyl; a C7-30 alkenyl; a C7-30 alkynyl; an alkyl 50 cottonseed oil , peanut oil ( arachis oil ) , poppy seed oil , substituted with a cycloalkyl, which has a total tea seed oil , and soybean oil , and the further pharma number of carbons between 5 and 16 ; an alkyl ceutically acceptable solvent, if present, comprises substituted with a phenyl, which has a total number benzyl alcohol , benzyl benzoate, or a combination of carbons between 7 and 16 ; a cycloalkyl optionally thereof, substituted with one or more alkyl, which has a total 55 [ 11 ] the pharmaceutical composition of any one of [6 ] number of carbons between 5 and 16 ; and [ 10 ] , which comprises the abiraterone decanoate or pharmaceutically acceptable salt thereof in an amount sufficient to provide a therapeutically effective blood plasma concentration of abiraterone , or a blood plasma 60 concentration of abiraterone of about 1 ng /ml or higher, for a period of at least two weeks ( e.g. , at least three weeks , at least four weeks , and up to six or eight weeks or more ), after a single administration to a subject [ 2 ] the compound of [ 1 ] , or a pharmaceutically acceptable having one or more disorders selected from a sex salt thereof, wherein Rl is a C7-16 alkyl, 65 hormone - dependent benign or malignant disorder, a [ 3 ] the compound of [ 1 ] or [ 2 ] , or a pharmaceutically syndrome due to androgen excess , and a syndrome to acceptable salt thereof, wherein R ' is an alkyl having glucocorticoid excess such as hypercortisolemia , US 10,792,292 B2 9 10 [ 12 ] a method of treating one or more disorders selected a pharmaceutically acceptable oil , and a pharmaceutically from a sex hormone -dependent benign or malignant acceptable solvent, wherein the abiraterone decanoate is in disorder, a syndrome due to androgen excess , and a its basic form , which is present at a concentration of about syndrome to glucocorticoid excess such as hypercorti 25 mg /ml to about 500 mg/ ml , wherein the pharmaceutical solemia , comprising administering to a subject in need 5 composition, e.g. , unit dosage form , is formulated for intra thereof a therapeutically effective amount of the phar muscular injection , intradermal injection , or subcutaneous maceutical composition of any one of [ 5 ] - [ 11 ] , injection , wherein the pharmaceutical composition , e.g. , unit [ 13 ] the method of [ 12 ] , wherein the administering is an dosage form , comprises the abiraterone decanoate in an intramuscular injection , intradermal injection , or sub amount of about 50 mg to about 2,000 mg , 10 [ 24 ] the pharmaceutical composition , e.g. , unit dosage cutaneous injection , form , of [ 23 ] , wherein the pharmaceutically acceptable [ 14 ] the method of any one of [ 12 ] - [ 13 ] , wherein the oil comprises a triglyceride, and the pharmaceutically pharmaceutical composition is administered to the sub acceptable solvent comprises an alcohol , ester, and / or ject with or without food , acid solvent, [ 15 ] the method of any one of [ 12 ] - [ 14 ] , wherein the one 15 [ 25 ] the pharmaceutical composition , e.g. , unit dosage or more disorders are selected from prostate cancer, form , of [ 23 ] or [ 24 ] , wherein pharmaceutically accept breast cancer , ovarian cancer , bladder cancer , hepato able oil comprises a vegetable oil , castor oil , corn oil , cellular carcinoma, lung cancer , endometriosis , poly sesame oil , cottonseed oil , peanut oil , poppy seed oil , cystic ovary syndrome, Cushing's syndrome, Cush tea seed oil , or soybean oil , the pharmaceutically ing's disease, classical congenital adrenal hyperplasia , 20 acceptable solvent comprises benzyl alcohol and /or nonclassical congenital adrenal hyperplasia , precocious benzyl benzoate , and wherein the abiraterone decano puberty, hirsutism , and combinations thereof. ate is present at a concentration of about 50 mg /mL to [ 16 ] the method of any one of [ 12 ] - [ 14 ] , wherein the one about 300 mg/ mL , such as about 100 mg /mL to about or more disorders is a sex hormone -dependent benign 300 mg/ mL , or malignant disorder selected from castration resistant 25 [ 26 ] a method of treating prostate cancer , comprising prostate cancer and castration sensitive prostate cancer , administering to a subject in need thereof the pharma [ 17 ] the method of any one of [ 12 ] - [ 14 ] , wherein the one ceutical composition , e.g. , unit dosage form , of any one or more disorders is a sex hormone - dependent benign of [ 23 ] - [ 25 ] via intramuscular injection , intradermal or malignant disorder selected from metastatic castra injection , or subcutaneous injection , once a month or tion resistant prostate cancer and metastatic castration 30 once in more than a month , e.g. , the dosing frequency sensitive prostate cancer , ranges from once a month to once every few months , [ 18 ] the method of any one of [ 12 ] - [ 17 ] , wherein the such as from once a month to once every two months, subject is treated with a gonadotropin - releasing hor or from once a month to once every three months, etc., mone analog and / or bilateral orchiectomy, [ 27 ] the method of [ 26 ] , wherein the pharmaceutical [ 19 ] the method of any one of [ 12 ] - [ 18 ] , further compris- 35 composition , e.g. , unit dosage form , is administered via ing administering to the subject a corticosteroid , intramuscular injection , [ 20 ] the method of any one of [ 12 ] - [ 19 ] , further compris [ 28 ] a method for preparing an abiraterone decanoate ing administering to the subject prednisone, predniso formulation , e.g. , suitable for parenteral administration lone , and / or methylprednisolone , to a subject having a sex hormone - dependent benign or [ 21 ] the method of any one of [ 12 ] - [ 20 ] , wherein the 40 malignant disorder, a syndrome due to androgen pharmaceutical composition is administered to the sub excess , and / or a syndrome due to glucocorticoid excess ject once a week or once in more than a week , e.g. , the such as hypercortisolemia , comprising: dosing frequency ranges from once a week to once a ) mixing abiraterone decanoate , which has the formula every few months, such as from once a week to once of: every eight weeks , or once a week to once every three 45 months, [ 22 ] the method of any one of [ 12 ] - [ 21 ] , wherein the administering provides ( a ) a blood plasma concentra tion of abiraterone above 1.0 ng /ml for a period of at least two weeks; ( b ) a single dose or steady state Cmax 50 of abiraterone between about 10 ng /ml and about 400 ng /ml ; or ( c ) both ( a ) and ( b ) , [ 23 ] a pharmaceutical composition , e.g. , a unit dosage form , comprising a therapeutically effective amount of ? abiraterone decanoate having the formula of: 55 in a pharmaceutically acceptable carrier to form a mixture; and optionally b ) sterilizing the mixture formed in a ) , 60 [ 29 ] the method of [ 28 ] , wherein the mixing comprises mixing a crystalline form of abiraterone decanoate in H the pharmaceutically acceptable carrier, wherein the crystalline form is characterized by an X -Ray Power Diffraction (XRPD ) spectrum having one or more ( e.g. , 65 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , or 9 ) of the following peaks : 4.6 , 6.9 , 8.7 , 17.5 , 18.3 , 18.6 , 19.1 , 19.6 , and 20.8 , degrees caso 2 theta , 10.2 ° ; a Differential Scanning Calorimetry US 10,792,292 B2 11 12 ( DSC ) pattern having an endothermic peak with an administration of various abiraterone or abiraterone acetate onset temperature at about 69.0 ° C .; or a combination formulations. FIG . 1 shows the profile obtained with abi thereof, raterone acetate solution in castor oil ( 70 mg/ ml ) ; the profile [ 30 ] the method of [ 28 ] or [ 29 ] , wherein the pharmaceu obtained with abiraterone acetate suspension , sodium phos tically acceptable carrier comprises a pharmaceutically 5 phate buffer, 0.1 % Tween ( 70 mg / ml ) ; the profile obtained acceptable oil and a pharmaceutically acceptable sol with abiraterone suspension in castor oil ( 62.5 mg /ml ) and vent, wherein the pharmaceutically acceptable oil com the profile obtained with abiraterone suspension , sodium prises a vegetable oil , castor oil , corn oil , sesame oil , phosphate buffer, 0.1 % Tween ( 62.5 mg /ml ) . cottonseed oil , peanut oil , poppy seed oil , tea seed oil , FIG . 2 shows the mean blood plasma concentrations of or soybean oil , the pharmaceutically acceptable solvent 10 abiraterone ( ng /ml ) in dogs at different times ( hours ) after comprises benzyl alcohol or benzyl benzoate, and IM or intravenous ( IV ) administration of various abiraterone wherein the abiraterone decanoate is present at a con acetate formulations. FIG . 2 shows the profile obtained with centration of about 50 mg /mL to about 300 mg/ mL , IV administration of abiraterone acetate solution ( 33 % aq such as about 100 mg /mL to about 300 mg/ mL . HP -beta - cyclodextrin ) dosed at 10 mg / kg ; the profile Embodiments of the present disclosure can fulfill a long 15 obtained with IM administration of abiraterone acetate solu felt need in the field of sex hormone - dependent disorders tion in castor oil ( 66 mg /ml ) dosed at 21 mg /kg ; the profile and oncology including the chemotherapy of prostate can obtained with IM administration of abiraterone acetate solu cer . Embodiments of the present disclosure can also fulfill a tion in castor oil with 10 % benzyl alcohol ( 91 mg /ml ) dosed long felt need in the field of treating syndromes due to at 30 mg /kg and the profile obtained with IM administration androgen excess syndrome and / or due to glucocorticoid 20 of abiraterone acetate solution in castor oil with 50 % benzyl excess such as hypercortisolemia. Embodiments of the pres benzoate ( 124 mg/ ml ) dosed at 42 mg/ kg . ent disclosure can overcome major disadvantages and defi FIG . 3 shows the mean blood plasma concentrations of ciencies of prior art formulations ( including commercially abiraterone ( top line ) and abiraterone acetate ( bottom line ) available oral dosage forms) of abiraterone acetate , by ( ng /ml ) in dogs at different times ( hours ) after IV adminis providing long - acting , sustained release depot - based paren- 25 tration of abiraterone acetate ( dosed at 10.3 mg/ ml as a teral formulations of abiraterone prodrugs, methods of pro solution in 33 % aqueous HP -beta - cyclodextrin ). ducing the same , methods of treatment using the same, and FIG . 4 shows the mean blood plasma concentration of kits for convenient administration of the formulations to abiraterone ( top line ) and abiraterone acetate (bottom line ) subjects in need of therapy for various disorders including ( ng /nl ) in dogs at different times ( days) after IM adminis prostate cancer . 30 tration of abiraterone acetate solution in castor oil with 10 % There has thus been outlined , rather broadly , features in benzyl alcohol ( 91 mg /ml ) dosed at 30 mg /kg . order that the detailed description thereof that follows may FIG . 5 shows mean abiraterone and abiraterone decanoate be better understood , and in order that the present contri plasma concentration versus time profile data following IV bution to the art may be better appreciated . There are , of administration of 1.2 mg /kg abiraterone decanoate in dogs . course , additional features that will be described further 35 Error bars represent standard deviation . hereinafter. Indeed , it is to be understood that both the FIG . 6 shows mean abiraterone and abiraterone propi foregoing general description and the following detailed onate plasma concentration versus time profile data follow description are exemplary and explanatory and are intended ing IV administration of 1 mg /kg abiraterone propionate in to provide further explanation of the disclosure. dogs . Error bars represent standard deviation . In this respect , before explaining at least one embodiment 40 FIG . 7 shows mean abiraterone and abiraterone decanoate in detail, it is to be understood that the invention is not plasma concentration versus time profile data following IM limited in its application to the details of construction and to Administration of 50 mg /kg abiraterone decanoate ( 90 % the arrangements of the components set forth in the follow castor oil / 10 % benzyl alcohol ) in dogs. Error bars represent ing description or illustrated in the drawings. The invention standard deviation . is capable of other embodiments and of being practiced and 45 FIG . 8 shows mean abiraterone and abiraterone decanoate carried out in various ways . Also , it is to be understood that plasma concentration versus time profile data following IM the phraseology and terminology employed herein are for Administration of 50 mg /kg abiraterone decanoate ( 90 % the purpose of description and should not be regarded as corn oil / 10 % benzyl alcohol) in dogs . Error bars represent limiting . standard deviation . As such , those persons skilled in the art will appreciate 50 FIG . 9 shows mean abiraterone and abiraterone propi that the conception upon which this disclosure is based can onate plasma concentration versus time profile data follow readily be utilized as a basis for the designing of other ing IM administration of 41 mg/ kg abiraterone propionate formulations, methods, systems , kits , and compositions for ( 90 % castor oil / 10 % benzyl alcohol ) in dogs. Error bars carrying out the several purposes of the present disclosure . represent standard deviation . It is important, therefore , that equivalent constructions inso- 55 FIG . 10 shows mean abiraterone and abiraterone propi far as they do not depart from the spirit and scope of the onate plasma concentration versus time profile data follow present disclosure, are included in the present disclosure. ing IM administration of 41 mg /kg abiraterone propionate The accompanying drawings are included to provide a ( 90 % corn oil / 10 % benzyl alcohol ) in dogs . Error bars further understanding and are incorporated in and constitute represent standard deviation . a part of this specification , illustrate several embodiments , 60 FIG . 11A , FIG . 11B , FIG . 11C , and FIG . 11D show and together with the description serve to explain the exemplary predicted human abiraterone plasma concentra principles. tions following intramuscular administration of abiraterone decanoate by computer modeling in human , using an input BRIEF DESCRIPTION OF THE DRAWINGS half - life assumed to be the same as that observed in dog . 65 FIG . 11A shows a computer modeling prediction following FIG . 1 shows the mean blood plasma concentrations of an IM dose of 120 mg abiraterone decanoate every two abiraterone ( ng /ml ) in rats at different times ( hours ) after IM weeks and FIG . 11B shows a computer modeling prediction US 10,792,292 B2 13 14 following an IM dose of 350 mg abiraterone decanoate Monkeys ( n = 3 ) at Day 0 , Day 7 and Day 35. Each dose is every four weeks . FIG . 11C shows a computer modeling of 90 mg/ kg abiraterone decanoate . prediction following an IM dose of 1000 mg abiraterone FIG . 14F shows mean abiraterone plasma concentration decanoate every six weeks. FIG . 11D shows a computer versus time profile data following multiple doses of IM modeling prediction following an IM dose of 1700 mg 5 administration of abiraterone decanoate Formulation 1 ( 90 % abiraterone decanoate every two months. The horizontal Corn Oil , 10 % Benzyl Alcohol , 207 mg /ml abiraterone lines in FIG . 11A , FIG . 11B , FIG . 11C , and FIG . 11D decanoate ) or Formulation 2 ( 70 % Corn Oil , 10 % Benzyl represent a targeted Cmin value of abiraterone of about 8 Alcohol, 20 % benzyl benzoate , 209 mg/ ml abiraterone decanoate ) in Male Cynomolgus Monkeys ( n = 1 ) at Day 0 , ng FIG/ml . . 12A presents a representative X -ray Powder Dif- 10 Day 7 and Day 14. Each dose is of 100 mg/ kg abiraterone fraction ( XRPD ) spectrum of the abiraterone decanoate solid decanoate . form prepared in Example 6A . FIG . 15A shows mean abiraterone and abiraterone FIG . 12B shows a Differential Scanning Calorimetry decanoate plasma concentration versus time profile data ( DSC ) spectrum of the abiraterone decanoate solid form 15 decanoatefollowing ( 0.4IV mgadministration /ml solution inof 40 % 1.2 HP mg- beta /kg -cyclodextrin abiraterone prepared in Example 6A . 25 mM Na phosphate buffer ( pH 7.4 ) ) in Male Rats ( n = 5 ). FIG . 12C shows a thermogravimetric analysis ( TGA ) of FIG . 15B shows mean abiraterone and abiraterone the abiraterone decanoate solid form prepared in Example decanoate plasma concentration versus time profile data 6A . following a single IM administration of abiraterone decano FIG . 13A presents a plot of abiraterone decanoate solu- 20 ate formulation ( 90 % Corn Oil , 10 % Benzyl Alcohol, 172 bility in corn oil in the presence of various amounts of mg/ ml abiraterone decanoate ) at a dose of 90 mg/ kg abi benzyl alcohol and benzyl benzoate . FIG . 13B shows a raterone decanoate in Male Rats ( n = 5 ). contour plot of abiraterone decanoate solubility in corn oil in FIG . 15C shows mean abiraterone and abiraterone the presence of various amounts of benzyl alcohol and decanoate plasma concentration versus time profile data benzyl benzoate. FIG . 13C shows viscositiy ( Pa * s ) for 25 following multiple doses of IM administration of abiraterone various oil vehicles , without additive or with 10 % benzyl decanoate formulation ( 90 % Corn Oil , 10 % Benzyl Alcohol , alcohol , 20 % benzyl benzoate , or combination of 10 % 172 mg /ml abiraterone decanoate ) in Male Rats ( n = 5 ) at Day benzyl alcohol and 20 % benzyl benzoate . FIGS . 13D and 0 , Day 7 and Day 35. Each dose is of 90 mg/ kg abiraterone 13E show Glide Foce ( N ) for various oil vehicles , without decanoate . additive or with 10 % benzyl alcohol , 20 % benzyl benzoate , 30 FIG . 16A shows allometric scaling of distribution volume or a combination of 10 % benzyl alcohol and 20 % benzyl ( Vss ) of abiraterone in rats , dogs and monkeys, with pre benzoate tested with 5 ml Syringe , with 23 Gauge needle or diction in man . 27 Gauge needle , respectively. FIG . 16B shows predicted plasma profile of abiraterone in FIG . 14A shows mean abiraterone and abiraterone man following a single intramuscular dose of abiraterone at decanoate plasma concentration versus time profile data 35 1 mg based on a bioavailability of 56 % . following IV administration of 1.2 mg/ kg abiraterone FIG . 16C shows predicted plasma profile of abiraterone in decanoate ( 0.4 mg/ ml solution in 40 % HP -beta - cyclodextrin man following repeated intramuscular doses of abiraterone 25 mM Na phosphate buffer ( pH 7.4 ) ) in Male Cynomolgus decanoate at 1000 mg every 4 weeks based on a bioavail Monkeys ( n = 3 ). ability of 56 % . FIG . 14B shows mean abiraterone and abiraterone 40 FIG . 16D shows predicted plasma profile of abiraterone in decanoate plasma concentration versus time profile data man following repeated intramuscular doses of abiraterone following a single IM administration of abiraterone decano decanoate at 1000 mg every 4 weeks assuming complete ate formulation ( 90 % Corn Oil , 10 % Benzyl Alcohol, 192 bioavailability . mg/ ml abiraterone decanoate ) at a dose of 90 mg /kg abi FIG . 17A shows mean abiraterone and abiraterone iso raterone decanoate in Male Cynomolgus Monkeys ( n = 3 ) . 45 caproate plasma concentration versus time profile data fol FIG . 14C shows the observed steroid levels ( progesterone, lowing IV administration of 1.0 mg/ kg abiraterone iso cortisol and testosterone levels ) versus time profile data caproate in dogs. Error bars represent standard deviation . following this single dose IM administration . As shown in FIG . 17B shows mean abiraterone and abiraterone iso FIG . 14C , following the single dose IM injection , a long caproate plasma concentration versus time profile data fol duration of CYP17A1 inhibition was achieved as evidenced 50 lowing IM administration of abiraterone isocaproate in dogs . by the sustained increase of progesterone level and reduction Error bars represent standard deviation . of glucocorticoid ( cortisol) and sex hormone ( testosterone) FIG . 17C shows mean abiraterone and abiraterone level . FIG . 14D presents biochemical pathways showing the decanoate plasma concentration versus time profile data effects of CYP17A1 inhibition on the synthesis of andro following IM administration of abiraterone decanoate in gens , estrogens, glucocorticoids, progesterone and miner- 55 dogs . Error bars represent standard deviation . alocorticoids . As shown in FIG . 14D , inhibition of FIG . 17D shows mean abiraterone plasma concentration CYP17A1 17a -hydroxylase and C17,20 - lyase activities will versus time profile data following IM administration of lead to ( 1 ) increases in levels of progesterone and the abiraterone isocaproate or decanoate in dogs . Error bars mineralocorticoids ; ( 2 ) reductions in levels of glucocorti represent standard deviation . coids such as cortisol; and ( 3 ) reductions in levels of sex 60 hormones, e.g. , androgens such as testosterone and dihy DETAILED DESCRIPTION drotestosterone , and estrogens such as estradiol. FIG . 14E shows mean abiraterone and abiraterone The present disclosure relates to compounds and compo decanoate plasma concentration versus time profile data sitions that deliver therapeutic blood plasma levels of the following multiple doses of IM administration of abiraterone 65 active drug abiraterone over an extended period of time to decanoate formulation ( 90 % Corn Oil , 10 % Benzyl Alcohol , subjects. Initial experiments in the rat determined that inject 192 mg /ml abiraterone decanoate ) in Male Cynomolgus ing suspensions of the active drug abiraterone intramuscu US 10,792,292 B2 15 16 larly did not achieve the desired therapeutic blood plasma ments , R 10 can be a linear C7-30 alkyl. In some embodiments , levels . However, as detailed herein , it was found that rep R10 can be a branched C7-30 alkyl. In some embodiments , resentative novel abiraterone prodrugs and formulations, R10 is a linear C7-16 alkyl, for example, Riº can have a when administered parenterally ( e.g. , intramuscularly ), formula ( CH2) n CH3, wherein n is an integer between 6 achieved desired therapeutic blood plasma levels for a 5 and 15 ( e.g. , between 6 and 12 , such as 6 , 7 , 8 , 9 , 10 , 11 , or prolonged period of time. 12 ) . In some embodiments , Riº can be a branched C7-16 Accordingly , various embodiments of the present disclo alkyl. sure are directed to such novel abiraterone prodrugs and In some embodiments, R10 can also be an alkyl substituted formulations, which can have various advantages over exist 10 with a cycloalkyl. Typically, in such embodiments, Riº has ing abiraterone formulations, such as the marketed oral a total number of carbons between 5 and 16 , i.e. , the total abiraterone acetate formulation. Such advantages include , number of carbons from the alkyl moiety and the cycloalkyl but are not limited to , improved bioavailability, elimination moiety are between 5 and 16. The cycloalkyl typically is of the food effect associated with oral abiraterone acetate unsubstituted. However, in some embodiments, the formulation , reduced pill burden , better patient compliance , 15 cycloalkyl can be optionally substituted , e.g. , with one or decreased dosing frequency, sustained stable blood levels of two lower alkyl ( e.g , a C1-4 alkyl ). In some embodiments , active drug , reduced Cmax , which can reduce associated side Riº can be an alkyl substituted with a C3-6 cycloalkyl, which effects, etc. In some embodiments, methods of using the typically has a total number of carbons between 6 and 12. In novel abiraterone prodrugs and formulations are also pro some embodiments, R10 can be a linear alkyl substituted vided, for example, for treating sex hormone - dependent 20 with a C3-6 cycloalkyl, for example, R 10 can have a formula benign or malignant disorders ( such as prostate cancer ), syndromes due to androgen excess , and / or syndromes due to ( CH2 ) n - Cy , wherein n is an integer of 1-6 ( e.g. , 1 , 2 , 3 , 4 , glucocorticoid excess such as hypercortisolemia . 5 , or 6 ) , and Cy is a C3-6 cycloalkyl ( such as cyclopropyl, Compounds of Formula I cyclobutyl, cyclopentyl, or cyclohexyl ). In some embodi In some embodiments, the present disclosure provides a 25 ments, Rlº can have a formula ( CH2) n - Cy, wherein n is 1 novel abiraterone prodrug. In some embodiments, the novel or 2 , and Cy is cyclopentyl or cyclohexyl. In some embodi abiraterone prodrug is a compound of Formula I , or a ments, Rºcan also be a branched alkyl ( e.g. , branched C2-6 ) pharmaceutically acceptable salt thereof: substituted with a C3-6 cycloalkyl. As used herein , a branched C2 alkyl should be understood as a 1,1- disubsti 30 tuted ethyl group , for example, CH (CH3 ) -Cy. Formula I In some embodiments , Riº can also be an alkyl substituted with a phenyl. Typically, in such embodiments, Riº has a total number of carbons between 7 and 16 , i.e. , the total number of carbons from the alkyl moiety and the phenyl 35 moiety are between 5 and 16. In some embodiments, Riº can be a linear alkyl substituted with a phenyl, for example, RIO can have a formula — (CH2 )n - Cy, wherein n is an integer of 1-6 ( e.g. , 1 , 2 , 3 , 4 , 5 , or 6 ) , and Cy is a phenyl. In some embodiments , R 10 can have a formula ( CH2 ) n -Cy , 40 wherein n is 1 or 2 , and Cy is phenyl. In some embodiments , R ! R10 can also be a branched alkyl ( e.g. , branched C2-6 ) substituted with a phenyl. The phenyl typically is unsubsti Various groups are suitable as Rl in Formula I. In some tuted . However, in some embodiments, the phenyl can be embodiments , R ' can be selected such that the compound of optionally substituted , e.g. , with one or two lower alkyl ( e.g , Formula I is an ester ( e.g. , a lipophilic ester ), a carbamate, 45 a C - 4 alkyl) . or a carbonate of abiraterone. In some embodiments , Rl is R10,0 R10, or NHR10 , wherein Riº is selected from : a In some embodiments, Riº can be a cycloalkyl optionally C7-30 alkyl; C7-30 alkenyl; C7-30 alkynyl; an alkyl substituted substituted with one or more alkyl. In such embodiments, with a cycloalkyl, which typically has a total number of R1 ° typically has a total number of carbons between 5 and carbons between 5 and 16 ; an alkyl substituted with a 50 16 , i.e. , the total number of carbons of the cycloalkyl and its phenyl, which typically has a total number of carbons optional substituents are between 5 and 16. In some embodi between 7 and 16 ; a cycloalkyl optionally substituted with ments, R1 ° can be a C3-6 cycloalkyl, either unsubstituted or one or more alkyl, which typically has a total number of substituted with a C1-4 alkyl. In some specific embodiments , carbons between 5 and 16 ; and a branched C5 or C6 alkyl R10 can be such as 55

In some preferred embodiments , R1 ° is a C7-30 alkyl. As used herein , unless expressly stated to be substituted , an 65 alkyl should be understood as unsubstituted . However, an alkyl can be either linear or branched . In some embodi US 10,792,292 B2 17 18 or useful. Unless specifically referred to as in its salt form or otherwise contradictory from context, the compound of Formula I can be in its basic form in the abiraterone prodrug formulations described herein . 5 Compounds of Formula I can be readily synthesized by those skilled in the art in view of the present disclosure. Exemplary synthesis of representative compounds are described in the Examples section . For example, typically , esters of Formula I can be prepared by reacting abiraterone In some embodiments , Rlº can be a branched C5 or C6 10 with a corresponding carboxylic acid , or an activated form alkyl. In some embodiments, R1 ° can be thereof, such as the corresponding acyl chloride, anhydride , etc. Exemplary reaction conditions using an activated form such as acyl chloride are shown in the Examples section . Abiraterone Prodrug Formulations 15 Abiraterone prodrugs herein , including compounds of x Formula I , are useful for delivering abiraterone to a subject in need thereof, for example, to a subject having a sex hormone -dependent benign or malignant disorder, a syn drome due to androgen excess, and / or a syndrome due to OtherIn some branched embodiments C5 or C6 , R10 alkyls can beare an also unsaturated suitable . aliphatic 20 glucocorticoid excess such as hypercortisolemia herein . group such as a C7-30 alkenyl or a C7-30 alkynyl. Typically, the abiraterone prodrugs can be formulated as a In some preferred embodiments, the compound of For parenteral formulation , such as an intramuscular, intrader mula I is an ester of abiraterone, e.g. , R ' is R10 , wherein R10 mal , or subcutaneous formulation , and can in some embodi is defined herein . In some embodiments, R ' in Formula I can ments be formulated to deliver a therapeutically effective be a C7-16 alkyl, e.g. , an alkyl having a formula of 25 plasma concentration of abiraterone over an extended period ( CH2 ) n - CH3 , wherein n is an integer between 6 and 12 of time , e.g. , for at least 1 week , at least 2 weeks , at least 3 (Formula e.g. , 6 , 7 I , can8 , 9 ,be 10 represented , 11 , or 12 ) . byIn thesome formula- embodiments ( CH2, ) Rl , -Cy in, weeksetc. , at least 4 weeks , and up to six or eight weeks or more , wherein n is an integer of 1-6 , and Cy is a C3-6 cycloalkyl or phenyl, for example, in more specific embodiments, n can 30 carbamatesVarious abiraterone, or carbonates prodrugs are suitable, such asfor abiraterone compositions esters and , be 1 or 2 , and Cy is cyclopentyl, cyclohexyl, or phenyl. In methods of the present disclosure . In some embodiments , some specific embodiments, R ' in Formula I can be the present disclosure provides a pharmaceutical composi tion ( alternatively sometimes referred to as abiraterone prodrug formulation herein ) comprising a compound of 35 Formula I ( e.g. , any one or more as defined herein ), or a pharmaceutically acceptable salt thereof. In some embodi xy ments, the pharmaceutical composition can be formulated for parenteral administration , such as intramuscular injec tion , intradermal injection , or subcutaneous injection . The In some specific embodiments , Rl in Formula I can be 40 pharmaceutical composition typically includes a pharma ceutically acceptable carrier . Suitable carriers include those known in the art, for example, those described in “ Reming ton : The Science and Practice of Pharmacy ” ( formerly “ Remington's Pharmaceutical Sciences , ” University of the 45 Sciences in Philadelphia , Lippincott, Williams & Wilkins , Philadelphia, Pa . ( 2005 ) ) and the U.S. Food and Drug Administration's Center for Drug Evaluation and Research's database of inactive ingredients present in FDA approved drugs. In some embodiments, the pharmaceuti 50 cally acceptable carrier can be a carrier that is approved for or use by the FDA for an intramuscular, intradermal, or sub cutaneous drug product, e.g. , those listed in the FDA's database of inactive ingredients . In some embodiments, the pharmaceutically acceptable carrier can be any suitable 55 nonaqueous vehicle suitable for injection , such as those described in U.S. Pharmacopeia . In some embodiments, the c pharmaceutically acceptable carrier can be a pharmaceuti cally acceptable oil , e.g. , a vegetable oil , castor oil , corn oil , sesame oil , cottonseed oil , peanut oil , poppy seed oil , tea Other suitable groups for R include any of the R10 defined 60 seed oil , or soybean oil . In some embodiments, the phar herein . maceutically acceptable oil can be oils ( e.g. , described In some embodiments, Rl in Formula I can also be herein ) suitable for use as vehicles for injection , e.g. , meet 0 R1° or NHR19 , wherein R10 is defined herein . ing the criteria as described in the corresponding U.S. Typically, compounds of Formula I can be present in a Pharmacopeia monograph . In some embodiments , the phar formulation in the basic form , for example, in a non - aqueous 65 maceutically acceptable oil can be an oil of vegetable origin formulation . However, in some embodiments , pharmaceu suitable for use as vehicles for injection . In some embodi tically acceptable salts of compounds of Formula I are also ments , the pharmaceutically acceptable oil can be a synthetic US 10,792,292 B2 19 20 oil suitable for use as vehicles for injection , such as a Various groups are suitable as R2 in Formula II . In some synthetic mono- or diglycerides of fatty acids , e.g. , those embodiments, R2 can be selected such that the compound of that are liquid and remain clear when cooled to 10 ° C. and Formula II is an ester, a carbamate , or a carbonate of or have an Iodine Value of not more than 140. In some abiraterone. In some embodiments, R2 is R20 , 0 R209 , embodiments, the pharmaceutically acceptable oil can be 5 NHR20 , and R20 is selected from : a C1-30 alkyl; a C2-30 nature oil , synthetic oil , or semi- synthetic oil , such as alkenyl; a C2-30 alkynyl; an alkyl substituted with a fractionated coconut oil and medium - chain triglycerides , cycloalkyl, which typically has a total number of carbons such as those sold under the trademark Miglyol . In some between 4 and 30 ; an alkyl substituted with a phenyl, which embodiments, the pharmaceutically acceptable carrier com typically has a total number of carbons between 7 and 30 ; prises a triglyceride derived from fatty acids . In some 10 and a cycloalkyl optionally substituted with one or more embodiments , the pharmaceutically acceptable carrier com alkyl, which typically has a total number of carbons between prises a triglyceride derived from long and / or medium chain 3 and 30 . fatty acids , which can be independently poly - unsaturated , In some preferred embodiments, R20 is a C1-16 alkyl. In mono - unsaturated , or saturated . In some embodiments, two some embodiments, R20 can be a linear C1-16 alkyl. In some or more different pharmaceutically acceptable oil can be 15 embodiments, R20 can be a branched C3-16 alkyl. In some used . In some embodiments , the pharmaceutical composi embodiments, R20 can be a branched C5 or C6 alkyl. In tion is a non - aqueous solution or suspension . In some 20 embodiments, the pharmaceutical composition further com some embodiments, R can be prises a pharmaceutically acceptable solvent, such as benzyl alcohol . In some embodiments, the compound of Formula I 20 or pharmaceutically acceptable salt thereof can be present in the pharmaceutical composition at a concentration of about 25 mg/ ml to about 500 mg /ml ( e.g. , about 25 mg/ ml , about 50 mg /ml , about 100 mg/ ml , about 150 mg /ml , about 200 mg /ml , about 250 mg /ml , about 300 mg /ml , about 400 25 mg/ ml , about 500 mg/ ml , or any range between the recited In some embodiments, R20 can have a formula (CH2 ) n values ) . CH3 , wherein n is an integer between 0 and 12 ( e.g. , between In some embodiments, the present disclosure also pro 6 and 12 , such as 6 , 7 , 8 , 9 , 10 , 11 , or 12 ) . vides a pharmaceutical composition (alternatively some In some embodiments , R20 can also be an alkyl substituted times referred to as abiraterone prodrug formulation herein ) 30 with a cycloalkyl. Typically, in such embodiments, R20 has comprising a compound of Formula II , or a pharmaceuti a total number of carbons between 4 and 30 , such as between cally acceptable salt thereof. 5 and 16 ( i.e. , the total number of carbons from the alkyl moiety and the cycloalkyl moiety are between 5 and 16 ) . The cycloalkyl typically is unsubstituted . However, in some Formula II 35 embodiments, the cycloalkyl can be optionally substituted , e.g. , with one or two lower alkyl ( e.g , a C1-4 alkyl ). In some embodiments, R20 can be an alkyl substituted with a C3-6 cycloalkyl, which typically has a total number of carbons between 6 and 12. In some embodiments , R20 can be a linear 40 alkyl substituted with a C3-6 cycloalkyl, for example, R20 can have a formula — (CH2 ) n -Cy , wherein n is an integer of 1-6 ( e.g. , 1 , 2 , 3 , 4 , 5 , or 6 ) , and Cy is a Cz. cycloalkyl ( such as cyclopropyl , cyclobutyl, cyclopentyl, or cyclohexyl) . In some embodiments, R20 can have a formula ( CH2 ) n - Cy , 45 wherein n is 1 or 2 , and Cy is cyclopentyl or cyclohexyl. In R2 I some embodiments , R20 can also be a branched alkyl ( e.g. , branched C2-6 ) substituted with a C3-6 cycloalkyl. wherein R2 is defined herein . In some embodiments , the In some embodiments, R2 ° can also be an alkyl substituted pharmaceutical composition can be formulated for intramus with a phenyl. Typically, in such embodiments, R20 has a cular injection, intradermal injection , or subcutaneous injec- 50 total number of carbons between 7 and 30 , e.g. , between 7 tion . In some embodiments, the compound of Formula II or and 16 ( i.e. , the total number of carbons from the alkyl pharmaceutically acceptable salt thereof can be present in moiety and the phenyl moiety are between 7 and 16 ) . In the pharmaceutical composition at a concentration of about some embodiments, R20 can be a linear alkyl substituted 25 mg /ml to about 500 mg /ml ( e.g. , about 25 mg /ml , about with a phenyl, for example, R20 can have a formula 50 mg /ml , about 100 mg/ ml , about 150 mg /ml , about 200 55 - (CH2 ) .- Cy, wherein n is an integer of 1-6 ( e.g. , 1 , 2 , 3 , 4 , mg /ml , about 250 mg /ml , about 300 mg /ml , about 400 5 , or 6 ) , and Cy is a phenyl. In some embodiments, R20 can mg /ml , about 500 mg /ml , or any range between the recited have a formula ( CH2 ) n - Cy , wherein n is 1 or 2 , and Cy is values ) . In some embodiments , the pharmaceutical compo phenyl. In some embodiments, R20 can also be a branched sition is a non - aqueous solution or suspension . In some alkyl ( e.g. , branched C2-6 ) substituted with a phenyl. The embodiments , the compound of Formula II or pharmaceu- 60 phenyl typically is unsubstituted . However, in some embodi tically acceptable salt thereof is dissolved or suspended in a ments , the phenyl can be optionally substituted , e.g. , with pharmaceutically acceptable oil ( e.g. , described herein ), one or two lower alkyl ( e.g , a C1-4 alkyl ). such as a vegetable oil , castor oil , corn oil , sesame oil , In some embodiments , R20 can be a cycloalkyl optionally cottonseed oil , peanut oil , poppy seed oil , tea seed oil , or substituted with one or more alkyl. In such embodiments, soybean oil . In some embodiments, the pharmaceutical 65 R20 typically has a total number of carbons between 3 and composition further comprises a pharmaceutically accept 30 , e.g. , 5 and 16 ( i.e. , the total number of carbons of the able solvent, such as benzyl alcohol . cycloalkyl and its optional substituents are between 5 and US 10,792,292 B2 21 22 16 ) . In some embodiments , R20 can be a C3-6 cycloalkyl , ate , abiraterone heptanoate , abiraterone decanoate , either unsubstituted or substituted with a C1-4 alkyl. In some abiraterone isocaproate , or abiraterone cypionate . specific embodiments, R20 can be In some embodiments, R2 in Formula II can also be 0 - R20 or NHR20 , wherein R20 is defined herein . 5 Typically, compounds of Formula Il can be present in a formulation in the basic form , for example, in a non - aqueous formulation . However, in some embodiments , pharmaceu tically acceptable salts of compounds of Formula II are also useful. Unless specifically referred to as in its salt form or 10 otherwise contradictory from context , the compound of Formula II can be in its basic form in the abiraterone prodrug formulations described herein . Compounds of Formula II can be readily synthesized by or those skilled in the art in view of the present disclosure . 15 Exemplary synthesis of representative compounds are described in the Examples section . For example, typically, esters of Formula II can be prepared by reacting abiraterone with a corresponding carboxylic acid , or an activated form thereof, such as the corresponding acyl chloride, anhydride, ?a 20 etc. Exemplary reaction conditions using an activated form such as acyl chloride are shown in the Examples section . Typically, the abiraterone prodrugs of the present disclo sure are formulated as a non - aqueous solution or suspension . In some embodiments, R20 can be an unsaturated aliphatic In some embodiments, the non - aqueous solution or suspen group such as a C2-30 alkenyl or a C2-30 alkynyl. 25 sion provides higher levels of abiraterone in the plasma for In some preferred embodiments, the compound of For a longer duration , when compared to an aqueous solution or mula II is an abiraterone ester, e.g. , R2 is R20 , wherein R2 suspension . For example , as detailed herein , IM injections of is defined herein . In some embodiments, R2 in Formula II an aqueous suspension and a vegetable oil solution of the can be a C1-16 alkyl, e.g. , an alkyl having a formula of abiraterone acetate prodrug were evaluated in rats . Surpris (CH2 ) n CH3, wherein n is an integer between 0 and 12. 30 ingly, it was determined that the vegetable oil solution (but In some embodiments , R² in Formula II can be represented not the aqueous suspension ) of abiraterone acetate prodrug by the formula - ( CH2 ) n - Cy , wherein n is an integer of 1-6 , gave the highest blood plasma levels and also the longest and Cy is a C3-6 cycloalkyl or phenyl, for example, in more duration of exposure of active drug abiraterone ( see FIG . 1 ) . specific embodiments , n can be 1 or 2 , and Cy is cyclopentyl, Accordingly, in some embodiments, the abiraterone prodrug cyclohexyl , or phenyl. In some specific embodiments , R2 in 35 formulations herein can include an abiraterone prodrug of Formula II can be the present disclosure ( e.g. , compound of Formula I or II ) dissolved or dispersed in a pharmaceutically acceptable carrier. In some embodiments , the pharmaceutically accept able carrier can be any suitable nonaqueous vehicle suitable 40 for injection, such as those described in U.S. Pharmacopeia . In some embodiments, the pharmaceutically acceptable car rier can be a pharmaceutically acceptable oil , e.g. , a veg xy etable oil , castor oil , corn oil , sesame oil , cottonseed oil , peanut oil , poppy seed oil , tea seed oil , or soybean oil . In rt 45 some embodiments, the pharmaceutically acceptable oil can be oils ( e.g. , described herein ), suitable for use as vehicles or for injection, e.g. , meeting the criteria as described in the corresponding U.S. Pharmacopeia monograph . In some embodiments, the pharmaceutically acceptable oil can be an 50 oil of vegetable origin suitable for use as vehicles for injection . In some embodiments, the pharmaceutically acceptable oil can be a synthetic oil suitable for use as vehicles for injection, such as synthetic mono- or diglycer ides of fatty acids , e.g. , those that are liquid and remain clear 55 when cooled to 10 ° C. and have an Iodine Value of not more Other suitable groups for R2 include any of the R20 defined than 140. In some embodiments , the pharmaceutically herein . In some embodiments, the abiraterone ester can be acceptable oil can be nature oil , synthetic oil , or semi an acetate , a propionate, a butanoate, a ( vaterate) pentanoate , synthetic oil , such as fractionated coconut oil and medium an isocaproate, a buciclate , a cyclohexanecarboxylate, a chain triglycerides, such as those sold under the trademark phenyl propionate , caproate (hexanoate ), a enanthate ( hep- 60 Miglyol . In some embodiments , the pharmaceutically tanoate ), a cypionate , an octanoate, a noncanoate, a decano acceptable carrier comprises a triglyceride derived from ate , an undecanoate, a dodecanoate, a tridecanoate , a tetra fatty acids . In some embodiments, the pharmaceutically decanoate, a pentadecanoates, or a hexadecanoate of acceptable carrier comprises a triglyceride derived from abiraterone . In some embodiments, the abiraterone ester can long and /or medium chain fatty acids , which can be inde be abiraterone acetate , abiraterone propionate , and abirater- 65 pendently poly - unsaturated , mono - unsaturated , or saturated . one decanoate . In some specific embodiments, the abirater In some embodiments, the pharmaceutically acceptable oil one ester can be abiraterone pentanoate , abiraterone hexano can be any of those that are approved for use by the FDA for US 10,792,292 B2 23 24 an intramuscular, intradermal, or subcutaneous drug prod 0-15 % or 0-10 % , such as about 10 % ) of the oil vehicle , and uct , e.g. , those listed in the FDA's database of inactive benzyl benzoate in an amount of about 0-50 % ( e.g. , 0-35 % ingredients. In some specific embodiments, the pharmaceu or 0-30 % , such as about 20 % ) of the oil vehicle, wherein the tically acceptable oil is castor oil or corn oil . In some balance of the oil vehicle can be any one or more of the embodiments , two or more different pharmaceutically 5 pharmaceutically acceptable oil described herein , such as acceptable oil can be used . corn oil , castor oil , sesame oil , peanut oil , cottonseed oil , Other ingredients can also be optionally included in the and /or Miglyol 812 , etc. abiraterone prodrug formulations herein . In some embodi The solubility of the abiraterone esters can be affected ments , the abiraterone prodrug formulation can further com upon adding a co - solvent to the vegetable oil vehicle . In prise a pharmaceutically acceptable solvent, such as benzyl 10 some embodiments, the abiraterone ester is completely alcohol , benzyl benzoate , ethanol, glycerol, polyethylene dissolved in the composition , and in other embodiments the glycol , polysorbate 80 , acetic acid , and ethyl acetate . It was abiraterone ester is partly dispersed in the composition . In determined that the additives / co - solvents benzyl alcohol and one embodiment, the abiraterone esters are fully dissolved in benzyl benzoate had the advantage of increasing the solu the vehicle . bility of the prodrugs as well as reducing the viscosity and /or 15 The abiraterone prodrug formulations can also contain glide force of the solution , see e.g. , FIGS . 13A - 13E and pharmaceutically acceptable preservatives , polymers, anti Tables 2A - 2D , which provided a more concentrated solution oxidants , antimicrobials, chelating agents, and other excipi that was easier to inject through an acceptable gauge needle ents such as citric acid , dextrose , ascorbic acid , benzalko for IM injection ( e.g. , 20-27 gauge such as 22-25 gauge ). nium chloride, benzoic acid , sodium betadex sulfobutyl The co - solvent can be selected based on its ability to reduce 20 ether, calcium chloride, sodium carbomethoxycellulose , the viscosity of the vehicle to allow injection through chlorobutanol, creatine , croscarmellose , dibasic potassium suitable injection needles or cannula . Benzyl alcohol as an phosphate, sodium docusate , sodium edetate, glycerin , additive in IM or subcutaneous injections also has the sodium hyaluronate , hydroxypropyl betadex , lactic acid , advantage that it can act as a local anesthetic at the injection lactose , lecithin , maleic acid , mannitol, meglumine , meth site ( Wilson et al . Ann . Emer. Med . 33 ( 5 ) , 495 , 1999 ) . In 25 ylcellulose , methylparaben , microcrystalline cellulose , mir some embodiments, the abiraterone prodrug formulation ipitium chloride , momothioglycerol, phenol, poloxamer further comprises benzyl alcohol . In some embodiments, the 188 , polyglactin , polysorbate 20 , polysorbate 40 , polysor cosolvent, if present, can be included at a level ( e.g. , about bate 80 , propylparaben , sodium acetate , sodium benzoate , 0-50 % of the solvent, such as about 10 % ) such that it does sodium citrate, sorbitan monolaurate , sorbitol, sucrose , tar not cause irritation ( or only minimal or tolerable irritation ) 30 taric acid , trisodium citrate, tromantadine, tromethamine, at the injection site . and urea . In some embodiments , the abiraterone prodrug formula The abiraterone prodrug formulations can be sterilized by tion can comprise benzyl benzoate as a cosolvent, for methods known by persons skilled in the art ( for example , example, about 0-50 % of the solvent, typically 0-35 % or gamma irradiation , micron filtration , and autoclaving ). 0-30 % , or about 20 % . In some embodiments, the abiraterone 35 Lon - Actin Release of Abiraterone prodrug formulation can comprise a combination of benzyl The abiraterone prodrugs and abiraterone prodrug formu alcohol and benzyl benzoate as cosolvents . In some embodi lations ( e.g. , those containing compounds of Formula I or II ments , the benzyl alcohol can be present in an amount of as described herein ) of the present disclosure are typically about 0-20 % ( e.g. , 0-15 % or 0-10 % , such as about 10 % ) of formulated to provide a long -acting release of abiraterone to the solvent, and benzyl benzoate can be present in an amount 40 a subject in need thereof, such as those having a sex of about 0-50 % ( e.g. , 0-35 % or 0-30 % , such as about 20 % ) hormone -dependent benign or malignant disorder, a syn of the solvent, wherein the balance of the solvent can be any drome due to androgen excess , and / or a syndrome due to one or more of the pharmaceutically acceptable oil described glucocorticoid excess such as hypercortisolemia , preferably herein , such as corn oil , castor oil , sesame oil , peanut oil , as a parenteral formulation such as intramuscular, intrader cottonseed oil , and / or Miglyol 812 , etc. As discussed in 45 mal , or subcutaneous formulation . In some embodiments , more detail in the Examples section , the inclusion of benzyl the abiraterone prodrugs and abiraterone prodrug formula benzoate in various oil vehicles was found to be advanta tions ( e.g. , those containing compounds of Formula I or II as geous in various aspects . See e.g. , FIGS . 13A - 13E and described herein ) of the present disclosure can be formulated Tables 2A - 2D . For example, the combination of benzyl to deliver therapeutic blood plasma levels of abiraterone alcohol and benzyl benzoate were shown to achieve a lower 50 over an extended period of time ( e.g. , at least 1 week , e.g. , viscosity and glide force , when compared with using just at least two weeks , at least 3 weeks, at least 4 weeks , and up benzyl alcohol or benzyl benzoate. Further, it was unexpect to six or eight weeks or more , etc. ) to subjects having a edly found that a representative abiraterone prodrug (abi hormone - dependent benign or malignant disorder, a syn raterone decanoate ) formulation comprising an oil ( corn oil , drome due to androgen excess , and / or a syndrome due to 70 % ) and benzyl alcohol ( 10 % ) and benzyl benzoate ( 20 % ) 55 glucocorticoid excess such as hypercortisolemia, following achieved a much higher abiraterone plasma exposure in a single administration . In some embodiments, the thera monkeys when compared with a formulation comprising the peutic blood plasma concentration of abiraterone can be a same oil vehicle without benzyl benzoate , i.e. , corn oil , at concentration of at least 1 ng /ml , e.g. , at least 2 ng /ml , at 90 % , and benzyl alcohol at 10 % , which has substantially the least 4 ng /ml , at least 8 ng /ml . In some embodiments , the same concentration of abiraterone decanoate , and dosed at 60 therapeutic blood plasma concentration of abiraterone can the same amount . also be about 0.5 ng / ml or higher. While the oil vehicles described herein are typically used As shown herein , abiraterone acetate vegetable oil IM for the abiraterone prodrugs of the present disclosure , it is injections were evaluated in dogs . Abiraterone acetate solu also contemplated that such oil vehicles can be used for tions in castor oil and the co - solvents benzyl alcohol and formulating other active ingredients. In some embodiments , 65 benzyl benzoate were prepared at various strengths ( 66-124 the present disclosure also provides an oil vehicle compris mg /ml ) and injected intramuscularly into dogs, and the ing benzyl alcohol in an amount of about 0-20 % ( e.g. , parent abiraterone drug blood plasma levels were measured US 10,792,292 B2 25 26 over three weeks ( see FIG . 2 ) . The data from the dog study e.g. , a vegetable oil such as castor oil , corn oil , sesame oil , indicate that abiraterone acetate given as a solution in castor cottonseed oil , peanut oil , poppy seed oil , tea seed oil , or oil (with or without benzyl alcohol ) produced measurable soybean oil . In some embodiments, two or more different blood levels out to 504 hours . The absolute bioavailabilities pharmaceutically acceptable oil can be used in the unit for these formulations were found to range between 61.7 and 5 dosage forms. In some embodiments, the unit dosage form 86.2 % . This represents the first showing that it is possible to can further comprise a pharmaceutically acceptable solvent, deliver abiraterone to a subject for a prolonged period of e.g. , an alcohol, an ester, and / or an acid , such as benzyl time with a single injection, which therefore allows a less alcohol , benzyl benzoate , or a combination thereof. Other frequent dosing, such as once a week or once in more than suitable ingredients for the unit dosage forms include those a week , e.g. , the dosing frequency ranges from once a week 10 described herein . to once every few months, such as from once a week to once The abiraterone prodrug ( e.g. , compound of Formula I or every eight weeks or from once a week to once every three II ) is typically present in the unit dosage form at a concen months. tration of about 25 mg/ ml to about 500 mg/ ml ( e.g. , about 25 Without wishing to be bound by theories, it is believed mg/ ml , about 50 mg /ml , about 100 mg /ml , about 150 mg/ ml , that the duration of action of the prodrug is dependent on the 15 about 200 mg/ ml , about 250 mg/ ml , about 300 mg / ml , about selection of the prodrug ( e.g. , the ester moiety ) and the 400 mg /ml , about 500 mg /ml , or any range between the selection of the oil vehicle since it is controlled by both the recited values ) . The amount of abiraterone prodrug in the release rate of the prodrug from the oil vehicle into the unit dosage forms can vary , depending on various factors aqueous tissue and the bioconversion rate of the ester such as the clearance rate of the respective abiraterone prodrug to the parent drug abiraterone. Unlike the case 20 prodrug, the intended dosing frequency and the desired where abiraterone acetate is dosed orally and the biocon plasma levels , etc. Typically, the amount of the abiraterone version occurs prior to the drug being absorbed ( and thus the prodrug can be in the range of about 50 mg to about 2000 prodrug is not observed in blood plasma ) , when abiraterone mg , which if expressed as equivalent of abiraterone , can prodrug is dosed parenterally in dogs ( either IV or IM ) the typically range from about 25 mg to about 1750 mg . In some prodrug is observed in blood plasma ( see e.g. , FIGS . 3-10 ) 25 embodiments , to achieve a less frequent dosing frequency, where it is converted into parent drug abiraterone . There such as a once a month dosing frequency, the prodrug can be fore, an aspect of this disclosure is the selection of the ester included in the unit dosage form at a concentration as high prodrug and the vegetable oil / co - solvent vehicle so as to as safely tolerable to a subject user . Typically, the unit allow adequate solubility of the ester prodrug in the vehicle dosage form is formulated to have a viscosity suitable for to allow injection, controlled release of the ester prodrug 30 parenteral injection, such as suitable for intramuscular, intra from the oil depot ( dependent on the partition coefficient of dermal , or subcutaneous injection . the drug between oil and aqueous phases ) , and then biocon In some embodiments, the unit dosage form can be version of the ester prodrug to the abiraterone parent drug. formulated to achieve certain pharmacokinetic ( PK ) profiles, A selection of abiraterone pro - drugs were prepared ( acetate , e.g. , a PK profile with a substantially flat curve after an propionate, butanoate, pentanoate, hexanoate , heptanoate, 35 initial rising period . Typically, after the unit dosage form is isocaproate, cypionate , and decanoate ) and their solubilities administered to a subject, during the initial few hours and up in several vegetable oils and co - solvents determined ( see to a few days ( e.g. , 5 days or a week ) post administration , the Table 2 ) . plasma concentration of abiraterone in the subject can be Unit Dosage Forms increased , which is then gradually plateaued , see e.g. , FIGS . In some embodiments, the abiraterone prodrugs and abi- 40 2-4 . In some embodiments, after this initial rising period, the raterone prodrug formulations ( e.g. , those containing com plasma concentration of abiraterone in the subject can be pounds of Formula I or II as described herein ) of the present plateaued and can be substantially constant for an extended disclosure can be formulated as a unit dosage form . In some period of time , for example, for at least a few days ( e.g. , 2 , embodiments, the unit dosage form can include a sufficient 3 , 4 , 5 , or 6 days ), or for at least 1 week , at least 2 weeks, amount of the respective prodrug such that after a single 45 etc. administration ( e.g. , intramuscular injection ) to a subject, In some embodiments, the unit dosage form is suitable for e.g. , a subject having a sex hormone - dependent benign or once a month ( or once in more than a month ) dosing , and malignant disorder ( e.g. , metastatic castration resistant pros upon a single administration ( e.g. , intramuscularly ) to a tate cancer or metastatic castration sensitive prostate can subject in need thereof, the unit dosage form achieves a PK cer ), a syndrome due to androgen excess, and / or a syndrome 50 profile characterized by one or more of the following : ( a ) the due to glucocorticoid excess such as hypercortisolemia, the unit dosage form provides a therapeutically effective blood unit dosage form provides a therapeutically effective blood plasma concentration of abiraterone in the subject for at least plasma concentration of abiraterone in the subject for a 4 weeks ; ( b ) a single dose Cmax of abiraterone of between period of at least two weeks , such as at least 3 weeks , at least about 10 ng /ml and about 400 ng /ml ( e.g. , between about 50 4 weeks , at least 5 weeks, and up to six or eight weeks or 55 ng /ml and about 100 ng /ml , or between about 15 ng /ml and more , etc. In some embodiments, the therapeutic blood about 160 ng /ml ); ( c ) no food effect; ( d ) a single dose Cm??? plasma concentration of abiraterone can be a concentration of abiraterone reduced by at least 30 % compared to the Cmax of at least 1 ng /ml , e.g. , at least 2 ng /ml , at least 4 ng /ml , at of abiraterone observed at steady state for a once daily oral least 8 ng /ml . In some embodiments , the therapeutic blood dose of Zytiga® at 1000 mg without food ; ( e ) a single dose plasma concentration of abiraterone can also be about 0.5 60 Cmin of abiraterone at day 28 post administration between ng /ml or higher. In some embodiments , the unit dosage form about 1 ng /ml and about 8 ng /ml , or above about 8 ng /ml ; is a parenteral formulation such as intramuscular, intrader ( f ) the blood plasma concentration of abiraterone remains mal , or subcutaneous formulation . In some embodiments, substantially constant, e.g. , for at least 1 week , e.g. , between the unit dosage form is a non - aqueous solution or suspen 1 week and 3 weeks post administration . In some embodi sion . In some embodiments, the unit dosage form comprises 65 ments, substantially constant for a period of time can mean the abiraterone prodrug ( e.g. , compound of Formula I or II ) that the highest concentration observed for any day ( i.e. , 24 dissolved or suspended in a pharmaceutically acceptable oil , hours ) during that time period is no greater than 4 fold , for US 10,792,292 B2 27 28 example , no greater than 2 fold , of the lowest concentration of the pharmaceutically acceptable oil as described herein . observed for the same day . No food effect should be gen Suitable co - solvents also include any of those described erally understood as that no significant differences in PK are herein , e.g. , an alcohol , an ester, and / or an acid , such as observed when the unit dosage form is administered to benzyl alcohol , benzyl benzoate, or a combination thereof, subjects with food or without food , for example , in some 5 see e.g. , Table B. One example of suitable co - solvents is embodiments, no food effect can mean that the Cmax and benzyl alcohol . One example of suitable co - solvents is a AUC of abiraterone are substantially the same ( e.g. , between combination of benzyl alcohol and benzyl benzoate . In some 80 % to 125 % ) between subjects dosed at a fed state or fasted state . A single dose Cmax as used herein should be under embodiments , no co - solvent is included in the formulation . stood as the Cmax achieved following a single administration 10 In some embodiments, the co - solvent does not include to a treatment naïve subject ( generally refers to a subject benzyl benzoate . Other optionally ingredients are described who has not received any abiraterone medication within at herein . least 3 days, such as at least 1 week , prior to the adminis tration and with no observable plasma abiraterone prior to TABLE A the administration ). A single dose Cmin used herein refers to 15 the minimum concentration observed for a given day fol Exemplary Formulations lowing a single administration to a treatment naïve subject, Amount / Concentration e.g. , at day 28 post administration . Exemplary More Exemplary In some embodiments , the unit dosage form is suitable for Ingredients Typical range Range once a month ( or once in more than a month ) dosing , and 20 Abiraterone prodrug 25 mg / ml 50 mg /ml to 75 mg /ml to 300 upon administration ( e.g. , intramuscularly ) of the unit dos (e.g. , abiraterone to 500 300 mg/ ml ; mg/ ml age form once in a month to a subject in need thereof, the acetate , abiraterone mg /ml 100 mg /ml to unit dosage form achieves ( a ) a steady state Cmax of abi decanoate , abiraterone 300 mg/ ml raterone of between about 10 ng /ml and about 400 ng /ml pentanoate, abiraterone ( e.g. , between about 50 ng /ml and about 100 ng /ml , or 25 hexanoate , abiraterone between about 15 ng /ml and about 160 ng /ml ); ( b ) no food heptanoate , abiraterone effect; ( c ) a steady state Cmax of abiraterone reduced by at isocaproate, or least 30 % compared to the Cmax of abiraterone observed at abiraterone cypionate ) steady state for a once daily oral dose of Zytiga® at 1000 mg Oil ( e.g. , castor oil , 50 % to 70 % to 100 % 80 % to 100 % of without food ; ( d ) a steady state Cmin of abiraterone between 30 corn oil ) 100 % of of solvent solvent, such as about 1 ng /ml and about 8 ng /ml , or above about 8 ng /ml ; solvent 90 % and ( g ) the blood plasma concentration of abiraterone Co - solvent ( e.g. , benzyl 0 % to 50 % 0 % to 40 % 0 % to 30 % or 0 % remains substantially constant, e.g. , for at least 1 eek , e.g. , alcohol , benzyl of solvent or 0 % to 30 % to 20 % of solvent , between 1 week and 3 weeks post each administration . A benzoate , or of solvent such as 10 % , or 30 % steady state C max or Cmin as used herein should be under- 35 combination thereof) stood as the Cmax or Cmin observed after a steady state is Other optional reached , typically following several administrations to a ingredients subject. In some embodiments, the unit dosage form can be packaged in a container such as a vial or ampule. In some 40 As shown in FIGS . 13A - 13E and the Examples section , embodiments , the unit dosage form can be included in a benzyl alcohol and / or benzyl benzoate can enhance solu pre - filled syringe or in a kit with a syringe , such as a bilities of abiraterone prodrugs of the present disclosure in disposable syringe . Other packaging and / or containers are oil vehicles , such corn oil , and can lower viscosities and also useful, which are known to those skilled in the art . In glide force of various oil vehicles, including corn oil , sesame some embodiments , a kit comprising multiple unit dosage 45 oil , peanut oil , cottonseed oil , and Miglyol 812 ( a mixture of forms described herein is also provided . In some embodi medium chain triglycerides, mainly caprylic / capric triglyc ments, the kit can further comprise a syringe . While in some erides ). In some embodiments, the present disclosure pro embodiments, it is advantageous to prepare the abiraterone vides an abiraterone prodrug formulation comprising the prodrug formulations in unit dosage forms, in some embodi abiraterone prodrug and a pharmaceutically acceptable car ments, the present disclosure also provides abiraterone pro- 50 rier, wherein the pharmaceutically acceptable carrier com drug formulations that allow multiple single uses , or abi prises a pharmaceutically acceptable oil ( e.g. , described raterone prodrug formulations that can be subdivided into multiple unit dosage forms. herein ), benzyl alcohol , and benzyl benzoate . In some Exemplary Specific Formulations embodiments , the abiraterone prodrug can be abiraterone In some embodiments , the present disclosure also pro- 55 decanoate . In some embodiments , the abiraterone prodrug vides some specific abiraterone prodrug formulations, which can be abiraterone isocaproate. The pharmaceutically can in some embodiments be in a unit dosage form or a acceptable oil typically comprises a triglyceride derived multiple unit dosage form . For example , the tables below from fatty acids . In some embodiments, the pharmaceuti ( Table A and B ) show some representative abiraterone ester cally acceptable oil can be nature oil , synthetic oil , or prodrug formulation in an oil vehicle . All numeric values in 60 semi- synthetic oil , such as fractionated coconut oil and the tables should be understood as preceded by the term medium - chain triglycerides, such as those sold under the “ about. ” The concentration of abiraterone prodrug refers to trademark Miglyol . In some embodiments, the pharmaceu the amount of abiraterone prodrug in mg per ml of the final tically acceptable oil can be selected from vegetable oil , formulation , which can be a solution or suspension . The castor oil , corn oil , sesame oil , cottonseed oil , peanut oil amount of oil ( the primary solvent) and co - solvent in the 65 ( arachis oil ) , poppy seed oil , tea seed oil , and soybean oil . In tables is expressed as volume percentage of solvent, which some embodiments , the present disclosure provides certain includes both the oil and co - solvent. Suitable oil include any exemplary formulations shown in Table B. US 10,792,292 B2 29 30 TABLE B Further Exemplary Formulations Amount/ Concentration More Exemplary Ingredients Typical Exemplary range Range Abiraterone prodrug 25 mg/ ml to 500 50 mg /ml to 300 75 mg /ml to 300 ( e.g. , abiraterone mg /ml mg /ml ; 100 mg /ml to mg /ml , such as 150 decanoate or 300 mg /ml mg ml/ to about 250 abiraterone mg /ml isocaproate ) Oil ( e.g. , corn oil , 30 % to 100 % of 50 % to 90 % of solvent 60 % to 90 % of sesame oil , peanut oil , solvent solvent, such as 70 % cottonseed oil , and / or Miglyol 812 ) Co - solvent 1 ( e.g. , 0 % to 20 % of solvent 0 % to 15 % of solvent 0 % to 10 % of solvent , benzyl alcohol ) such as 10 % benzyl benzoate 0 % to 50 % of solvent 0 % to 35 % of solvent 0 % to 30 % of solvent , such as 20 % Other optional ingredients

In some embodiments, the present disclosure also pro the method comprising administering to the subject any of vides the following specific formulations : abiraterone the abiraterone prodrugs or abiraterone prodrug formula acetate solution in Castor oil with a concentration of about 25 tions of the present disclosure . In some embodiments, the 50 mg/ mL to about 200 mg/ mL ( such as 70 mg/ mL ) ; subject suffers from a sex hormone -dependent benign or abiraterone acetate solution in 10 % Benzyl alcohol/ 90 % malignant disorder, e.g. , an androgen -dependent or an estro Castor oil with a concentration of about 50 mg /mL to about gen - dependent disorder as described herein . In some 200 mg /mL ( such as about 90 mg/ mL ); abiraterone acetate embodiments , the subject suffers from a syndrome due to solution in 50 % Benzyl benzoate / 50 % Castor oil with a 30 androgen excess and / or a syndrome due to glucocorticoid concentration of about 50 mg /mL to about 200 mg /mL ( such excess such as hypercortisolemia , e.g. , as described herein . as about 125 mg /mL ); abiraterone propionate solution in In any of the embodiments described herein , unless directly 10 % Benzyl alcohol / 90 % Castor oil with a concentration of contradictory, the subject can be a human subject, e.g. , a about 50 mg/ mL to about 300 mg /mL ( such as about 200 human patient having a hormone - dependent benign or mg/ mL ); abiraterone propionate solution in 10 % Benzyl 35 malignant disorder, a syndrome due to androgen excess , alcohol / 90 % Corn oil with a concentration of about 50 and / or a syndrome due to glucocorticoid excess such as mg /mL to about 300 mg /mL ( such as about 168 mg/ mL ); hypercortisolemia , e.g. , as described herein . Hormone -de abiraterone decanoate solution in Castor oil with a concen pendent benign or malignant disorder as used herein , tration of about 100 mg / mL to about 300 mg /mL ( such as whether preceded with the term “ sex ” should be understood 160 mg /mL or 170 mg/ mL ); abiraterone decanoate solution 40 as sex hormone -dependent benign or malignant disorder, in Corn oil with a concentration of about 100 mg /mL to such as androgen - dependent or estrogen - dependent disor about 300 mg /mL ( such as 160 mg/ mL or 170 mg/ mL ); ders . abiraterone decanoate solution in 10 % Benzyl alcohol/ 90 % As detailed herein , in a monkey PK study, it was shown Castor oil with a concentration of about 100 mg /mL to about that a single intramuscular injection of a representative 300 mg/ mL ( such as 160 mg/ mL or 170 mg/ mL ); abiraterone 45 abiraterone prodrug, abiraterone decanoate , can achieve a decanoate solution in 10 % Benzyl alcohol/ 90 % Corn oil prolonged CYP17A1 inhibition, with sustained increase of with a concentration of about 100 mg /mL to about 300 progesterone level and reduction of cortisol and testosterone mg /mL ( such as 160 mg/ mL or 170 mg /mL ); abiraterone level up to eight weeks. As shown in FIG . 14D , it is expected decanoate solution in 70 % Corn Oil , 10 % Benzyl Alcohol , that inhibition of CYP17A1 17a -hydroxylase and C17,20 20 % Benzyl Benzoate with a concentration of about 150 50 lyase activities will lead to ( 1 ) increases in levels of pro mg/ mL to about 300 mg /mL ( such as about 200 mg /ml or gesterone and the mineralocorticoids; ( 2 ) reductions lev about 240 mg /ml ) ; abiraterone isocaproate 90 % in Corn Oil , els of glucocorticoids such as cortisol; and ( 3 ) reductions in 10 % Benzyl Alcohol Solution with a concentration of about levels of sex hormones , e.g. , androgens such as testosterone 120 mg /mL to about 200 mg/ mL ( such as about 150 mg/ ml and dihydrotestosterone, and estrogens such as estradiol. or about 160 mg /ml ) . In some embodiments, the present 55 Thus, the abiraterone prodrugs and prodrug formulations of disclosure also provides any of the specific formulations the present disclosure can be advantageously used for inhib prepared herein such as in Examples 3A - 3J . In some iting CYP17A1 activity, reducing glucocorticoids levels , embodiments, the present disclosure also provides a formu such as cortisol levels , reducing sex hormone levels such as lation described herein in Example 1 . androgen and / or estrogen levels , and / or treating disorders Method of Treatment 60 associated with high glucocorticoids levels , such as cortisol Some embodiments of the present disclosure are directed levels , and / or treating disorders due to high sex hormone to methods of delivering abiraterone to a subject in need levels such as androgen and / or estrogen levels . thereof. In various embodiments, the present disclosure also In some embodiments, the present disclosure provides a provides methods of treating or prevent diseases or disorders method of inhibiting CYP17A1 activity such as inhibiting for which administering abiraterone is beneficial . 65 17a -hydroxylase activity and 17,20 - lyase activity , the In some embodiments , the present disclosure provides a method comprising administering to the subject any of the method of delivering abiraterone to a subject in need thereof, abiraterone prodrugs or abiraterone prodrug formulations of US 10,792,292 B2 31 32 the present disclosure . In some embodiments, the subject cancer. In some embodiments, the sex hormone -dependent suffers from a sex hormone - dependent benign or malignant benign or malignant disorder can be metastatic castration disorder, e.g. , as described herein . In some embodiments , the resistant prostate cancer or metastatic castration sensitive subject suffers from a syndrome due to androgen excess prostate cancer . In some embodiments , the sex hormone and / or a syndrome due to glucocorticoid excess such as 5 dependent benign or malignant disorder can also be ovarian hypercortisolemia, e.g. , as described herein . cancer , bladder cancer, hepatocellular carcinoma, or lung In some embodiments , the present disclosure provides a cancer . Various non - oncologic syndromes due to androgen method of reducing the level of glucocorticoids ( e.g. , cor excess and / or due to glucocorticoid excess such as hyper tisol ) in a subject in need thereof, the method comprising cortisolemia can also be treated with the methods herein , for administering to the subject any of the abiraterone prodrugs 10 example, syndromes due androgen excess such as endo or abiraterone prodrug formulations of the present disclo metriosis, polycystic ovary syndrome, classical or nonclas sure . In some embodiments, the subject suffers from a sical congenital adrenal hyperplasia , precocious puberty , syndrome due to glucocorticoid excess such as hypercorti hirsutism , etc., and / or syndromes due to cortisole excess solemia as described herein , such as Cushing's syndrome or such as Cushing's syndrome, Cushing's disease , etc. Cushing's disease. 15 The methods herein can be used in conjunction with one In some embodiments, the present disclosure provides a or more additional therapies for the respective disease or method of reducing the level of androgens ( e.g. , testosterone disorder . For example, the Zytiga® label (abiraterone and / or dihydrotestosterone) and / or estrogens in a subject in acetate ) states that patients receiving Zytiga® should also need thereof, the method comprising administering to the receive a gonadotropin - releasing hormone (GnRH ) analog subject any of the abiraterone prodrugs or abiraterone pro- 20 concurrently or should have had bilateral orchiectomy. drug formulations of the present disclosure . In some Accordingly, in some embodiments of methods of the pres embodiments, the subject suffers from a syndrome due to ent disclosure , the subject can also be treated with a gonado androgen excess , such as congenital adrenal hyperplasia tropin - releasing hormone analog and / or bilateral orchiec ( e.g. , classical or nonclassical congenital adrenal hyperpla tomy. In some embodiments, the method also comprises sia ) , endometriosis , polycystic ovary syndrome precocious 25 administering to the subject an effective amount of pred puberty, hirsutism , etc. In some embodiments, the subject nisone or prednisolone , either concurrently or sequentially. suffers from an androgen and / or estrogen associated cancer , However, in some embodiments , the methods herein can such as prostate cancer or breast cancer . also achieve the desired therapeutic effect without causing In some embodiments, a method of treating a sex hor adrenocortical insufficiency, which thus can avoid co - ad mone - dependent benign or malignant disorder, a syndrome 30 ministering prednisone or prednisolone. In some embodi due to androgen excess and / or a syndrome due to glucocor ments, the subject is not treated with a gonadotropin ticoid excess such as hypercortisolemia is provided . Typi releasing hormone analog and / or bilateral orchiectomy. In cally, the method comprises administering to a subject in some embodiments, the subject is not administered with need thereof a therapeutically effective amount of any of the prednisone or prednisolone. abiraterone prodrugs or abiraterone prodrug formulations of 35 In some embodiments, the method can comprise admin the present disclosure . In any of the embodiments described istering one or more other drug or agent ( for example , herein , unless directly contradictory, the subject can be a another cancer chemotherapeutic drug, hormone replace human subject, e.g. , a human patient having a hormone ment drug, or hormone ablation drug) to the subject, either dependent benign or malignant disorder, a syndrome due to concurrently or sequentially , through the same route or a androgen excess and / or a syndrome due to glucocorticoid 40 different route of administration . In some embodiments , the excess such as hypercortisolemia, e.g. , as described herein . other drug or agent can be a steroid , such as prednisone, The administering in the methods herein is not limited to prednisolone, and / or methylprednisolone . In some embodi any particular route . However, in some preferred embodi ments, the other drug or agent can be a chemotherapy drug, ments , the administering can be a parenteral administration , such as paclitaxel, mitoxantrone, and / or docetaxel. In some such as an intramuscular injection , intradermal injection , or 45 embodiments, the other agent or drug can be a GnRH subcutaneous injection . Parenteral administration can in agonist , such as Leuprolide , deslorelin , goserelin , or trip some embodiments be advantageous. For example, in some torelin , e.g. , leuprolide acetate ( e.g. , a long acting IM embodiments, the administering can be a parenteral admin injectable formulation ). In some embodiments , the other istration , such as an intramuscular injection , which can be agent or drug can be seocalcitol , bicalutamide , flutamide, a carried out without regard to whether the subject has food . 50 glucocorticoid including, but not limited to , hydrocortisone, In other words , the fed or fasted status of the subject is not prednisone , prednisolone, or dexamethasone . The amount of important. This removes the restriction associated with the the other drugs or agents to be administered can vary , currently marketed Zytiga® formulation , which states that typically can be an amount that is effective in treating the the medication “ must be taken on an empty stomach with respective disease or disorder ( e.g. , prostate cancer ) either water at least 1 hour before or 2 hours after a meal . ” 55 alone or in combination with the abiraterone prodrug or Therefore, among other advantages, the methods herein can abiraterone prodrug formulation of the present disclosure . improve patient compliance. Additional suitable other drugs or agents include those Various sex hormone- dependent benign or malignant dis described herein . For example, useful other drugs or agents orders can be treated with the methods herein . In some include , but are not limited to , anticancer agents, hormone embodiments, the hormone -dependent benign or malignant 60 ablation agents, anti- androgen agents, differentiating agents, disorders can be androgen - dependent disorders and estro anti- neoplastic agents, kinase inhibitors, anti- metabolite gen - dependent disorders such as androgen or estrogen agents, alkylating agents , antibiotic agents, immunological dependent cancers . In some embodiments , the sex hormone agents , interferon - type agents , intercalating agents , growth dependent benign or malignant disorder can be prostate factor inhibitors , cell cycle inhibitors, enzymes , topoi cancer or breast cancer. In some embodiments, the sex 65 somerase inhibitors, biological response modifiers , mitotic hormone - dependent benign or malignant disorder is castra inhibitors, matrix metalloprotease inhibitors, genetic thera tion resistant prostate cancer or castration sensitive prostate peutics, and anti - androgens. US 10,792,292 B2 33 34 For example, suitable anti - cancer agents, including but yguanosine, didox , doxifluridine , fazarabine, floxuridine , not limited to , acemannan , aclarubicin , aldesleukin , alem fludarabine phosphate , 5 - fluorouracil, N-( 2 - furanidyl) -5 tuzumab , alitretinoin , altretamine, amifostine, amsacrine, fluorouracil, isopropyl pyrrolizine, methobenzaprim , metho anagrelide , anastrozole , ancestim , bexarotene, broxuridine, trexate , norspermidine, pentostatin , piritrexim , plicamycin , capecitabine , celmoleukin , cetrorelix , cladribine , clotrima- 5 thioguanine, tiazofurin , trimetrexate, tyrosine kinase inhibi zole , daclizumab , dexrazoxane , dilazep , docosanol, doxiflu tors , and uricytin . Suitable alkylating agents may be selected ridine , bromocriptine , carmustine, cytarabine, diclofenac , from , but not limited to , aldo -phosphamide analogues, edelfosine , edrecolomab , eflornithine , emitefur, exemestane , altretamine, anaxirone, bestrabucil, budotitane, carboplatin , exisulind , fadrozole , filgrastim , finasteride, fludarabine carmustine, chlorambucil, cisplatin , cyclophosphamide, phosphate , formestane , fotemustine, gallium nitrate , gem- 10 cyplatate, diphenylspiromustine, diplatinum cytostatic, citabine , glycopine , heptaplatin , ibandronic acid , imiqui elmustine , estramustine phosphate sodium , fotemustine, mod , iobenguane, irinotecan , irsogladine , lanreotide, hepsul- fam , ifosfamide , iproplatin , lomustine, mafosfamide, leflunomide, lenograstim , lentinan sulfate, letrozole , liaro mitolactol , oxaliplatin , prednimustine, ranimustine, semus zole , lobaplatin , lonidamine, masoprocol, melarsoprol , tine , spiromustine, tauromustine , temozolomide, teroxirone, metoclopramide, mifepristone, miltefosine, mirimostim , 15 tetraplatin and trimelamol. Suitable antibiotic agents may be mitoguazone, mitolactol , molgramostim , nafarelin , nar selected from , but not limited to , aclarubicin , actinomycin tograstim , nedaplatin , nilutamide , noscapine , oprelvekin , D , actinoplanone, adriamycin , aeroplysinin derivative, osaterone , oxaliplatin , pamidronic acid , pegaspargase , pen amrubicin , anthracycline, azino -mycin - A , bisucaberin , bleo tosan polysulfate sodium , pentostatin , picibanil, pirarubicin , mycin sulfate, bryostatin - 1, calichemycin , chromoximycin , porfimer sodium , raloxifene, raltitrexed , rasburicase, ritux- 20 dactinomycin , daunorubicin, ditrisarubicin B , dexametha imab , romurtide, sargramostim , sizofiran , sobuzoxane , son sone, doxorubicin , doxorubicin - fibrinogen , elsamicin - A , ermin , suramin , tasonermin , tazarotene, tegafur , temoporfin , epirubicin , erbstatin , esorubicin , esperamicin - A1, esperami temozolomide , teniposide, tetrachlorodecaoxide , thalido cin - Alb , fostriecin , glidobactin , gregatin - A , grincamycin , mide , thymalfasin , thyrotropin alfa , topotecan , toremifene , herbimycin , corticosteroids such as hydrocortisone , idaru trastuzumab , treosulfan , tretinoin , trilostane , trimetrexate, 25 bicin , illudins , kazusamycin , kesarirhodins, menogaril, ubenimex , valrubicin , verteporfin , vinorelbine . Suitable mitomycin , neoenactin , oxalysine , oxaunomycin , peplomy anti - androgen agents include but are not limited to bicalu cin , pilatin , pirarubicin , porothramycin , prednisone, predni tamide, flutamide and nilutamide . Suitable differentiating solone , pyrindanycin A , rapamycin , rhizoxin , rodorubicin , agents include, but are not limited to , polyamine inhibitors ; sibanomicin , siwenmycin , sorangicin - A , sparsomycin, tal vitamin D and its analogs, such as , calcitriol, doxercalciferol 30 isomycin , terpentecin , thrazine, tricrozarin A , and zorubicin . and seocalcitol ; metabolites of vitamin A , such as , ATRA , Non - limiting examples of suitable steroids include hydro retinoic acid , retinoids, short- chain fatty acids ; phenylbu cortisone, prednisone , prednisolone , or dexamethasone . tyrate ; and nonsteroidal anti - inflammatory agents . anti- neo Dosing Regimen plastic agent , including, but not limited to , tubulin interact The abiraterone prodrugs and formulations of the present ing agents , topoisomerase inhibitors and agents, acitretin , 35 disclosure can generally provide a long - acting release of alstonine, amonafide, amphethinile, amsacrine , ankinomy abiraterone to a subject user . This long - acting release profile cin , anti -neoplaston , aphidicolin glycinate, asparaginase, allows administering abiraterone to a subject user at a low baccharin , batracylin , benfluron , benzotript, bromofosf dosing frequency, such as once a week or even less fre amide , caracemide, carmethizole hydrochloride, chlorsulfa quently, which can improve patient compliance and reduce quinoxalone , clanfenur, claviridenone, crisnatol, curaderm , 40 pill burdens . cytarabine, cytocytin , dacarbazine, datelliptinium , dihae In some embodiments , the methods herein can have a matoporphyrin ether, dihydrolenperone, dinaline, distamy dosing regimen of once a week or once in more than a week . cin , docetaxel, elliprabin , elliptinium acetate , epothilones, Typically, the dosing frequency can range from once a week ergotamine , etoposide, etretinate, fenretinide, gallium to once every few months, such as from once a week to once nitrate , genkwadaphnin , hexadecylphosphocholine, homo- 45 every eight weeks , or from once a week to once every three harringtonine, hydroxyurea, ilmofosine, isoglutamine, isot months. In some embodiments, the dosing amount for each retinoin , leukoregulin , lonidamine , merbarone , merocyanine dose is about 50 mg to about 2000 mg ( e.g. , about 500 mg , derivatives, methylanilinoacridine, minactivin , mitonafide , about 1000 mg , about 1500 mg , or any ranges between the mitoquidone, mitoxantrone , mopidamol , motretinide , recited values ) of abiraterone prodrug. In some embodi N- ( retinoyl ) amino acids, N - acylated - dehydroalanines , 50 ments, the dosing amount of abiraterone prodrug for each nafazatrom , nocodazole derivative , ocreotide, oquizanocinc , dose is about 0.5 mg/ kg to about 100 mg / kg ( e.g. , about 0.5 paclitaxel , pancratistatin , pazelliptine, piroxantrone, poly mg /kg , about 1 mg/ kg , about 5 mg /kg , about 10 mg /kg , haematoporphyrin , polypreic acid , probimane , procarba about 20 mg/ kg , about 30 mg/ kg , about 50 mg /kg , about 90 zine , proglumide, razoxane , retelliptine, spatol , spirocyclo mg/ kg , about 100 mg/ kg , or any ranges between the recited propane derivatives, spirogermanium , strypoldinone, 55 values ) of body weight of a subject. In some embodiments, superoxide dismutase , teniposide, thaliblastine, tocotrienol, the methods herein can comprise administering to the sub topotecan , ukrain , vinblastine sulfate , vincristine , vindesine, ject in need thereof an abiraterone prodrug or abiraterone vinestramide, vinorelbine , vintriptol, vinzolidine , and witha prodrug formulation of the present disclosure, once a week , nolides . a kinase inhibitor including p38 inhibitors and CDK or once in more than a week , such as once in two weeks , inhibitors, TNF inhibitors, metallomatrix proteases inhibi- 60 once in a month , wherein the administering provides a tors ( MMP ) , COX - 2 inhibitors including celecoxib , rofe therapeutically effective plasma concentration ( e.g. , as coxib , parecoxib , valdecoxib , and etoricoxib , SOD mimics described herein , such as 0.5 ng /ml and above, 1 ng /ml and or a , B3 inhibitors. Suitable anti -metabolite agents may be above , 8 ng /ml and above , or 8.4 ng /ml and above ) of selected from , but not limited to , 5 - FU - fibrinogen , acanthi abiraterone in the subject for a prolong period of time , such folic acid , aminothiadiazole, brequinar sodium , carmofur, 65 as more than 1 week , more than 2 weeks , more than 3 weeks, cyclopentyl cytosine, cytarabine phosphate stearate , cytara more than 4 weeks , and up to six or eight weeks or more , etc. bine conjugates, dezaguanine , dideoxycytidine, dideox In some embodiments, the administering can provide a US 10,792,292 B2 35 36 single dose Cmax of abiraterone between about 10 ng /ml and CH3 , wherein n is an integer between 0 and 12 ; or R2 in about 400 ng /ml ( e.g. , between about 50 ng /ml and about Formula II can be represented by the formula ( CH2 ) n - Cy , 100 ng/ ml , or between about 15 ng /ml and about 160 ng /ml ). wherein n is an integer of 1-6 , and Cy is a C3-6 cycloalkyl In some embodiments, the administering can provide a or phenyl, for example, in more specific embodiments , n can steady state Cmax of abiraterone between about 10 ng /ml and 5 be 1 or 2 , and Cy is cyclopentyl, cyclohexyl, or phenyl; or about 400 ng /ml ( e.g. , between about 50 ng / ml and about R2 in Formula II can be 100 ng /ml , or between about 15 ng /ml and about 160 ng /ml ) . In some embodiments, the administering can provide a single dose Cmin of abiraterone between about 1 ng /ml and about 8 ng /ml , or above about 8 ng / ml such as above 8.4 10 ng /ml , at each day from day 1 to day 7 , or day 1 to day 14 , or day 1 to day 21 , or day 1 to day 28 post administration . In some embodime ts , the administering can provide a steady state Cmin of abiraterone between about 1 ng /ml and about 8 ng /ml , or above about 8 ng /ml such as above 8.4 15 ng /ml . xro Abiraterone prodrugs suitable for use for a once a week or or once in more than a week dosing methods above include those described herein . In some embodiments, the abirater one prodrug can be a lipophilic ester of abiraterone 20 described herein , for example, an acetate , a propionate, a butanoate , a ( vaterate ) pentanoate, an isocaproate, a buci clate, a cyclohexanecarboxylate , a phenyl propionate, caproate ( hexanoate ), a enanthate ( heptanoate ), a cypionate , an octanoate , a noncanoate , a decanoate , an undecanoate , a 25 not dodecanoate, a tridecanoate, a tetradecanoate, a pentade In some embodiments, the abiraterone prodrug can also be canoates , and a hexadecanoate . In some preferred embodi abiraterone acetate or any of the Examples 2A - 2H . In some ments , the abiraterone prodrug can be a compound of embodiments, the abiraterone prodrug can be abiraterone RFormula ' is a IC7-16 , for examplealkyl, e.g., a ,compound an alkyl ofhaving Formula a formulaI , wherein of 30 acetate, abiraterone propionate, or abiraterone decanoate. In ( CH2 ) n - CH3 , wherein n is an integer between 6 and 12 some specific embodiments, the abiraterone ester can be ( e.g. , n is 6 , 7 ,8 , 9 , 10 ); or R is represented by the formula abiraterone pentanoate , abiraterone hexanoate, abiraterone - (CH2 ) n - Cy, wherein n is an integer of 1-6 , and Cy is a C3-6 he ate , abiraterone decanoate , abiraterone isocaproate, cycloalkyl or phenyl, for example, in more specific embodi or abiraterone cypionate. In any of the embodiments ments, n can be 1 or 2 , and Cy is cyclopentyl, cyclohexyl , 35 described herein , unless otherwise specified or directly con or phenyl; or R1 is tradictory from context, the abiraterone prodrug can be abiraterone decanoate . In some embodiments, a once a month or once in more than a month dosing is desired , e.g. , the dosing frequency 40 ranges from once a month to once every few months, such as from once a month to once every two months, or from once a month to once every three months. In such embodi ments, the abiraterone prodrug needs to not only release abiraterone slowly but also to release abiraterone in a or Rl is 45 sufficient plasma concentration such that it can be beneficial to the subject user. The once a month or once in more than a month dosing is typically a parenteral administration , such as intramuscularly, intradermally, or subcutaneously . In any of the embodiments herein , unless directly contradictory, the 50 administration can be an intramuscular administration . As detailed herein , a single intramuscular administration of abiraterone acetate was found to provide extended release of abiraterone . However, the dog PK study shows that similar administration of abiraterone propionate did not 55 improve the extend release of abiraterone acetate , and in or fact, the abiraterone release observed from the propionate was below that observed for the acetate at all time points measured . Further, it was also unexpectedly found that elongation of the alkyl chain to abiraterone butanoate led to 60 a sharp reduction of solubility in various oil vehicle . Despite of this unexpected trend, the present inventors found that certain abiraterone prodrugs or abiraterone prodrug formu lations of the present disclosure , for example, compounds of Formula I , such as abiraterone decanoate , can be superior for In some embodiments, the abiraterone prodrug can be a 65 use in a once a month or once in more than a month dosing compound of Formula II , wherein R2 in Formula II can be than the acetate , propionate , or butanoate . It was also found a C1-16 alkyl, e.g. , an alkyl having a formula of— (CH2 ) n that the PK profile, such as t1 / 2 , of certain abiraterone US 10,792,292 B2 37 38 prodrugs or abiraterone prodrug formulations of the present and about 100 ng /ml , or about 15 ng /ml and about 160 disclosure , for example, compounds of Formula I , such as ng /ml ). In some embodiments , the administering can pro abiraterone decanoate , does not vary significantly when a vide a steady state Cmax of abiraterone between about 10 different oil vehicle is used . In contrast, as detailed in ng / ml and about 400 ng /ml ( e.g. , between about 50 ng /ml Example 5B , some variabilities of PK profiles for abirater- 5 and about 100 ng /ml , or between about 15 ng /ml and about one propionate were observed , depending on whether it was 160 ng /ml ) . In some embodiments , the administering can formulated in castor oil or corn oil . provide a single dose Cmin of abiraterone at day 28 post In some specific embodiments, the present disclosure administration between about 1 ng /ml and about 8 ng /ml , or provides a method of treating a sex hormone -dependent above about 8 ng /ml , e.g. , above about 8.4 ng /ml . In some benign or malignant disorder ( e.g. , as described herein ) , a 10 embodiments, the administering can provide a steady state syndrome due to androgen excess , and /or a syndrome due to Cmin of abiraterone between about 1 ng /ml and about 8 glucocorticoid excess such as hypercortisolemia , in a subject ng /ml , or above about 8 ng /ml , e.g. , above about 8.4 ng /ml . in need ther the method comprising parenterally admin In some embodiments, the blood plasma concentration of istering to the subject a therapeutically effective amount of abiraterone in the subject can remain substantially constant, a compound of Formula I ( e.g. , described herein ), or a 15 e.g. , for at least 1 week , e.g. , between 1 week and 3 weeks pharmaceutical composition comprising the compound of post administration . In some embodiments, the administer Formula I ( e.g. , described herein ), once a month or once in ing is carried out without regard to whether the subject has more than a month . In some embodiments, the parenterally food . In some embodiments , the administering provides a administering is intramuscularly, intradermally , or subcuta single dose Cmax of abiraterone reduced by at least 30 % neously administering. In some preferred embodiments , in 20 compared to the Cmax of abiraterone observed at steady state the compound of Formula 1 , R ' is a C7-16 alkyl, e.g. , an alkyl for a once daily oral dose of Zytiga® at 1000 mg without having a formula of — (CH2 ) n CH3, wherein n is an integer food . In some embodiments, the administering provides a between 6 and 12 ( e.g. , n is 6 , 7 , 8 , 9 , or 10 ) ; or R ' is steady state Cmax of abiraterone reduced by at least 30 % represented by the formula ( CH2 ) n - Cy , wherein n is an compared to the Cmax of abiraterone observed at steady state integer of 1-6 , and Cy is a C3-6 cycloalkyl or phenyl, for 25 for a once daily oral dose of Zytiga® at 1000 mg without example , in more specific embodiments , n can be 1 or 2 , and food . In some embodiments, the pharmaceutical composi Cy is cyclopentyl, cyclohexyl, or phenyl; or R is tion comprising the compound of Formula I can be formu lated as a unit dosage form described herein . Suitable carriers, oil vehicles , excipients for such pharmaceutical 30 compositions include those described herein . The abiraterone prodrugs and abiraterone prodrug formu lations of the present disclosure can be administered to a subject in need thereof as the only source of abiraterone . However, in some embodiments, other abiraterone medica 35 tions / formulations are not excluded . For example, in some or Rl is embodiments, the administering herein can be combined , either concurrently or sequentially in any order, with an oral administration of abiraterone acetate , such as the Zytigar formulation . In some embodiments, the subject can use the ni 40 abiraterone prodrugs and abiraterone prodrug formulations as a supplement to an existing abiraterone therapy. More over, the administering herein is not limited to administering a single abiraterone prodrug or abiraterone prodrug formu lation of the present disclosure . In some embodiments , two 45 or more abiraterone prodrugs and abiraterone prodrug for mulations of the present disclosure can be administered to or the subject. In some embodiments , prior to a once a month or once in more than a month dosing, the methods herein can include 50 an initial treatment period with a higher dosing frequency, such as a once a week or once in two weeks dosing . The initial treatment period can include administering the same abiraterone prodrug or a different abiraterone medication such as a different abiraterone prodrug. Typically, the initial 55 treatment period can be used to achieve a blood plasma In some embodiments , the administering provides a thera concentration of abiraterone of about 1 ng /ml to about 8 peutically effective blood plasma concentration of abirater ng/ ml or above about 8 ng/ ml , prior to the once a month or one in the subject for a period of at least 4 weeks , such as once in more than a month dosing described herein . How at least 5 weeks , and up to six or eight weeks or more , etc. ever, in some embodiments, the methods herein do not In some embodiments, the therapeutic blood plasma con- 60 include such initial treatment period. centration of abiraterone can be a concentration of at least 1 As discussed herein , the abiraterone prodrugs and abi ng /ml , e.g. , at least 2 ng /ml , at least 4 ng /ml , at least 8 ng /ml . raterone prodrug formulations of the present disclosure have In some embodiments, the therapeutically effective blood many advantages over the currently marketed Zytiga® prod plasma concentration of abiraterone can also be about 0.5 uct . For example , administering the abiraterone prodrugs ng /ml or higher. In some embodiments, the administering 65 and abiraterone prodrug formulations of the present disclo can provide a single dose Cmax of abiraterone between about sure to a subject typically results in reduced Cmax of abi 10 ng /ml and about 400 ng /ml ( e.g. , between about 50 ng /ml raterone ( e.g. , reduced by at least 30 % compared to the Cmax US 10,792,292 B2 39 40 of abiraterone observed at steady state for a once daily oral CYP17A1 inhibition , with sustained increase of progester dose of Zytiga at 1000 mg without food ). one level and reduction of cortisol and testosterone level . Thus, in some embodiments, the present disclosure pro Further, based on the PK studies in rats , dogs, and monkeys, vides a method of treating subjects having side effects a human PK prediction was made based on allometric related to high abiraterone exposure , such as having abi- 5 scaling. As shown in FIG . 16C , based on allometric scaling , raterone Cmax related side effects, the method comprising administering abiraterone prodrugs and abiraterone prodrug it was predicted that following intramuscular doses of abi formulations of the present disclosure to the subject, raterone decanoate , once in every 4 weeks with about 1000 wherein the administering reduces the side effects when mg each dose , to a human , a Cmin is expected to be at 5 compared to administering of a once daily oral dose of 10 ng /mL at steady state . Additionally, as detailed in the Zytiga® at 1000 mg without food . Suitable routes of admin Examples section and FIG . 14F , it was unexpectedly found istration , dosing amounts , frequencies include those that abiraterone decanoate formulations with certain com described herein . Various side effects or adverse effects are bination of oil and solvents can achieve significantly higher described in the Zytiga® prescribing information approved abiraterone plasma concentrations in monkeys following IM by the FDA , see e.g. , the February 2018 or June 2019 15 injections compared to abiraterone decanoate formulation in version . In some embodiments , the present disclosure pro 90 % corn oil and 10 % benzyl alcohol at the same dose , with vides a method of treating subjects who are also adminis abiraterone decanoate concentration substantially the same . tered a drug , the metabolism of which is inhibited by Thus, the dosing amount of abiraterone decanoate needed to abiraterone , for example, drugs that are CYP2D6 and / or achieve the predicted Cmin of 5 ng /mL at steady state can be CYP2C8 substrates, the method comprising administering to 20 lowered . Alternatively, the steady state Cmin can also be the subject the abiraterone prodrugs and abiraterone prodrug increased to above the predicted level of 5 ng /mL . These formulations of the present disclosure, wherein the admin disclosures demonstrate that abiraterone can be delivered in istering reduces the inhibition of the metabolism of the drug a therapeutically effective amount to a subject ( e.g. , a human when compared to administering of a once daily oral dose of subject) by injection of an abiraterone prodrug, such as an Zytiga® at 1000 mg without food . In some embodiments, 25 abiraterone lipophilic ester prodrug, more particularly, abi the present disclosure provides a method of treating a raterone decanoate, with a less frequent dosing than once a subject who has , or is at risk of having, hypertension, week , such as once in two weeks, once a month , or once in hypokalemia , or fluid retention due to mineralocorticoid more than a month . Typically, the dosing frequency can excess , the method comprising administering to the subject range from once a week to once every few months, such as the abiraterone prodrugs and abiraterone prodrug formula- 30 from once a week to once every eight weeks , or from once tions of the present disclosure, wherein the administering a week to once every three months, such as once a month , reduces hypertension , hypokalemia , and fluid retention or once every eight weeks, etc. the risk of hypertension , hypokalemia , and fluid retention In some specific embodiments, the present disclosure when compared to administering of a once daily oral dose of provides a compound , which is abiraterone decanoate hav Zytiga® at 1000 mg without food. In some embodiments, 35 ing the formula of: the present disclosure provides a method of treating a subject who has , or is at risk of having, adrenocortical insufficiency , the method comprising administering to the subject the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure , wherein the admin- 40 istering reduces adrenocortical insufficiency or the risk of having adrenocortical insufficiency when compared to administering of a once daily oral dose of Zytiga® at 1000 mg without food . In some embodiments, the present disclo sure provides a method of treating a subject who has severe 45 or fatal hepatotoxicity after taking Zytiga® , the method comprising administering to the subject the abiraterone prodrugs and abiraterone prodrug formulations of the pres or a pharmaceutically acceptable salt thereof. In some ent disclosure, wherein the administering reduces hepato embodiments, abiraterone decanoate can be in its basic toxicity . Without wishing to be bound by theories, it is 50 form . In some embodiments, abiraterone decanoate can also believed that administering the abiraterone prodrugs and be in a pharmaceutically acceptable salt , such as an oxalate abiraterone prodrug formulations of the present disclosure salt , a hydrochloride salt , a benzene sulfonate salt , a p - tolu typically results in a reduced , yet efficacious abiraterone ene sulfonate salt , a phosphate salt , etc. In some embodi exposure and therefore is beneficial for subjects who need a ments , the salts of abiraterone decanoate can be used as a lower dose of abiraterone , e.g. , as described above . Suitable 55 synthetic intermediate for the preparation and purification of dosing regimens , routes of administrations include those abiraterone decanoate in its basic form . As discussed herein , described herein . abiraterone decanoate is typically present in the abiraterone Abiraterone Decanoate prodrug formulation herein in its basic form . Unless spe Some embodiments of the present disclosure are specifi cifically referred to as in its salt form or otherwise contra cally directed to abiraterone decanoate. As discussed in more 60 dictory from context, abiraterone decanoate should be details in the Examples section , pharmacokinetic studies understood as in its basic form . show that intramuscular injection of abiraterone decanoate Abiraterone decanoate or its pharmaceutically acceptable formulations can provide a therapeutically effective amount salts can be readily prepared by those skilled in the art in of plasma abiraterone for an extended period of time in view of the present disclosure. Some exemplary methods of various animal models . In the monkey PK studies , it was 65 synthesis are described herein . In some embodiments, the further shown that a single intramuscular injection of abi present disclosure provides a method of synthesizing abi raterone decanoate formulation can achieve a prolonged raterone decanoate , which comprises reacting abiraterone US 10,792,292 B2 41 42 with decanoic acid , or an activated form thereof, such as the abiraterone decanoate are also described in the Examples corresponding acyl chloride, anhydride ( e.g. , mixed anhy section . The substantially pure abiraterone decanoate can be dride ), etc. The reaction can be typically carried out in the in a solid form ( e.g. , a crystalline form described herein , presence of a coupling agent, such as a carbodiimide. As amorphous form , or a combination thereof) or in a solution , shown in the Examples section , the coupling of abiraterone 5 suspension , or another form . For the avoidance of doubt, an and decanoic acid can be carried out in the presence of abiraterone prodrug formulation comprising the substan 1 - Ethyl -3- (3 -dimethylaminopropyl )carbodiimide , a base tially pure abiraterone decanoate herein and one or more ( such as triethyl amine ) and a catalytic amount of DMAP . other ingredients should be understood as a mixture of the Salts of abriaterone decanoate can be prepared by reacting substantially pure abiraterone decanoate herein and the one abiraterone decanoate with a suitable acid , such as oxalic 10 or more other ingredients , for example, such formulation can acid , benzene sulfonic acid , p - toluene sulfonic acid , hydro be obtained directly or indirectly from mixing ( e.g. , dissolv chloric acid , or phosphoric acid , typically in an organic ing , suspending, or otherwise forming a mixture ) the sub solvent such as isopropyl acetate , ethyl acetate , etc. stantially pure abiraterone decanoate with the one or more a solidIn some form embodiments such as a crystalline, abiraterone form decanoate, an amorphous can exist form in , is other ingredients , such as pharmaceutically acceptable oil , or a combination thereof. For example, in some embodi solvent, etc. ments, the present disclosure provides abiraterone decanoate In some specific embodiments, the present disclosure in a crystalline form . In some embodiments, the crystalline provides a pharmaceutical composition comprising abirater form can be characterized by an X -Ray Power Diffraction one decanoate having the formula of: ( XRPD ) spectrum having one or more ( e.g. , 1 , 2 , 3 , 4 , 5 , 6 , 20 7 , 8 , or 9 ) of the following peaks : 4.6 , 6.9 , 8.7 , 17.5 , 18.3 , 18.6 , 19.1 , 19.6 , and 20.8 , degrees 2 theta , + 0.2 ° ; a Differ ential Scanning Calorimetry ( DSC ) pattern having an endo thermic peak with an onset temperature at about 69.0 ° C .; or a combination thereof. In some embodiments, the crystalline 25 form can be characterized by an XRPD spectrum substan tially the same as shown in FIG . 12A , for example , the XRPD spectrum shows peaks at the respective diffraction i angels ( degrees 2 theta , 10.2 ° ) corresponding to the peaks as shown in FIG . 12A , regardless of their relative intensities . In 30 some embodiments , the crystalline form can be character ized by a DSC spectrum substantially the same as shown in or a pharmaceutically acceptable salt thereof, and a phar FIG . 12B . maceutically acceptable carrier. The abiraterone decanoate In some embodiments, the present disclosure also pro is typically present in the pharmaceutical composition in its vides a method of preparing a crystalline form of abiraterone 35 basic form and should be understood as such unless other decanoate . In some embodiments, the method can include wise obvious to the contrary from context . In some embodi recrystallizing abiraterone decanoate in a suitable solvent, ments, the abiraterone decanoate can also be in a substan such as acetone and water . In a typical method , the abirater tially pure form described herein . For example, the one decanoate can be first dissolved in a first solvent, such pharmaceutical composition can be prepared from mixing as acetone, at room temperature or under heat ( such as about 40 the substantially pure abiraterone decanoate with the phar 40 ° C. ) , to form a solution ; the solution can then be cooled maceutically acceptable carrier and optional other ingredi to form a suspension ; and optionally, this can then be ents. In some specific embodiments , the substantially pure followed by dilution of the suspension with a second solvent abiraterone decanoate is in a crystalline form described ( typically an antisolvent in which abiraterone decanoate has herein , and the pharmaceutical composition can be prepared a low solubility ), such as water, and stirring for a period of 45 from mixing ( e.g. , dissolving, suspending , or otherwise time ( such as about 12 hours ) to form the crystalline form . forming a mixture ) the crystalline form with the pharma The amount of solvent, concentration , etc. can be adjusted ceutically acceptable carrier and optional other ingredients. by those skilled in the art in view of this disclosure . An Typically , the pharmaceutical composition is formulated exemplary procedure is also shown in Example 6A . for parenteral administration . For example, in some embodi Abiraterone decanoate is typically prepared in a high 50 ments, the pharmaceutical composition can be formulated purity form , e.g. , suitable for pharmaceutical use . In some for intramuscular injection , intradermal injection, or subcu embodiments , the present disclosure provides abiraterone taneous injection . decanoate in a substantially pure form , such as having a The pharmaceutical composition is generally a non -aque purity of greater than 80 % , preferably greater than 90 % ous formulation , for example , an oil based formulation , and ( e.g. , greater than 95 % , greater than 97 % , greater than 98 % , 55 include a non -aqueous pharmaceutically acceptable carrier greater than 99 % , greater than 99.5 % ) , by weight, by HPLC ( e.g. , described herein ). For example, in some embodiments, area , or both . In some embodiments, the abiraterone decano the pharmaceutically acceptable carrier comprises a phar ate can be characterized by a purity by weight and / or by maceutically acceptable oil , such as a pharmaceutically HPLC area of about 95 % , about 97 % , about 99 % , about acceptable oil for injection, including oils of vegetable 99.5 % , about 99.9 % , or any ranges between the specified 60 origin or synthetic mono- or diglycerides of fatty acids . In values . For example, in some embodiments , the abiraterone some embodiments , the pharmaceutically acceptable oil can decanoate can be characterized by a purity by weight of be nature oil , synthetic oil , or semi- synthetic oil , such as about 95 % , about 97 % , about 99 % , about 99.5 % , about fractionated coconut oil and medium - chain triglycerides, 99.9 % , or any ranges between the specified values . Exem such as those sold under the trademark Miglyol . In some plary procedures for preparing the substantially pure abi- 65 embodiments , the pharmaceutically acceptable carrier com raterone decanoate are shown in the Examples section . prises a triglyceride derived from fatty acids . In some HPLC methods suitable for measuring the purity of the embodiments, the pharmaceutically acceptable carrier com US 10,792,292 B2 43 44 prises a triglyceride derived from long and / or medium chain androgen excess , and / or a syndrome due to glucocorticoid fatty acids , which can be independently poly - unsaturated , excess such as hypercortisolemia. In some embodiments, the mono - unsaturated , or saturated . As understood by those abiraterone decanoate can be present in the pharmaceutical skilled in the art, medium chain fatty acids typically include composition in an amount sufficient to provide a therapeu 6-12 carbons, such as caprioic acid , caprylic acid , capric 5 tically effective blood plasma concentration of abiraterone at acid , lauric acid , etc .; short chain fatty acids typically have about 1 ng /ml or higher, such as about 2 ng /ml or higher, fewer than 6 carbons; whereas long -chain fatty acids typi about 4 ng /ml or higher, about 5 ng /ml or higher, about 8 pharmaceuticallycally include 13-21 acceptable carbons carrier. In some comprises embodiments a pharmaceu, the ng /ml or higher, etc. for a period of at least one week , e.g. , tically acceptable oil , which can be selected from vegetable 10 weeksat least ortwo more weeks , after , at least a single four weeksadministration, and up to to six a orsubject eight oil , castor oil , corn oil , sesame oil , cottonseed oil , peanut oil having a sex hormone- dependent benign or malignant dis ( arachis oil ) , poppy seed oil , tea seed oil , and soybean oil . In order, a syndrome due to androgen excess , and / or a syn some specific embodiments, the pharmaceutically accept drome due to glucocorticoid excess such as hypercorti able carrier can comprise corn oil , which includes a triglyc solemia . In some embodiments , the abiraterone decanoate eride , in which the fatty acid constituents are primarily 15 can be present in the pharmaceutical composition in an linoleic acid , oleic acid , palmitic acid , and stearic acid . amount sufficient to provide a therapeutically effective blood In some embodiments, in addition to the pharmaceutically plasma concentration of abiraterone at about 0.5 ng /ml or acceptable oil , the pharmaceutically acceptable carrier can higher for a period of at least four weeks, e.g. , at least six further comprise a pharmaceutically acceptable solvent ( or weeks and up to eight weeks or more , after a single co - solvent if the oil is counted as a solvent ), such as an 20 administration to a subject having a sex hormone -dependent alcohol , ester, acid , etc. In some embodiments , the pharma benign or malignant disorder, a syndrome due to androgen ceutically acceptable solvent can include benzyl alcohol , excess , and / or a syndrome due to glucocorticoid excess such benzyl benzoate , ethanol , glycerol, polyethylene glycol , as hypercortisolemia . polysorbate 80 , acetic acid , and / or ethyl acetate . In some embodiments, the pharmaceutically acceptable solvent can 25 providesIn some a pharmaceuticalspecific embodiments composition, the ,present e.g. , unit disclosure dosage be benzyl alcohol and /or benzyl benzoate . In some embodi ments, the pharmaceutically acceptable solvent can be ben form , comprising a therapeutically effective amount of abi zyl alcohol . In some embodiments, the pharmaceutically raterone decanoate having the formula of : acceptable solvent can be a combination of benzyl alcohol and benzyl benzoate . As discussed herein , the solubility of 30 abiraterone decanoate in a pharmaceutically acceptable oil can be significantly enhanced by a combination of benzyl alcohol and benzyl benzoate . In some specific embodiments, the present disclosure provides a pharmaceutical composition comprising abirater- 35 one decanoate, a pharmaceutically acceptable oil ( e.g. , described herein ), benzyl alcohol, and benzyl benzoate . In some embodiments, the pharmaceutically acceptable oil is corn oil . In some embodiments , the benzyl alcohol is present in an amount of about 5-10 % by volume, the benzyl ben- 40 a pharmaceutically acceptable oil , and a pharmaceutically zoate is present in an amount of about 10-20 % by volume, acceptable solvent, wherein the abiraterone decanoate is in and corn oil is present in an amount of about 70-85 % by its basic form , which is present at a concentration of about volume , with the combined volume of benzyl alcohol , 25 mg / ml to about 500 mg/ ml , such as about 50 mg /ml , benzyl benzoate , and corn oil being 100 % . about 100 mg /ml , about 150 mg /ml , about 200 mg / ml , about The pharmaceutical composition typically include abi- 45 250 mg/ ml , about 300 mg/ ml , about 350 mg/ ml , about 400 raterone decanoate at a concentration of about 25 mg / ml to mg /ml , about 500 mg /ml , or any ranges between the recited about 500 mg /ml . In some embodiments, the abiraterone values , wherein the pharmaceutical composition , e.g. , unit decanoate can be present in a concentration of about 50 dosage form , is formulated for parenteral injection , such as mg /ml , about 100 mg /ml , about 150 mg /ml , about 200 intramuscular injection , intradermal injection , or subcutane mg/ ml , about 250 mg/ ml , about 300 mg/ ml , about 350 50 ous injection , wherein the pharmaceutical composition , e.g. , mg / ml , about 400 mg /ml , about 500 mg /ml , or any ranges unit dosage form , comprises the abiraterone decanoate in an between the recited values . In some embodiments, the amount of about 50 mg to about 2,000 mg , such as about 100 abiraterone decanoate can be present in a concentration of mg , about 350 mg , about 500 mg , about 1000 mg , about about 100 mg/ ml to about 300 mg /ml , such as about 150 1500 mg , about 2000 mg , or any ranges between the recited mg /ml to about 250 mg/ ml , about 200 mg /ml to about 300 55 values . In some embodiments, the pharmaceutical compo mg /ml , etc. sition can be in a unit dosage form . Typically, depending on The abiraterone decanoate in the pharmaceutical compo the dosing amount, one or more ( e.g. , 1 ) of the unit dosage sition is typically included in a therapeutically effective forms can be administered to a subject in need thereof. The amount for treating a disease or disorder described herein , pharmaceutically acceptable oil in the pharmaceutical com such as prostate cancer . In some embodiments , the abirater- 60 position , e.g. , unit dosage form , can be any of those one decanoate can be present in the pharmaceutical compo described herein . For example, in some embodiments , the sition in an amount sufficient to provide a therapeutically pharmaceutically acceptable oil is a pharmaceutically effective blood plasma concentration of abiraterone for a acceptable oil for injection, including oils of vegetable period of at least one week , e.g. , at least two weeks , at least origin or synthetic mono- or diglycerides of fatty acids . In four weeks , and up to six or eight weeks or more , after a 65 some embodiments, the pharmaceutically acceptable oil can single administration to a subject having a sex hormone be nature oil , synthetic oil , or semi- synthetic oil , such as dependent benign or malignant disorder, a syndrome due to fractionated coconut oil and medium - chain triglycerides , US 10,792,292 B2 45 46 such as those sold under the trademark Miglyol . In some oil include any of the pharmaceutically acceptable oil as embodiments, the pharmaceutically acceptable oil can com described herein , such as corn oil . Optional additional prise a triglyceride derived from fatty acids . In some ingredients are not shown in Table C. Examples 3F - 3H embodiments, the pharmaceutically acceptable oil can com herein show procedures of preparing representative abirater prise a triglyceride derived from long and / or medium chain one decanoate formulations of Table C. TABLE C Exemplary Abiraterone Decanoate Formulations Amount /Concentration More Exemplary Ingredients Typical Exemplary range Range Abiraterone 25 mg /ml to 500 50 mg /ml to 300 75 mg /ml to 300 decanoate mg /ml mg/ ml ; 100 mg/ ml to mg/ ml , such as 150 300 mg /ml mg/ ml to about 250 mg /ml Oil ( e.g. , corn oil , 30 % to 100 % of 50 % to 90 % of solvent 60 % to 90 % of castor oil , sesame oil , solvent solvent , such as 70 % peanut oil , cottonseed oil , and / or Miglyol 812 ) benzyl alcohol 0 % to 20 % of solvent 0 % to 15 % of solvent 0 % to 10 % of solvent , such as 10 % benzyl benzoate 0 % to 50 % of solvent 0 % to 35 % of solvent 0 % to 30 % of solvent , such as 20 % fatty acids , which can be independently poly - unsaturated , The pharmaceutical composition or unit dosage form mono -unsaturated , or saturated . In some embodiments, the herein can be prepared by those skilled in the art in view of pharmaceutically acceptable oil can be selected from veg the methods disclosed herein . In some embodiments, the etable oil , castor oil , corn oil , sesame oil , cottonseed oil , 30 present disclosure provides a method for preparing an abi peanut oil ( arachis oil ) , poppy seed oil , tea seed oil , and raterone decanoate formulation suitable for parenteral soybean oil . In some specific embodiments , the pharmaceu administration to a subject having a sex hormone -dependent tically acceptable oil can comprise corn oil , which includes benign or malignant disorder, a syndrome due to androgen a triglyceride, in which the fatty acid constituents are excess , and / or a syndrome due to glucocorticoid excess such primarily linoleic acid , oleic acid , palmitic acid , and stearic 35 as hypercortisolemia. In some embodiments, the method acid . The pharmaceutically acceptable solvent in the phar comprises mixing ( such as dissolving or suspending ) abi maceutical composition , e.g. , unit dosage form , also include raterone decanoate , which has the formula of: any of those described herein . In some embodiments, the pharmaceutically acceptable solvent ( or co -solvent if the oil is counted as a solvent ), such as an alcohol , ester, acid , etc. 40 In some embodiments, the pharmaceutically acceptable sol vent can include benzyl alcohol, benzyl benzoate , ethanol, glycerol, polyethylene glycol , polysorbate 80 , acetic acid , and / or ethyl acetate . In some embodiments, the pharmaceu 45 tically acceptable solvent can be benzyl alcohol and / or i benzyl benzoate . In some embodiments, the pharmaceutical H composition, e.g. , unit dosage form , comprises abiraterone decanoate, a pharmaceutically acceptable oil ( e.g. , described herein ), benzyl alcohol , and benzyl benzoate . In some 50 in a pharmaceutically acceptable carrier to form a mixture embodiments, the pharmaceutically acceptable oil is corn ( such as a solution or suspension ) . In some embodiments , oil . In some embodiments, the benzyl alcohol is present in the method further comprises sterilizing the mixture ( e.g. , an amount of about 5-10 % by volume , the benzyl benzoate solution or suspension ). In some embodiments, the dissolv is present in an amount of about 10-20 % by volume , and ing or suspending can comprise mixing ( e.g. , dissolving or corn oil is present in an amount of about 70-85 % by volume , 55 suspending ) the crystalline form of abiraterone decanoate with the combined volume of benzyl alcohol , benzyl ben described herein in the pharmaceutically acceptable carrier. zoate , and corn oil being 100 % . In some embodiments , the mixing ( such as dissolving or In some embodiments , the present disclosure provides suspending ) can comprise mixing ( e.g. , dissolving or sus exemplary abiraterone decanoate formulations as shown in pending) the substantially pure abiraterone decanoate Table C. All numeric values in the table should be under- 60 described herein in the pharmaceutically acceptable carrier . stood as preceded by the term “ about. ” The concentration of Suitable pharmaceutically acceptable carriers and amounts, abiraterone decanoate refers to the amount of abiraterone amount of abiraterone decanoate, concentration of abirater decanoate in mg per ml of the final formulation , which can one decanoate , include any of those described herein . For be a solution or suspension . The amount of oil ( the primary example, in some embodiments , the pharmaceutically solvent) and co - solvent ( benzyl alcohol and / or benzyl ben- 65 acceptable carrier comprises a pharmaceutically acceptable zoate ) in the tables is expressed as volume percentage of oil and a pharmaceutically acceptable solvent, wherein the solvent, which includes both the oil and co - solvent. Suitable pharmaceutically acceptable oil comprises a vegetable oil , US 10,792,292 B2 47 48 castor oil , corn oil , sesame oil , cottonseed oil , peanut oil , tion in biosynthesis of androgens ( such as testosterone ), poppy seed oil , tea seed oil , or soybean oil , the pharmaceu reduction in glucocorticoids ( such as cortisol ), and an min tically acceptable solvent comprises benzyl alcohol and / or eralocorticoid excess ( e.g. , increase in progesterone ). Adre benzyl benzoate , and wherein the abiraterone decanoate is nal insufficiency has also been noted to be associated with present at a concentration of about 50 mg /mL to about 300 5 abiraterone therapy, such as Zytiga® . Intramuscular admin istration of a pharmaceutical composition comprising abi mg /mL such as about 100 mg /mL to about 300 mg/ mL . raterone decanoate herein was shown to provide an effective In some specific embodiments, the present disclosure also plasma level of abiraterone and inhibit CYP17A1 in vivo for provides a method of treating a sex hormone - dependent a prolonged period of time , with an increase in progesterone benign or malignant disorder, a syndrome due to androgen level and a reduction in cortisol level . excess , and / or a syndrome due to glucocorticoid excess such 10 In some embodiments , the method herein ( e.g. , treating a as hypercortisolemia, comprising administering to a subject prostate cancer , or treating classical or nonclassical congeni in need thereof a therapeutically effective amount of the tal adrenal hyperplasia ) can comprise administering to the pharmaceutical composition comprising abiraterone subject an agent that offsets the reduction of decanoate described herein ( e.g. , the unit dosage form glucocorticoid ( s ) associated with the administration of abi described herein ). The administering is not limited to any 15 raterone decanoate as described herein . In some embodi particular route . However, the abiraterone decanoate is typi ments , the method can comprise administering to the subject cally administered parenterally , for example, via an intra in need an agent effective in treating one or more symptoms muscular injection, intradermal injection , or subcutaneous associated with adrenal insufficiency, such as acute stress , injection . In some embodiments , the administering is fatigue , etc. In some specific embodiments , the method can through intramuscular injection. Unlike oral administration 20 comprise administering to the subject a steroid , such as a of abiraterone acetate , the pharmaceutical composition com corticosteroid . In some embodiments, the method can com prising abiraterone decanoate described herein ( e.g. , the unit prise administering to the subject a glucocorticoid . In some dosage form described herein ) can be administered to the specific embodiments, the method also comprises adminis subject in need with or without food . tering to the subject prednisone , prednisolone , and / or meth Sex hormone - dependent benign or malignant disorder 25 ylprednisolone. In some embodiments, the method also that can be treated with the methods include any of those comprises administering to the subject an agent effective in described herein . In some embodiments, the sex hormone treating cortisol deficiency, for example, hydrocortisone , dependent benign or malignant disorders can be selected prednisone, prednisolone, methylprednisolone, and / or dex from androgen -dependent disorders and estrogen - dependent amethasone. In any such embodiments , the agent can be disorders such as androgen - dependent or estrogen -depen- 30 administered to the subject either concurrently or sequen dent cancers . In some embodiments , the sex hormone tially in any order, via a same or different route of admin dependent benign or malignant disorders can be selected istration . from prostate cancer , breast cancer, ovarian cancer, bladder In some embodi ents , the methods herein can be char cancer, hepatocellular carcinoma, and lung cancer, etc. In acterized by a dosing frequency of once a week or even less some embodiments, the sex hormone - dependent benign or 35 frequent. Typically, the dosing frequency can range from malignant disorder can be prostate cancer or breast cancer . once a week to once every few months, such as from once In some embodiments, the sex hormone -dependent benign a week to once every three months, or from once a week to or malignant disorder is castration resistant prostate cancer once every eight weeks, such as once a month . In some or castration sensitive prostate cancer . In some embodi embodiments, the method comprises administering to the ments , the sex hormone -dependent benign or malignant 40 subject the pharmaceutical composition comprising abirater disorder can be metastatic castration resistant prostate can one decanoate ( e.g. , the unit dosage form described herein ) cer or metastatic castration sensitive prostate cancer . Syn once a week , once in two weeks , once in three weeks, once dromes due to androgen excess and / or syndromes due to a month , or once in more than a month . In some embodi glucocorticoid excess such as hypercortisolemia that can be ments , the method comprises administering to the subject treated with the methods include any of those described 45 the pharmaceutical composition comprising abiraterone herein . In some embodiments, the method herein can be a decanoate ( e.g. , the unit dosage form described herein ) once method for treating a non - oncologic syndrome in the subject in two weeks , once a month , or once in more than a month . due to androgen excess , such as endometriosis, polycystic In some embodiments, the dosing amount for each dose is ovary syndrome, congenital adrenal hyperplasia ( e.g., clas about 50 mg to about 2000 mg ( e.g. , about 100 mg , about sical or nonclassical congenital adrenal hyperplasia ), preco- 50 350 mg , about 500 mg , about 1000 mg , about 1500 mg , or cious puberty, hirsutism , etc. In some embodiments, the any ranges between the recited values ) of abiraterone method herein can be a method for treating a non - oncologic decanoate . In some embodiments, the dosing amount of syndrome due to glucocorticoid ( e.g. , cortisole) excess , such abiraterone decanoate for each dose is about 0.5 mg/ kg to as Cushing's syndrome or Cushing's disease. about 100 mg/ kg ( e.g. , about 0.5 mg/ kg , about 1 mg /kg , The methods herein can be used in conjunction with one 55 about 5 mg/ kg , about 10 mg/ kg , about 20 mg / kg , about 30 or more additional therapies for the respective disease or mg/ kg , about 50 mg /kg , about 90 mg/ kg , about 100 mg/ kg , disorder . For example, the method can comprise adminis or any ranges between the recited values ) of body weight of tering one or more other drug or agent ( for example , as a subject. In some embodiments, the administering is via described herein , such as another cancer chemotherapeutic intramuscular injection. In some embodiments , the admin drug , hormone replacement drug, or hormone ablation drug ) 60 istering provides a therapeutically effective blood plasma to the subject, either concurrently or sequentially , through concentration of abiraterone a period of at least one week , the same route or a different route of administration . In some e.g. , at least two weeks , such as at least three weeks, at least embodiments, the subject can also be treated with a gonado four weeks , and up to six or eight weeks or more , etc. In tropin - releasing hormone analog and / or bilateral orchiec some embodiments , the administering provides a blood tomy. 65 plasma concentration of abiraterone above 1.0 ng /ml ( e.g. , As discussed herein , abiraterone is a 17a -hydroxylase / between about 1 ng /ml and about 8 ng /ml , or about 2 ng /ml C17,20 - lyase ( CYP17 ) inhibitor, which can lead to reduc or higher, about 4 ng /ml or higher, about 5 ng / ml or higher, US 10,792,292 B2 49 50 or about 8 ng /ml or higher ) for a period of at least one week , 2000 mg ( e.g. , about 100 mg , about 350 mg , about 500 mg , e.g. , at least two weeks , such as at least 3 weeks, at least four about 1000 mg , about 1500 mg , or any ranges between the weeks, and up to six or eight weeks or more , etc. In some recited values ) of abiraterone decanoate or with each dose of embodiments , the administering provides a steady state Cmin abiraterone decanoate at about 0.5 mg /kg to about 100 of abiraterone above 1.0 ng /ml ( e.g. , between about 1 ng /ml 5 mg/ kg ( e.g. , about 0.5 mg/ kg , about 1 mg/ kg , about 5 mg /kg , and about 8 ng /ml , about 2 ng /ml or higher, about 4 ng /ml about 10 mg /kg , about 20 mg/ kg , about 30 mg /kg , about 50 or higher, about 5 ng /ml or higher, or about 8 ng /ml or mg /kg , about 90 mg / kg , about 100 mg /kg , or any ranges higher ). In some embodiments, the administering provides a between the recited values ) of body weight of the subject. In single dose or steady state Cmax of abiraterone between some embodiments, the unit dosage form is administered via about 10 ng /ml and about 400 ng /ml , such as about 10 ng /ml , 10 intramuscular injection. In some embodiments, the prostate about 15 ng /ml , about 20 ng /ml , about 30 ng /ml , about 50 cancer is castration resistant prostate cancer or castration ng /ml , about 60 ng /ml , about 100 ng /ml , about 150 ng /ml , sensitive prostate cancer . In some embodiments , the prostate about 160 ng / ml, or any ranges recited between the values , cancer is metastatic castration resistant prostate cancer or for example, about 10-30 ng /ml , about 20-60 ng /ml , about metastatic castration sensitive prostate cancer . 15-160 ng /ml or about 50-100 ng /ml . In some embodiments, 15 In some specific embodiments, the present disclosure also the abiraterone decanoate formulation can be administered provides a method of delivering abiraterone to a subject in to the subject in need thereof as the only source of abirater need thereof, the method comprising administering to the one . However, in some embodiments, the abiraterone subject the pharmaceutical composition comprising abirater decanoate formulation can also be administered to the one decanoate described herein ( e.g. , the unit dosage form subject in need thereof as a supplement to another abirater- 20 described herein ) via intramuscular injection , intradermal one therapy. injection , or subcutaneous injection , once a week or once in In some specific example, the present disclosure provides more than a week , such as once a month or once in more than a method of treating prostate cancer , the method comprising a month , with each dose at about 50 mg to about 2000 mg administering to a subject in need thereof abiraterone ( e.g. , about 100 mg , about 350 mg , about 500 mg , about decanoate via intramuscular injection , intradermal injection , 25 1000 mg , about 1500 mg , or any ranges between the recited or subcutaneous injection , once a week or once in more than values ) of abiraterone decanoate or with each dose of a week , such as once a month or once in more than a month , abiraterone decanoate at about 0.5 mg /kg to about 100 with each dose at about 50 mg to about 2000 mg ( e.g. , about mg/ kg ( e.g. , about 0.5 mg/ kg , about 1 mg /kg , about 5 mg /kg , 100 mg , about 350 mg , about 500 mg , about 1000 mg , about about 10 mg / kg , about 20 mg/ kg , about 30 mg / kg, about 50 1500 mg , or any ranges between the recited values ) of 30 mg/ kg , about 90 mg / kg , about 100 mg/ kg , or any ranges abiraterone decanoate . In some embodiments, the abirater between the recited values ) of body weight of the subject. In one decanoate is administered via intramuscular injection. In some embodiments, the pharmaceutical composition is some embodin nts , the prostate cancer is castration resis administered via intramuscular injection. In some embodi tant prostate cancer or castration sensitive prostate cancer. In ments, the subject suffers from a hormone -dependent benign some embodiments, the prostate cancer is metastatic castra- 35 or malignant disorder, a syndrome due to androgen excess , tion resistant prostate cancer or metastatic castration sensi and / or a syndrome due to glucocorticoid excess such as tive prostate cancer . hypercortisolemia , e.g. , as described herein . In some specific example, the present disclosure provides In some specific embodiments, the present disclosure also a method of treating prostate cancer, the method comprising provides a method of inhibiting CYP17A1 activity in a administering to a subject in need thereof the pharmaceutical 40 subject in need thereof, the method comprising administer composition comprising abiraterone decanoate described ing to the subject the pharmaceutical composition compris herein ( e.g. , the unit dosage form described herein ) via ing abiraterone decanoate described herein ( e.g. , the unit intramuscular injection, intradermal injection , or subcutane dosage form described herein ) via intramuscular injection , ous injection , once a week or once in more than a week , such intradermal injection , or subcutaneous injection , once a as once a month or once in more than a month , with each 45 week or once in more than a week , such as once a month or dose at about 50 mg to about 2000 mg ( e.g. , about 100 mg , once in more than a month , with each dose at about 50 mg about 350 mg , about 500 mg , about 1000 mg , about 1500 to about 2000 mg ( e.g. , about 100 mg , about 350 mg, about mg , or any ranges between the recited values ) of abiraterone 500 mg , about 1000 mg , about 1500 mg , or any ranges decanoate or with each dose of abiraterone decanoate at between the recited values ) of abiraterone decanoate or with about 0.5 mg / kg to about 100 mg /kg ( e.g. , about 0.5 mg /kg , 50 each dose of abiraterone decanoate at about 0.5 mg /kg to about 1 mg /kg , about 5 mg /kg , about 10 mg /kg , about 20 about 100 mg/ kg ( e.g. , about 0.5 mg/ kg , about 1 mg /kg , mg /kg , about 30 mg /kg , about 50 mg /kg , about 90 mg /kg , about 5 mg/ kg , about 10 mg /kg , about 20 mg /kg , about 30 about 100 mg/ kg , or any ranges between the recited values ) mg /kg , about 50 mg /kg , about 90 mg /kg , about 100 mg/ kg , of body weight of the subject. In some embodiments, the or any ranges between the recited values ) of body weight of pharmaceutical composition is administered via intramus- 55 the subject. In some embodiments, the pharmaceutical com cular injection. In some embodiments , the prostate cancer is position is administered via intramuscular injection . In some castration resistant prostate cancer or castration sensitive embodiments , the subject suffers from a sex hormone prostate cancer. In some embodiments, the prostate cancer is dependent benign or malignant disorder , e.g. , as described metastatic castration resistant prostate cancer or metastatic herein . In some embodiments , the subject suffers from a castration sensitive prostate cancer. 60 syndrome due to androgen excess and / or a syndrome due to In some specific example , the present disclosure provides glucocorticoid excess such as hypercortisolemia, e.g. , as a method of treating prostate cancer, the method comprising described herein . administering to a subject in need thereof the unit dosage In some specific embodiments, the present disclosure also form described herein via intramuscular injection , intrader provides a method of reducing the level of glucocorticoids mal injection , or subcutaneous injection , once a week or 65 ( e.g. , cortisol) in a subject in need thereof in a subject in once in more than a week , such as once a month or once in need thereof, the method comprising administering to the more than a month , with each dose about 50 mg to about subject the pharmaceutical composition comprising abirater US 10,792,292 B2 51 52 one decanoate described herein ( e.g. , the unit dosage form amount of the pharmaceutical composition comprising abi described herein ) via intramuscular injection , intradermal raterone isocaproate described herein ( e.g. , the unit dosage injection , or subcutaneous injection , once a week or once in form described herein ). In some embodiments, the pharma more than a week , such as once a month or once in more than ceutical composition comprising abiraterone isocaproate a month , with each dose at about 50 mg to about 2000 mg 5 described herein ( e.g. , the unit dosage form described ( e.g. , about 100 mg , about 350 mg , about 500 mg , about herein ) can be administered to the subject in need with or 1000 mg , about 1500 mg , or any ranges between the recited without food . Suitable sex hormone -dependent benign or values ) of abiraterone decanoate or with each dose of malignant disorders, syndromes due to androgen excess , abiraterone decanoate at about 0.5 mg/ kg to about 100 syndromes due to glucocorticoid excess such as hypercor mg /kg ( e.g. , about 0.5 mg/ kg , about 1 mg /kg , about 5 mg /kg , 10 tisolemia , dosing regimen , combination therapies, etc. about 10 mg /kg , about 20 mg/ kg , about 30 mg /kg , about 50 include those described herein , e.g. , in connection with mg/ kg , about 90 mg / kg , about 100 mg/ kg , or any ranges abiraterone decanoate . between the recited values ) of body weight of the subject. In In some specific example , the present disclosure provides some embodiments, the pharmaceutical composition is a method of treating prostate cancer , the method comprising administered via intramuscular injection . In some embodi- 15 administering to a subject in need thereof the pharmaceutical ments , the subject suffers from a hypercortisolemia as composition comprising abiraterone isocaproate described described herein , such as Cushing's syndrome or Cushing's herein via intramuscular injection , intradermal injection, or disease . subcutaneous injection , once a week or once in more than a In some specific embodiments , the present disclosure also week , such as once a month or once in more than a month , provides a method of reducing the level of androgens ( e.g. , 20 with each dose at about 50 mg to about 2000 mg ( e.g. , about testosterone and / or dihydrotestosterone) and / or estrogens in 100 mg , about 350 mg , about 500 mg , about 1000 mg , about a subject in need thereof in a subject in need thereof, the 1500 mg , or any ranges between the recited values ) of method comprising administering to the subject the phar abiraterone isocaproate or with each dose of abiraterone maceutical composition comprising abiraterone decanoate isocaproate at about 0.5 mg/ kg to about 100 mg/ kg ( e.g. , described herein ( e.g. , the unit dosage form described 25 about 0.5 mg/ kg , about 1 mg/ kg , about 5 mg/ kg , about 10 herein ) via intramuscular injection , intradermal injection , or mg/ kg , about 20 mg /kg , about 30 mg/ kg , about 50 mg /kg , subcutaneous injection , once a week or once in more than a about 90 mg / kg , about 100 mg/ kg , or any ranges between the week , such as once a month or once in more than a month , recited values ) of body weight of the subject. In some with each dose at about 50 mg to about 2000 mg ( e.g. , about embodiments, the pharmaceutical composition is adminis 100 mg , about 350 mg , about 500 mg , about 1000 mg , about 30 tered via intramuscular injection . In some embodiments, the 1500 mg , or any ranges between the recited values ) of prostate cancer is castration resistant prostate cancer or abiraterone decanoate or with each dose of abiraterone castration sensitive prostate cancer . In some embodiments , decanoate at about 0.5 mg /kg about 100 mg /kg ( e.g. , the prostate cancer is metastatic castration resistant prostate about 0.5 mg /kg , about 1 mg /kg , about 5 mg /kg , about 10 cancer or metastatic castration sensitive prostate cancer . mg/ kg , about 20 mg/ kg , about 30 mg/ kg , about 50 mg /kg , 35 In some specific example , the present disclosure provides about 90 mg /kg , about 100 mg/ kg , or any ranges between the a method of treating prostate cancer, the method comprising recited values ) of body weight of the subject. In some administering to a subject in need thereof the unit dosage embodiments, the pharmaceutical composition is adminis form comprising abiraterone isocaproate described herein tered via intramuscular injection . In some embodiments , the via intramuscular injection , intradermal injection , or subcu subject suffers from a syndrome due to androgen excess , 40 taneous injection , once a week or once in more than a week , such as congenital adrenal hyperplasia ( e.g. , classical or such as once a month or once in more than a month , with nonclassical congenital adrenal hyperplasia ), endometriosis , each dose at about 50 mg to about 2000 mg ( e.g. , about 100 polycystic ovary syndrome precocious puberty , hirsutism , mg , about 350 mg , about 500 mg , about 1000 mg , about etc. In some embodiments , the subject suffers from an 1500 mg , or any ranges between the recited values ) of androgen and /or estrogen associated cancer , such as prostate 45 abiraterone isocaproate or with each dose of abiraterone cancer or breast cancer . isocaproate at about 0.5 mg/ kg to about 100 mg/ kg ( e.g. , Other Abiraterone Prodrugs about 0.5 mg/ kg , about 1 mg/ kg , about 5 mg/ kg , about 10 While the present disclosure describes embodiments mg/ kg , about 20 mg/ kg , about 30 mg/ kg , about 50 mg/ kg , relating to abiraterone decanoate in more details, those about 90 mg /kg , about 100 mg/ kg , or any ranges between the skilled in the art would understand similar embodiments are 50 recited values ) of body weight of the subject. In some also applicable to other abiraterone prodrugs of the present embodiments, the unit dosage form is administered via disclosure in view of the descriptions herein . For example , intramuscular injection . In some embodiments, the prostate like abiraterone decanoate , pharmacokinetics studies show cancer is castration resistant prostate cancer or castration that intramuscular injection of abiraterone isocaproate for sensitiveprostate cancer . In some embodiments, the prostate mulations can also provide a therapeutically effective 55 cancer is metastatic castration resistant prostate cancer or amount of plasma abiraterone for an extended period of metastatic castration sensitive prostate cancer . time . Thus , embodiments described herein specifically to In some specific embodiments , the present disclosure also abiraterone decanoate formulations and methods of treat provides a method of delivering abiraterone to a subject in ment can also be similarly applicable to abiraterone iso need thereof , the method comprising administering to the caproate , with abiraterone decanoate replaced with abirater- 60 subject the pharmaceutical composition comprising abirater one isocaproate . one isocaproate described herein ( e.g. , the unit dosage form For example , in some embodiments, the present disclo described herein ) via intramuscular injection, intradermal sure also provides a method of treating a sex hormone injection , or subcutaneous injection , once a week or once in dependent benign or malignant disorder, a syndrome due to more than a week , such as once a month or once in more than androgen excess, and / or a syndrome due to glucocorticoid 65 a month , with each dose at about 50 mg to about 2000 mg excess such as hypercortisolemia , comprising administering ( e.g. , about 100 mg , about 350 mg , about 500 mg , about to a subject in need thereof a therapeutically effective 1000 mg , about 1500 mg , or any ranges between the recited US 10,792,292 B2 53 54 values ) of abiraterone isocaproate or with each dose of herein ) via intramuscular injection , intradermal injection , or abiraterone isocaproate at about 0.5 mg /kg to about 100 subcutaneous injection , once a week or once in more than a mg /kg ( e.g. , about 0.5 mg/ kg , about 1 mg/ kg , about 5 mg/ kg , week , such as once a month or once in more than a month , about 10 mg /kg , about 20 mg/ kg , about 30 mg /kg , about 50 with each dose at about 50 mg to about 2000 mg ( e.g. , about mg /kg , about 90 mg/ kg , about 100 mg /kg , or any ranges 5 100 mg , about 350 mg , about 500 mg , about 1000 mg , about between the recited values ) of body weight of the subject. In 1500 mg , or any ranges between the recited values ) of some embodiments, the pharmaceutical composition is abiraterone isocaproate or with each dose of abiraterone administered via intramuscular injection . In some embodi isocaproate at about 0.5 mg/ kg to about 100 mg/ kg ( e.g. , ments , the subject suffers from a hormone -dependent benign about 0.5 mg /kg , about 1 mg /kg , about 5 mg /kg , about 10 or malignant disorder, a syndrome due to androgen excess , 10 mg/ kg , about 20 mg/ kg , about 30 mg/ kg , about 50 mg/ kg , and / or a syndrome due to glucocorticoid excess such as about 90 mg/ kg , about 100 mg/ kg , or any ranges between the hypercortisolemia, e.g. , as described herein . recited values ) of body weight of the subject. In some In some specific embodiments, the present disclosure also embodiments, the pharmaceutical composition is adminis provides a method of inhibiting CYP17A1 activity in a tered via intramuscular injection . In some embodiments, the subject in need thereof, the method comprising administer- 15 subjectsuch as sufferscongenital from adrenala syndrome hyperplasia due to (androgen e.g., classical excess or , ing to the subject the pharmaceutical composition compris nonclassical congenital adrenal hyperplasia ), endometriosis, ing abiraterone isocaproate described herein ( e.g. , the unit polycystic ovary syndrome precocious puberty , hirsutism , dosage form described herein ) via intramuscular injection , etc. In some embodiments, the subject suffers from an intradermal injection, or subcutaneous injection , once a androgen and / or estrogen associated cancer , such as prostate week or once in more than a week , such as once a month or 20 cancer or breast cancer. once in more than a month , with each dose at about 50 mg to about 2000 mg ( e.g. , about 100 mg , about 350 mg , about NON - LIMITING EXEMPLARY EMBODIMENTS 500 mg , about 1000 mg , about 1500 mg , or any ranges In some embodiments , the present disclosure also pro withbetween each the dose recited of abiraterone values ) isocaproateof abiraterone at about isocaproate 0.5 mg /kg or 25 vides non - limiting exemplary Embodiments 1-66 as shown to about 100 mg /kg ( e.g. , about 0.5 mg /kg , about 1 mg /kg , below : about 5 mg/ kg , about 10 mg/ kg , about 20 mg /kg , about 30 mg/ kg , about 50 mg/ kg , about 90 mg/ kg , about 100 mg /kg , Embodiment 1 or any ranges between the recited values ) of body weight of An abiraterone prodrug formulation suitable for parent the subject. In some embodiments, the pharmaceutical com- 30 eral administration to a subject having a hormone position is administered via intramuscular injection . In some dependent benign or malignant disorder, comprising: embodiments , the subject suffers from a sex hormone ( a ) one or more lipophilic - ester forms of abiraterone, dependent benign or malignant disorder, e.g. , as described and herein . In some embodiments, the subject suffers from ( b ) one or more pharmaceutically acceptable carriers , syndromes due to androgen excess and / or syndromes due to 35 diluents , or excipients, wherein upon said adminis glucocorticoid excess such as hypercortisolemia , e.g. , as tration to said subject, said abiraterone prodrug for described herein . mulation achieves a therapeutic blood plasma con In some specific embodiments, the present disclosure also centration of abiraterone. provides a method of reducing the level of glucocorticoids ( e.g. , cortisol) in a subject in need thereof in a subject in 40 Embodiment 2 need thereof, the method comprising administering to the subject the pharmaceutical composition comprising abirater The abiraterone prodrug formulation of Embodiment 1 , one isocaproate described herein ( e.g. , the unit dosage form wherein said therapeutic blood plasma concentration of described herein ) via intramuscular injection , intradermal abiraterone is at least 1.0 ng /ml . injection, or subcutaneous injection, once a week or once in 45 more than a week , such as once a month or once in more than Embodiment 3 a month , with each dose at about 50 mg to about 2000 mg The abiraterone prodrug formulation of Embodiment 1 , ( e.g. , about 100 mg , about 350 mg , about 500 mg , about wherein said therapeutic blood plasma concentration of 1000 mg , about 1500 mg , or any ranges between the recited abiraterone is at least 8 ng /ml . values ) of abiraterone isocaproate or with each dose of 50 abiraterone isocaproate at about 0.5 mg /kg to about 100 Embodiment 4 mg/ kg ( e.g. , about 0.5 mg/ kg , about 1 mg/ kg , about 5 mg/ kg , about 10 mg/ kg , about 20 mg/ kg , about 30 mg/ kg , about 50 The abiraterone prodrug formulation of Embodiment 1 , mg / kg , about 90 mg/ kg , about 100 mg /kg , or any ranges wherein said therapeutic blood plasma concentration of between the recited values ) of body weight of the subject. In 55 abiraterone persists for at least two weeks . some embodiments, the pharmaceutical composition is administered via intramuscular injection . In some embodi Embodiment 5 ments, the subject suffers from a hypercortisolemia as described herein , such as Cushing's syndrome or Cushing's The abiraterone prodrug formulation of Embodiment 1 , disease . 60 wherein said parenteral administration is selected from In some specific embodiments , the present disclosure also the group consisting of intramuscular injection, intra provides a method of reducing the level of androgens ( e.g. , dermal injection , and subcutaneous injection. testosterone and / or dihydrotestosterone ) and / or estrogens in a subject in need thereof in a subject in need thereof, the Embodiment 6 method comprising administering to the subject the phar- 65 maceutical composition comprising abiraterone isocaproate The abiraterone prodrug formulation of Embodiment 1 , described herein ( e.g. , the unit dosage form described wherein said lipophilic - ester form is selected from the US 10,792,292 B2 55 56 group consisting of acetate , propionate , butanoate , val Embodiment 15 erate , caproate, enanthate, cypionate, isocaproate, buci clate , cyclohexanecarboxylate , phenyl propionate, The method of Embodiment 10 , wherein said lipophilic decanoate and undecanoate . ester form is selected from the group consisting of 5 acetate , propionate , butanoate, valerate , caproate , enan thate , cypionate, isocaproate , buciclate , cyclohexan Embodiment 7 ecarboxylate, phenyl propionate , decanoate and unde The abiraterone prodrug formulation of Embodiment 1 , canoate . wherein said hormone - dependent benign or malignant Embodiment 16 disorder is selected from the group consisting of andro 10 gen -dependent disorders and estrogen -dependent dis The method of Embodiment 10 , wherein said hormone orders . dependent benign or malignant disorder is selected from the group consisting of androgen -dependent dis Embodiment 8 orders and estrogen -dependent disorders . 15 The abiraterone prodrug formulation of Embodiment 1 , Embodiment 17 wherein said hormone -dependent benign or malignant The method of Embodiment 10 , wherein said hormone disorder is selected from the group consisting of pros dependent benign or malignant disorder is selected tate cancer and breast cancer. 20 from the group consisting of prostate cancer and breast cancer . Embodiment 9 Embodiment 18 The abiraterone prodrug formulation of Embodiment 8 , wherein said prostate cancer is selected from the group 25 The method of Embodiment 17 , wherein said prostate cancer is selected from the group consisting of castra consisting of castration resistant prostate cancer and tion resistant prostate cancer and castration sensitive castration sensitive prostate cancer . prostate cancer . Embodiment 10 Embodiment 19 30 A method for treating a hormone -dependent benign or The method of Embodiment 10 , wherein the method malignant disorder comprising parenterally administer further comprises once -monthly administration of said ing to a subject in need of such treatment an effective at least one abiraterone prodrug formulation . dose of at least one abiraterone prodrug formulation comprising: 35 Embodiment 20 ( a ) one or more lipophilic - ester forms of abiraterone, and The method of Embodiment 10 , wherein said at least one ( b ) one or more pharmaceutically acceptable carriers, abiraterone prodrug formulation is administered in a diluents , or excipients , wherein upon said adminis divided dose . tration , said at least one abiraterone prodrug formu- 40 Embodiment 21 lation achieves a therapeutic blood plasma concen tration of abiraterone . The method of Embodiment 10 , wherein said at least one abiraterone prodrug formulation is administered simul Embodiment 11 45 taneously with at least one other drug or agent. The method of Embodiment 10 , wherein said therapeutic Embodiment 22 blood plasma concentration of abiraterone is at least 1.0 ng /ml . The method of Embodiment 10 , wherein said at least one abiraterone prodrug formulation is administered before Embodiment 12 50 at least one other drug or agent. The method of Embodiment 10 , wherein said therapeutic Embodiment 23 blood plasma concentration of abiraterone is at least 8.0 ng /ml . The method of Embodiment 10 , wherein said at least one 55 abiraterone prodrug formulation is administered after at Embodiment 13 least one other drug or agent. The method of Embodiment 10 , wherein said therapeutic Embodiment 24 blood plasma concentration of abiraterone persists for at least two weeks. 60 A kit for treating the hormone - dependent benign or malig nant disorder of Embodiment 10 , comprising at least Embodiment 14 one abiraterone prodrug formulation . The method of Embodiment 10 , wherein said parenteral Embodiment 25 administration is selected from the group consisting of 65 intramuscular injection , intradermal injection , and sub A method for preparing an abiraterone decanoate formu cutaneous injection . lation suitable for parenteral administration to a subject US 10,792,292 B2 57 58 having a hormone - dependent benign or malignant dis Embodiment 29 order, comprising the steps of: ( a ) preparing and purifying abiraterone decanoate, The compound of Embodiment 28 , or a pharmaceutically ( b ) preparing an oil and co - solvent mixture , acceptable salt thereof, wherein R10 is a C7-16 alkyl. ( c ) combining said prepared and purified abiraterone 5 decanoate with one of said oil and alcohol mixture from step ( b ), Embodiment 30 ( d ) sterilizing the mixture formed in step ( c ) , and ( e ) optionally combining the sterilized mixture of step The compound of Embodiment 28 , or a pharmaceutically ( d ) with one or more pharmaceutically acceptable acceptable salt thereof, wherein R10 is an alkyl substi 10 tuted with a C3-6 cycloalkyl, which has a total number carriers , diluents , or excipients. of carbons between 6 and 12 . Embodiment 26 Embodiment 31 The method of Embodiment 25 , wherein said prepared and purified abiraterone decanoate has the following 15 The compound of Embodiment 28 , or a pharmaceutically chemical properties : LCMS m / z 504.4 ( M + H ) ; ' H acceptable salt thereof, wherein Rl is a C7-16 alkyl. NMR ( CDC13 , 200 MHz ) : SH 0.877 ( 3H , t , = 7 Hz ) , 1.043 ( 3H , s ) , 1.082 ( 3H , s ) , 1.268 ( 16H , m ) , 1.643 Embodiment 32 ( 15H , m ) , 1.842 ( 3H , m ) , 2.065 ( 3H , m ) , 2.290 ( 5H , m ) , 20 4.602 ( 1H , m ) , 5.404 ( 1H , d , J = 5 Hz ) , 5.998 ( 1H , 4 , J = 5 The compound of Embodiment 28 , or a pharmaceutically Hz ) , 7.215 ( 1H , ddd , J = 1,5.8 Hz ) , 7.643 ( 1H , dt, J = 2.8 acceptable salt thereof, wherein R ' is an alkyl having Hz ) , 8.455 ( 1H , dd , J = 2.5 Hz ) , 8.617 ( 1H , dd , J = 1.2 the formula (CH2 ) n CH3, wherein n is an integer Hz ) . between 6 and 12 , such as 6 , 7 , 8 , 9 , 10 , 11 , or 12 . Embodiment 27 25 Embodiment 33 The method of Embodiment 25 , wherein said oil and co - solvent mixture is selected from the group consist The compound of Embodiment 28 , or a pharmaceutically ing of 90 % castor oil / 10 % benzyl alcohol and 90 % corn acceptable salt thereof, wherein Rl is represented by oil / 10 % benzyl alcohol . 30 the formula – (CH2 ) ,, - Cy , wherein n is an integer of 1-6 , and Cy is a C3-6 cycloalkyl or phenyl. Embodiment 28 A compound of Formula I , or a pharmaceutically accept Embodiment 34 able salt thereof, 35 The compound of Embodiment 33 , or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl. Formula I N 40 Embodiment 35 The compound of Embodiment 28 , or a pharmaceutically acceptable salt thereof, wherein Rl is

H 45 .

R1 50 wherein Rl is R10,0 - R10 , or NHR 10 wherein R10 is selected from : a C7-30 alkyl; a C7-30 alkenyl; a C7-30 alkynyl; an alkyl Embodiment 36 substituted with a cycloalkyl, which has a total number of carbons between 5 and 16 ; an alkyl 55 The compound of Embodiment 28 , or a pharmaceutically substituted with a phenyl, which has a total number acceptable salt thereof, wherein Rl is of carbons between 7 and 16 ; a cycloalkyl optionally substituted with one or more alkyl, which has a total number of carbons between 5 and 16 ; and 60

65 ? US 10,792,292 B2 59 60 or Formula II

10 Embodiment 37 R2 A pharmaceutical composition comprising the compound wherein R² is R20 , OR20 , or NHR20 , of any one of Embodiments 28-36 , or a pharmaceuti- 15 wherein R20 is selected from : cally acceptable salt thereof. a C -30 alkyl; a C2-30 alkenyl; a C2-30 alkynyl; an alkyl substituted with a cycloalkyl, which has a total number of carbons between 4 and 30 ; an alkyl Embodiment 38 substituted with a phenyl, which has a total number 20 of carbons between 7 and 30 ; and a cycloalkyl The pharmaceutical composition of Embodiment 37 , for optionally substituted with one or more alkyl, which mulated for parenteral administration . has a total number of carbons between 3 and 30 , wherein the pharmaceutical composition is formulated for intramuscular injection , intradermal injection , or Embodiment 39 25 subcutaneous injection, and the compound of For mula II or pharmaceutically acceptable salt thereof is The pharmaceutical composition of Embodiment 38 , for present in the pharmaceutical composition at a con mulated for intramuscular injection , intradermal injec centration of about 25 mg / ml to about 500 mg /ml . tion , or subcutaneous injection . Embodiment 45 30 Embodiment 40 The pharmaceutical composition of Embodiment 44 , wherein R2 in Formula II is selected from a C1-16 alkyl; an alkyl substituted with a cycloalkyl, which has a total The pharmaceutical composition of Embodiment 37 , fur number of carbons between 5 and 16 ; an alkyl substi ther comprising a pharmaceutically acceptable carrier. 35 tuted with a phenyl, which has a total number of carbons between 7 and 16 ; and a cycloalkyl optionally Embodiment 41 substituted with one or more alkyl, which has a total number of carbons between 5 and 16 . The pharmaceutical composition of Embodiment 40 , Embodiment 46 wherein the pharmaceutically acceptable carrier com 40 prises a pharmaceutically acceptable oil , e.g. , an oil The pharmaceutical composition of Embodiment 44 , suitable for use as vehicles for injection , such as an oil wherein R2 in Formula II is an alkyl having the formula of vegetable origin or synthetic mono- or diglycerides (CH2 ) n CH3, wherein n is an integer between 0 and of fatty acids , e.g. , a vegetable oil , castor oil , corn oil , 12 . sesame oil , cottonseed oil , peanut oil , poppy seed oil , 45 Embodiment 47 tea seed oil, or soybean oil . The pharmaceutical composition of Embodiment 44 , wherein R² in Formula II is represented by the formula Embodiment 42 ( CH2 ) n - Cy , wherein n is an integer of 1-6 , and Cy is 50 a C3-6 cycloalkyl or phenyl. The pharmaceutical composition of Embodiment 40 or 41 , further comprising a pharmaceutically acceptable Embodiment 48 solvent, e.g. , benzyl alcohol . The pharmaceutical composition of Embodiment 44 , 55 wherein R2 in Formula II is Embodiment 43 The pharmaceutical composition of any one of Embodi ments 37-42 , which is a non - aqueous solution or sus pension. 60

Embodiment 44 A pharmaceutical composition comprising a compound of 65 Formula II , or a pharmaceutically acceptable salt thereof, US 10,792,292 B2 61 62 or a pharmaceutically acceptable salt thereof, or the phar maceutical composition of any one of Embodiments 37-54 .

5 Embodiment 56 The method of Embodiment 55 , wherein the administer ing is an intramuscular injection , intradermal injection, or subcutaneous injection . 10 Embodiment 49 Embodiment 57 The pharmaceutical composition of any one of Embodi The method of Embodiment 55 or 56 , wherein the admin ments 44-48 , which is a non -aqueous solution or sus istering is carried out without regard to whether the pension. 15 subject has food , i.e. , the compound or pharmaceutical composition is administered with or without food . Embodiment 50 Embodiment 58 The pharmaceutical composition of any one of Embodi ments 44-49 , wherein the compound of Formula II or 20 The method of any one of Embodiments 55-57 , wherein pharmaceutically acceptable salt thereof is dissolved or the hormone - dependent benign or malignant disorder is suspended in a pharmaceutically acceptable oil , e.g. , an prostate cancer or breast cancer . oil suitable for use as vehicles for injection , such as an oil of vegetable origin or synthetic mono- or di- glyc Embodiment 59 erides of fatty acids , e.g. , a vegetable oil , castor oil , 25 corn oil , sesame oil , cottonseed oil , peanut oil , poppy The method of any one of Embodiments 55-57 , wherein seed oil , tea seed oil , or soybean oil . the hormone -dependent benign or malignant disorder is castration resistant prostate cancer or castration sensi Embodiment 51 30 tive prostate cancer . The pharmaceutical composition of any one of Embodi Embodiment 60 ments 44-50 , further comprising a pharmaceutically acceptable solvent, e.g. , benzyl alcohol. The method of any one of Embodiments 55-57 , wherein 35 the hormone -dependent benign or malignant disorder is Embodiment 52 metastatic castration resistant prostate cancer or meta static castration sensitive prostate cancer . The pharmaceutical composition of any one of Embodi ments 44-51 , which comprises the compound of For mula II or pharmaceutically acceptable salt thereof in 40 Embodiment 61 an amount sufficient to provide a therapeutically effec The method of any one of Embodiments 55-60 , wherein tive blood plasma concentration of abiraterone for a the subject is treated with a gonadotropin - releasing period of at least two weeks , after a single administra tion to a subject having a hormone -dependent benign or hormone analog and / or bilateral orchiectomy. malignant disorder ( e.g. , metastatic castration resistant 45 Embodiment 62 prostate cancer or metastatic castration sensitive pros tate cancer ). The method of any one of Embodiments 55-61 , further comprising administering to the subject an effective Embodiment 53 50 amount of prednisone or prednisolone. The pharmaceutical composition of Embodiment 52 , Embodiment 63 wherein the therapeutically effective blood plasma con centration of abiraterone is about 1 ng /ml or higher. The method of any one of Embodiments 55-62 , wherein the pharmaceutical composition is administered to the Embodiment 54 55 subject once a week or once in more than a week , e.g. , the dosing frequency ranges from once a week to once The pharmaceutical composition of Embodiment 53 , every few months, such as from once a week to once wherein the therapeutically effective blood plasma con every eight weeks, or once a week to once every three centration of abiraterone is about 8 ng /ml or higher. 60 months . Embodiment 55 Embodiment 64 A method of treating a hormone -dependent benign or The method of any one of Embodiments 55-63 , wherein malignant disorder comprising administering to a sub- 65 the administering provides a blood plasma concentra ject in need thereof a therapeutically effective amount tion of abiraterone above 1.0 ng /ml for a period of at of the compound of any one of Embodiments 28-36 or least two weeks . US 10,792,292 B2 63 64 Embodiment 65 include any device or method capable of releasing an agent or product ( for example, a drug or a biologic ) at a time later The method of any one of Embodiments 55-63 , wherein than immediately following its administration ( and can the administering provides a blood plasma concentra include, for example , implants ). Various modified release tion of abiraterone above 8.4 ng/ ml for a period of at 5 devices have been described ( Stubbe et al . , Pharm . Res . least two weeks . 21 : 1732 , 2004 ) and could be applicable to the representative embodiments . Modified - release devices and methods can be Embodiment 66 identified and employed without undue experimentation by a person skilled in the art after consideration of all criteria The method of any one of Embodiments 55-65 , wherein 10 and use of best judgment on the subject's behalf. the administering provides a single dose or steady state The formulations and agents of the embodiments are Cmax of abiraterone between about 10 ng /ml and about administered in a pharmacologically or physiologically 400 ng /ml ( e.g. , between about 50 ng /ml and about 100 acceptable and effective amount to reduce or eliminate the ng/ ml , or between about 15 ng /ml and about 160 presence , for example, of prostate tumor tissue and abnor ng /ml ) . 15 mal or malignant prostate cells in a subject presenting with Provided herein are formulations, methods, and kits for prostate cancer. Similarly, the formulations and agents of the treating a subject with a sex hormone- dependent benign or embodiments are administered alone or in combination with malignant disorder such as prostate cancer. Also provided other therapeutic agents or therapeutic modalities ( for are methods for preparing the formulations useful for treat example, radiotherapy and surgery ) in prophylactically or ing a subject with a sex hormone - dependent benign or 20 therapeutically effective amounts , which are to be under malignant disorder ( such as prostate cancer ), a syndrome stood as amounts meeting the intended prophylactic or due to androgen excess, and / or a syndrome due to gluco therapeutic objectives, and providing the benefits available corticoid excess such as hypercortisolemia. Reference will from administration of such formulations and agents. now be made in detail to representative embodiments , The terms " effective amount, " " effective dose , ” and examples of which are illustrated in the accompanying 25 “ therapeutic blood plasma concentration ” as used herein drawings. mean , but are not limited to , an amount, dose , or concen The term “ subject ” as used herein means, but is not tration capable of treating , delaying , slowing , inhibiting or limited to , an animal or human in need of or capable of eliminating the onset, existence or progression of a disorder, receiving chemotherapy for a sex hormone -dependent disease or condition . For example , an “ effective amount, " benign or malignant disorder such as , for example, an 30 “ effective dose , ” or “ therapeutic blood plasma concentra androgen -dependent disorder or an estrogen - dependent dis tion ” is capable of reducing or eliminating the presence of order ( including prostate cancer and breast cancer ), an prostate tumor tissue and abnormal or malignant prostate animal or human in need of or capable of receiving therapy cells in a subject presenting with prostate cancer , which is for non - oncologic syndromes due to androgen excess , such sufficient to cure (partly or completely ) illness or prevent the as endometriosis, polycystic ovary syndrome, congenital 35 onset or further spread of disorder , disease or condition . For adrenal hyperplasia ( e.g. , classical or nonclassical congeni further example , an effective amount of formulation refers to tal adrenal hyperplasia ), precocious puberty , hirsutism , etc. , the amount administered alone or in combination with other and / or due to glucocorticoid excess such as hypercorti therapeutic agents or therapeutic modalities ( for example , solemia , such as Cushing's syndrome or Cushing's disease . radiotherapy and surgery ) to achieve clinically - significant In preferred embodiments, the subject is a human subject. 40 reduction in tumor burden . A person skilled in the art would The term " other drug or agent ” as used herein (when , for understand when a clinically - significant reduction in tumor example , referring to prior, simultaneous , and post -admin burden ( or improvement of a sex hormone- dependent benign istration of at least one other drug or agent with at least one or malignant disorder or another disorder or syndrome abiraterone prodrug formulation ) means at least one other described herein ) has occurred following administration of a compound, formulation, molecule , biologic , or the like , 45 formulation . An “ effective amount , ” " effective dose ,” or capable of enhancing the efficacy of the formulation ( s ), “ therapeutic blood plasma concentration ” is understood to decreasing an undesirable side effect ( s) of the be an amount, dose , or concentration not critically harmful formulation ( s ), or improving the treatment of the particular to the subject and , in any case , where any harmful side disorder . Any suitable routes of administration of such effects are outweighed by benefits . By way of example only , “ other drug or agent " can be used , for example , oral admin- 50 an effective amount or dose of an abiraterone prodrug istration , parenteral administration , etc. A person skilled in formulation means an amount capable of attaining blood the art of treating a subject having a sex hormone -dependent plasma concentrations of at least 1 ng /ml , e.g. , at least 1 benign or malignant disorder ( such as an androgen -depen ng /ml , at least 2 ng /ml , at least 4 ng /ml , or at least 8 ng /ml , dent disorder or an estrogen -dependent disorder ), syndromes of abiraterone in the subject following parenteral adminis due to androgen excess syndrome, and / or syndromes due to 55 tration of the prodrug formulation , and the efficacious blood glucocorticoid excess such as hypercortisolemia would plasma concentrations are attained for at least one week , know and understand how to choose and use such " other e.g. , at least two weeks ( for example, four, six , eight or more drug or agent ” for the intended purpose ( s ). weeks) following administration . The formulations can optionally be administered via a In general, the dosage ranges for administration of the modified - release device or method . The term “ modified- 60 formulation according to the present disclosure are those release ” as used herein should be understood as encompass that produce the desired effect ( s ). The useful dosage to be ing delayed release , prolonged or extended release , sus administered will vary depending on the age , weight, and tained release , or a targeted release , etc. For example , in health of the subject treated , the mode , route , and schedule some embodiments, the modified release device or method of administration, the response of the individual subject, and can further prolong the release of abiraterone of the prodrugs 65 the type or staging of prostate cancer ( or severity of a sex and formulations of the present disclosure . In some embodi hormone -dependent benign or malignant disorder or another ments, the modified release device or method can also syndrome or disorder described herein ) against which treat US 10,792,292 B2 65 66 ment with the formulation is sought. The dosage will also It is also meant to be understood that a specific embodi vary with the nature or the severity of the primary tumor and ment of a variable moiety herein may be the same or other underlying conditions, with epidemiologic conditions, different as another specific embodiment having the same with the concomitant use of other active compounds, and the identifier . route of administration . In addition , the dosage will be 5 Definitions of specific functional groups and chemical determined by the existence of any adverse side effects such terms are described in more detail below . The chemical as local hypersensitivity, systemic adverse effects, and elements are identified in accordance with the Periodic Table immune tolerance . of the Elements, CAS version , Handbook of Chemistry and An effective dose of the formulations ( and other agent ( s )) Physics, 75th Ed . , inside cover, and specific functional can be determined without undue experimentation ( for 10 groups are generally defined as described therein . Addition example, by pharmacokinetic studies ) by a person skilled in ally , general principles of organic chemistry, as well as the art after consideration of all criteria and use of best specific functional moieties and reactivity, are described in judgment on the patient's behalf ( and will most often be Thomas Sorrell, Organic Chemistry, University Science contingent upon the particular formulation utilized ). The 15 AdvancedBooks , Sausalito Organic , Chemistry1999 ; Smith, 5th Editionand March , John , WileyMarch's & dosage to be administered will depend upon the particular Sons , Inc. , New York , 2001 ; Larock , Comprehensive case , but in any event, it is the amount sufficient to induce Organic Transformations, VCH Publishers, Inc., New York , clinical benefit against , or improvement of, a sex hormone 1989 ; and Carruthers, Some Modern Methods of Organic dependent benign or malignant disorder ( such as prostate Synthesis, 3rd Edition , Cambridge University Press, Cam cancer ), a syndrome due to androgen excess , and / or a 20 bridge, 1987. The disclosure is not intended to be limited in syndrome due to glucocorticoid excess such as hypercorti any manner by the exemplary listing of substituents solemia . described herein . The formulations and agents of the embodiments can , As used herein , the term “ alkyl ” as used by itself or as part optionally, be administered in combination with ( or can of another group refers to a straight- or branched - chain include ) one or more pharmaceutically acceptable carriers, 25 saturated aliphatic hydrocarbon . In some embodiments , the diluents, or excipients . Formulations, administration tech alkyl can include one to thirty carbon atoms ( i.e. , C1-30 alkyl niques, pharmaceutical compositions , methods of preparing or alternatively expressed as C , -C30 alkyl) or the number of pharmaceutical compositions, and pharmaceutically accept carbon atoms designated ( i.e. , a C , alkyl such as methyl, a C2 alkyl such as ethyl, a Cz alkyl such as propyl or isopropyl, andable arecarriers described, diluents , for ,example and excipients , in “ Remington are known : The in Science the art 30 etc.). In one embodiment, the alkyl group is a straight chain and Practice of Pharmacy ” ( formerly “ Remington's Phar C1-16 alkyl group . In another embodiment, the alkyl group is maceutical Sciences , ” University of the Sciences in Phila a branched chain C3-16 alkyl group. delphia, Lippincott , Williams & Wilkins, Philadelphia , Pa . As used herein , the term " cycloalkyl ” as used by itself or ( 2005) ), the disclosure of which is hereby incorporated by 35 unsaturatedas part of another ( e.g. , containinggroup refers one to orsaturated two double and partially bonds) reference. A person skilled in the art can use known inject cyclic aliphatic hydrocarbons containing one to three rings able , physiologically acceptable sterile solutions . For pre having from three to twelve carbon atoms ( i.e. , C3-12 paring a ready -to - use solution for parenteral injection or cycloalkyl) or the number of carbons designated . In one infusion , aqueous isotonic solutions , for example, saline, embodiment, the cycloalkyl group has two rings . In one phosphate buffered saline ( PBS ) or corresponding plasma 40 embodiment, the cycloalkyl group has one ring . In another protein solutions , are readily available . The formulations can embodiment, the cycloalkyl group is a C3-8 cycloalkyl be present as lyophilisates or dry preparations, which can be group . In another embodiment, the cycloalkyl group is a C3-6 reconstituted with a known injectable solution directly cycloalkyl group . “ Cycloalkyl ” also includes ring systems before use under sterile conditions, for example, as a kit of wherein the cycloalkyl ring , as defined above , is fused with parts. In addition , the formulations can include one or more 45 one or more aryl or heteroaryl groups wherein the point of acceptable carriers (which can include , for example , sol attachment is on the cycloalkyl ring, and in such instances , vents , dispersion media , coatings, adjuvants, stabilizing the number of carbons continue to designate the number of agents, diluents , preservatives, antibacterial and antifungal carbons in the cycloalkyl ring system . Non - limiting exem agents , isotonic agents, absorption -modifying agents , and plary cycloalkyl groups include cyclopropyl, cyclobutyl, the like . “ Diluents ” can include water , saline, phosphate- 50 cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, buffered saline ( PBS ) , dextrose, ethanol, glycerol, and the decalin , adamantyl, cyclopentenyl, and cyclohexenyl. like . Isotonic agents can include sodium chloride , dextrose , As used herein , the term “ alkenyl ” as used by itself or as mannitol, sorbitol, and lactose , among others . Stabilizers part of another group refers to a straight- or branched - chain include albumin and alkali salts of ethylenediaminetet aliphatic hydrocarbon containing one or more ( e.g. , 1 , 2 , or raacetic acid , among others . 55 3 ) carbon - to - carbon double bonds . In one embodiment, the Any suitable route of administration can be employed for alkenyl group is a C2-16 alkenyl group . providing a subject with an effective amount/ dosage of As used herein , the term “ alkynyl ” as used by itself or as formulation and agents according to the representative part of another group refers to a straight- or branched - chain embodiments . A suitable route of administration can be aliphatic hydrocarbon containing one or more ( e.g. , 1 , 2 , or determined readily by a person skilled in the art of pharma- 60 3 ) carbon -to - carbon triple bonds . In one embodiment, the cology , immunology, medicine, oncology , or the like with alkynyl has one carbon -carbon triple bond . In one embodi out undue experimentation . However, it is anticipated that ment, the alkynyl group is a C2-16 alkynyl group . the formulations are primarily suitable for parenteral admin As used herein , the term “ abiraterone prodrug ( s ) of the istration such as via IM injection , intradermal injection, or present disclosure ” refers to any of the compounds described subcutaneous injection. 65 herein according to Formula I or II , a lipophilic ester of The abbreviations used herein have their conventional abiraterone prodrug, or any of Example Nos . 2A - 2H , iso meaning within the chemical and biological arts . topically labeled compound (s ) thereof ( e.g. , deuterium US 10,792,292 B2 67 68 enriched compounds ), possible stereoisomers thereof ( in representative embodiments, the abiraterone esters are abi cluding diastereoisomers, enantiomers, and racemic mix raterone acetate , abiraterone propionate , and abiraterone tures ), tautomers thereof, conformational isomers thereof, decanoate . and / or pharmaceutically acceptable salts thereof ( e.g. , acid The formulations can comprise a solution or suspension addition salt such as HCl salt ) . Hydrates and solvates of the 5 of abiraterone prodrug in pharmaceutically acceptable oils , prodrugs of the present disclosure are considered composi such as pharmaceutically acceptable oils for injection, tions of the present disclosure, wherein the prodrug ( s) is in including oils of vegetable origin or synthetic mono- or association with water or solvent, respectively . Some of the diglycerides of fatty acids . In some embodiments, pharma prodrugs of the present disclosure can also exist in various ceutically acceptable oils can include triglycerides made up polymorphic forms or amorphous forms. The prodrugs 10 of fatty acids ( poly -unsaturated , mono -unsaturated , and described herein include those compounds that readily saturated ) such as the following: vegetable oil , castor oil , undergo chemical changes under physiological conditions to corn oil , sesame oil , cottonseed oil , peanut oil (arachis oil ) , provide active abiraterone . Additionally, prodrugs can be poppy seed oil , tea seed oil , and soybean oil . Vegetable oils converted by chemical or biochemical methods in an ex vivo 15 were selected based on the solubility of the prodrug in the environment. As used herein , the term “ abiraterone prodrug oil . It was determined that abiraterone acetate was most formulation ( s) of the present disclosure ” refers to any of the soluble in castor oil , which includes a triglyceride, in which pharmaceutical composition or formulation comprising any the fatty acid constituent is primarily rich in oleic acid ( a one or more of the abiraterone prodrugs of the present hydroxylated monounsaturated fatty acid ) . Conversely, it disclosure, for example, any of the formulations prepared in 20 was determined that the more lipophilic prodrugs ( abirater Examples 3A - 3 ) . In any of the embodiments described one propionate and abiraterone decanoate ) were more herein , unless directly contradictory from context, the abi soluble in corn oil , which includes a triglyceride, in which raterone prodrug of the present disclosure can be abiraterone the fatty acid constituents are primarily linoleic acid (non decanoate . In any of the embodiments described herein , hydroxylated polyunsaturated fatty acid ) , oleic acid (non unless directly contradictory from context, the abiraterone 25 hydroxylated unsaturated fatty acid ) , palmitic acid (non prodrug formulation of the present disclosure can be any of hydroxylated saturated fatty acid ) , and stearic acid (non the pharmaceutical composition comprising abiraterone hydroxylated saturated fatty acid ) . Surprisingly, it was decanoate as described herein . In any of the embodiments determined that abiraterone butanoate has lower solubility in described herein , unless directly contradictory from context, both castor oil and corn oil than the acetate, propionate , or the abiraterone prodrug of the present disclosure can also be 30 decanoate prodrugs. It was also noted that there is an inverse abiraterone isocaproate. In any of the embodiments correlation between the melting points and solubilities of the described herein , unless directly contradictory from context, prodrugs in vegetable oils . The melting points of the various the abiraterone prodrug formulation of the present disclosure abiraterone prodrugs were determined by differential scan can also be any of the pharmaceutical composition compris ning calorimetry as shown in Table 1 . ing abiraterone isocaproate as described herein . 35 The abiraterone prodrugs of the present disclosure can TABLE 1 exist in isotope - labeled or -enriched form containing one or more atoms having an atomic mass or mass number different Melting Points of Abiraterone Prodrugs . from the atomic mass or mass number most abundantly 40 Abiraterone Prodrug Melting point found in nature . Isotopes can be radioactive or non - radio Acetate 127-130 ° C. active isotopes . Isotopes of atoms such as hydrogen , carbon, Propionate 102 ° C. oxygen , and nitrogen , include , but are not limited to 2H , PH , Butanoate 147 ° C. 13C , 4C , 15N , and 180. Compounds that contain other Decanoate 38 ° C. isotopes of these and / or other atoms are within the scope of 45 this disclosure . The formulations can contain pharmaceutically accept Solid and dashed wedge bonds indicate stereochemistry able excipients such as co - solvents ( that is , solubilizing as customary in the art. agents ) such as benzyl alcohol , benzyl benzoate , ethanol, The following examples are provided for illustration glycerol, polyethylene glycol , polysorbate 80 , acetic acid , purposes only , and are in no way intended to limit the scope 50 and ethyl acetate . It was determined that the additives / co of the claimed subject matter . solvents benzyl alcohol and benzyl benzoate had the advan tage of increasing the solubility of the prodrugs as well as Example 1 Long - Acting Injectable Formulations of reducing the viscosity and glide force of the solution , see Abiraterone Prodrugs e.g. , FIGS . 13A - 13E and Tables 2A - 2D , which provided a 55 more concentrated solution that was easier to inject through The formulations include long acting injectable oil - based an acceptable gauge needle for IM injection ( e.g. , 20-27 formulations of a lipophilic abiraterone prodrug such as ( 1 ) gauge such as 22-25 gauge ) . Indeed , the co - solvent is abiraterone 3ß - alkanoates and ( 2 ) linear, branched , cyclic , selected based on its ability to reduce the viscosity of the and aromatic alkanoates of C - 2 to C - 16 carbons ( that is , vehicle to allow injection through suitable injection needles aliphatic and aromatic esters made of 2 to 16 carbon atoms ) . 60 or cannula . Benzyl alcohol as an additive in IM or subcu The abiraterone esters can include , for example, the follow taneous injections also has the advantage that it can act as a ing esters : an acetate, a propionate , a butanoate, a ( vaterate ) local anesthetic at the injection site ( Wilson et al . Ann . Emer. pentanoate, an isocaproate, a buciclate , a cyclohexanecar Med . 33 ( 5 ) , 495 , 1999 ) . boxylate, a phenyl propionate , caproate ( hexanoate ), a enan The solubility of the abiraterone esters can be affected thate ( heptanoate ), a cypionate , an octanoate , a noncanoate , 65 upon adding a co - solvent to the vegetable oil vehicle . Thus, a decanoate, an undecanoate , a dodecanoate , a tridecanoate , in some embodiments, the abiraterone ester is completely a tetradecanoate, a pentadecanoates, and a hexadecanoate. In dissolved in the composition , and in other embodiments the US 10,792,292 B2 69 70 abiraterone ester is partly dispersed in the composition. In -continued one embodiment, the abiraterone esters are fully dissolved in the vehicle . The formulations can also contain pharmaceutically acceptable preservatives, polymers, antioxidants , antimicro 5 bials , chelating agents, and other excipients such as citric acid , dextrose, ascorbic acid , benzalkonium chloride, ben zoic acid , sodium betadex sulfobutyl ether, calcium chloride , sodium carbomethoxycellulose, chlorobutanol, creatine, croscarmellose, dibasic potassium phosphate, sodium docu sate , sodium edetate , glycerin , sodium hyaluronate , 10 hydroxypropyl betadex , lactic acid , lactose , lecithin , maleic R2 acid , mannitol, meglumine, methylcellulose, methylpara ben , microcrystalline cellulose , miripitium chloride , momo thioglycerol, phenol, poloxamer 188 , polyglactin , polysor bate 20 , polysorbate 40 , polysorbate 80 , propylparaben , 15 Example 2A . Preparation of Abiraterone Propionate sodium acetate , sodium benzoate , sodium citrate , sorbitan monolaurate , sorbitol, sucrose , tartaric acid , trisodium cit Abiraterone propionate was prepared as follows : rate, tromantadine, tromethamine , and urea . 15.0 g ( 42.9 mmol) of abiraterone was added to a 500 ml The formulations can be sterilized by methods known by round - bottom flask followed by 450 ml of chloroform and persons skilled in the art ( for example, gamma irradiation , 20 11.96 ml ( 85.8 mmol , 2.0 equiv ) of triethylamine . The flask micron filtration , and autoclaving ). was purged with nitrogen and the mixture was cooled to 0 ° The abiraterone prodrug formulations can be prepared at C. in an ice bath . After stirring the mixture for 15 minutes, various concentrations including, for example, 25 mg /ml to 500 mg /ml . In representative embodiments the concentra 4.12 ml ( 47.2 mmol, 1.1 equiv ) of propanoyl chloride were tions are 50 mg / ml to 300 mg/ ml . added dropwise followed by addition of an additional 6.57 The formulations, following IM or subcutaneous injec 25 ml ( 47.2 mmol, 1.1 equiv ) of triethylamine. The ice bath was tion , release an effective amount of abiraterone over a period removed , and the solution was stirred for an additional 2 of at least one week and up to two, three, four, or more hours . The reaction was once again cooled to 0 ° C. , and an weeks . The therapeutic blood plasma levels of abiraterone additional 4.12 ml of propanoyl chloride and 6.57 mL of achieved following administration of the abiraterone prod triethylamine were added slowly . The ice bath was again rug formulations can be , for example , 6-15 ng /ml between 30 removed , and the reaction stirred for another 16 hours. The 14-28 days following parenteral administration. In represen solution was then washed twice with 300 ml of water and tative embodiments, the therapeutic levels are 8-12 ng /ml once with 300 ml of brine . The organic phase was dried over between 14-28 days following parenteral administration. It sodium sulfate , concentrated under vacuum , and loaded onto has been demonstrated that an abiraterone Cmin of > 8.4 silica . The crude compound was purified by flash chroma ng /ml is associated with a favorable prostate - specific antigen 35 tography using an ethyl acetate /hexane solvent system . The response and could be a crucial predictive factor for pro desired compound was eluted with approximately 30 % ethyl gression - free survival in castration resistant prostate cancer acetate . The pure fractions were combined and concentrated patients ( Carton et al . , Eur. J. Cancer, 72:54 , 2017 ) . under vacuum to provide 8.2 g of abiraterone propionate as a yellow solid , which was 97.8 % pure according to HPLC Example 2. Synthesis of Abiraterone Prodrugs 40 analysis. Other chemical properties were as follows: LCMS m / z 406.3 ( M + H ) ; ' H NMR ( CDC13 , 200 MHz ) : 84 1.096 Abiraterone Acetate ( 11H , m ) , 1.625 ( 11H , m ) , 1.846 ( 3H , m ) , 2.067 ( 3H , m ) , Abiraterone acetate was obtained from Hetero Labs Lim 2.323 ( 5H , m ) , 4.627 ( 1H , m ) , 5.415 ( 1H , d , J = 5 Hz ) , 5.992 ited , India . ( 1H , q , J = 5 Hz ) , 7.215 ( 1H , ddd, J = 1 , 5.8 Hz ) , 7.677 ( 1H , dt, reactingOther abiraterone withesters R²COOH can be synthesized or an appropriate generally acti by 45 J = 2.8 Hz) , 8.456 ( 1H , dd, J= 2.5 Hz) , 8.619 ( 1H , dd, J = 1.2 vated form thereof, such as R COC1 . The reaction is typi Hz ) ; melting point ( DSC ) 101 ° C. cally carried out in an aprotic solvent such as CHC13 with an appropriate base such as triethyl amine. Examples of prepa Example 2B . Preparation of Abiraterone Butanoate ration of abiraterone propionate, abiraterone butanoate , abi raterone pentanoate , abiraterone hexanoate, abiraterone hep 50 Abiraterone butanoate was prepared as follows: tanoate, abiraterone isocaproate, abiraterone cypionate , and 7.0 g ( 20.0 mmol) of abiraterone was added to a 500 ml round bottom flask followed by 210 ml of chloroform and abiraterone decanoate are shown below . 5.58 ml ( 40.0 mmol, 2.0 equiv ) of triethylamine. The flask was purged with nitrogen and the mixture was cooled to 0 ° 55 C. in an ice bath . After stirring the mixture for 15 minutes, 2.28 ml ( 22.0 mmol , 1.1 equiv ) of butanoyl chloride were added dropwise followed by addition of an additional 3.07 ml ( 22.0 mmol, 1.1 equiv ) of triethylamine . The ice bath was removed , and the solution was stirred for an additional 2 R21 CI 60 hours . The reaction was once again cooled to 0 ° C. , and an H i additional 2.28 ml of butanoyl chloride and 3.07 mL of triethylamine were added slowly . The ice bath was again removed , and the reaction stirred for another 16 hours . During the course of the reaction , the color changed quickly HO 65 from a white mixture to a yellow solution and then slowly abiraterone to a red solution . After confirmation by TLC and LCMS that the reaction was complete , the solution was then washed US 10,792,292 B2 71 72 twice with 150 ml of water and once with 150 ml of brine. The organic phase was dried over sodium sulfate, concen The organic phase was dried over sodium sulfate, concen trated under vacuum , and loaded onto silica . The crude trated under vacuum , and loaded onto silica . The crude compound was purified by flash chromatography using an compound was purified by flash chromatography using an ethyl acetate / hexane solvent system . The desired compound 5 ethyl acetate /hexane solvent system . The desired compound was eluted with approximately 25 % ethyl acetate . The pure was eluted with approximately 20 % ethyl acetate . The pure fractions were combined and concentrated under vacuum to fractions were combined and concentrated under vacuum to provide 5.5 g of abiraterone butanoate as a yellow solid . provide 8.0 g of abiraterone decanoate as a yellow solid . Chemical properties were as follows: LCMS m / z 420.4 Chemical properties were as follows: LCMS m / z 504.4 ( M + H ) ; ' H NMR ( CDC13 , 200 MHz ) : 8H 0.948 ( 3H , t , J = 7 10 Hz ) , 1.043 ( 3H , s ) , 1.090 ( 3H , s ) , 1.633 ( 15H , m ) , 1.842 ( 3H , ( M + H ) ; ' H NMR ( CDC13 , 200 MHz ) : 8H 0.877 ( 3H , t , J = 7 m ) , 2.065 ( 3H , m ) , 2.297 ( 5H , m ) , 4.608 ( 1H , m ) , 5.413 ( 1H , Hz ) , 1.043 ( 3H , s ) , 1.082 ( 3H , s ) , 1.268 ( 16H , m ) , 1.643 d , J = 5 Hz ) , 5.990 ( 1H , q , J = 5 Hz ) , 7.215 ( 1H , ddd, J = 1 , 5.8 ( 15H , m ) , 1.842 ( 3H , m ) , 2.065 ( 3H , m ) , 2.290 ( 5H , m ) , Hz ) , 7.643 ( 1H , dt, J = 2.8 Hz ) , 8.455 ( 1H , dd , J = 2.5 Hz ) , 4.602 ( 1H , m ) , 5.404 ( 1H , d , J = 5 Hz ) , 5.998 ( 1H , q , = 5 Hz ) , 8.615 ( 1H , dd , J = 1.2 Hz ) ; melting point ( DSC ) 147 ° C. 15 7.215 ( 1H , ddd, J = 1,5.8 Hz ) , 7.643 ( 1H , dt, J = 2.8 Hz ) , 8.455 ( 1H , dd , J = 2.5 Hz ) , 8.617 ( 1H , dd , J = 1.2 Hz ) ; melting point Example 2C . Preparation of Abiraterone Decanoate ( DSC ) 38 ° C.

CI, NEtz CHC13

HO abiraterone

abiraterone decanoate

Abiraterone decanoate was prepared as follows: Example 2D . Preparation of Abiraterone Pentanoate 10.0 g ( 28.6 mmol) of abiraterone was added to a 500 ml 50 round - bottom flask followed by 300 ml of chloroform and 7.97 ml ( 57.2 mmol, 2.0 equiv ) of triethylamine. The flask was purged with nitrogen and the mixture was cooled to 0 ° C. in an ice bath . After stirring the mixture for 15 minutes , 6.53 ml ( 31.5 mmol, 1.1 equiv ) of decanoyl chloride were 55 added dropwise followed by addition of an additional 4.39 ml ( 31.5 mmol, 1.1 equiv ) of triethylamine . The ice bath was removed , and the solution was stirred for an additional 2 hours . The reaction was once again cooled to 0 ° C. , and an additional 6.53 ml of decanoyl chloride and 4.39 mL of 60 triethylamine were added slowly . The ice bath was again removed , and the reaction stirred for another 16 hours . vianoCI, NEtz During the course of the reaction , the color changed quickly CHC13 from a white mixture to a yellow solution and then slowly to a red solution . After confirmation by TLC and LCMS that 65 HO the reaction was complete, the solution was then washed abiraterone twice with 200 ml of water and once with 200 ml of brine. ?? US 10,792,292 B2 73 74 -continued Example 2F . Preparation of Abiraterone Heptanoate

H H * CI , NEtz CHCl3 10 i HO abiraterone pentanoate abiraterone

15 z Abiraterone pentanoate was prepared using a procedure similar to the procedure for preparing abiraterone decanoate ( Example 2C ) , except that valeroyl chloride was used instead of decanoyl chloride. LCMS m / z 434.3 ( M + H ) ; ' H H NMR ( CDC13 , 200 MHz ) : 04 0.9-2.2 ( 32H , m ) , 4.61 ( 1H , 20 m ) , 5.41 ( 1H , d , J = 5 Hz ) , 5.99 ( 1H , 4 , J = 5 Hz ) , 7.22 ( 1H , ddd , J = 1 , 5.8 Hz ) , 7.63 ( 1H , dt, J = 2.8 Hz ) , 8.45 ( 1H , dd , J = 2.5 Hz ) , 8.62 ( 1H , dd , J = 1.2 Hz ) . abiraterone heptanoate 25 Abiraterone heptanoate was prepared using a procedure Example 2E . Preparation of Abiraterone Hexanoate similar to the procedure for preparing abiraterone decanoate ( Example 2C ) , except that heptanoyl chloride was used instead of decanoyl chloride . LCMS m / z 462.4 ( M + H ) ; ' H 30 NMR ( CDC1z , 200 MHz ) : 04 0.9-2.2 ( 36H , m ) , 4.61 ( 1H , m ) , 5.40 ( 1H , d , J = 5 Hz ) , 6.00 ( 1H , q , J = 5 Hz ) , 7.21 ( 1H , ddd , J = 1 , 5.8 Hz ) , 7.64 ( 1H , dt, J = 2.8 Hz ) , 8.45 ( 1H , dd , J = 2.5 Hz ) , 8.61 ( 1H , dd, J = 1.2 Hz ) . 35 Example 2G . Preparation of Abiraterone Isocaproate CI, NEt3 CHCl3 40 HO abiraterone CI, NEtz 45 CHCl3

HO Abiraterone 50 H page N

55 abiraterone hexanoate

Abiraterone hexanoate was prepared using a procedure similar to the procedure for preparing abiraterone decanoate 60 ( Example 2C ) , except that hexanoyl chloride was used instead of decanoyl chloride. LCMS m / z 448.4 ( M + H ) ; ' H Abiraterone Isocaproate NMR ( CDC12 , 200 MHz ) : du 0.9-2.2 ( 34H , m ) , 4.60 ( 1H , m ) , 5.40 ( 1H , d , J = 5 Hz ) , 5.98 ( 1H , q , J = 5 Hz ) , 7.21 ( 1H , 65 Abiraterone isocaproate was prepared using a procedure ddd , J = 1 , 5.8 Hz ) , 7.62 ( 1H , dt, J = 2.8 Hz ) , 8.43 ( 1H , dd , similar to the procedure for preparing abiraterone decanoate J = 2.5 Hz ) , 8.60 ( 1H , dd , J = 1.2 Hz ) . (Example 2C ) , except that 4 -methylvaleryl chloride was US 10,792,292 B2 75 76 used instead of decanoyl chloride. LCMS m / z 448.4 ( M + H ) ; Example 3B . Preparation of Abiraterone Acetate ' H NMR ( CDC12 , 200 MHz ) : 0 , 0.9-2.2 ( 34H , m ) , 4.61 ( 1H , 90 % Castor Oil , 10 % Benzyl Alcohol Solution m ) , 5.40 ( 1H , d , J = 5 Hz ) , 6.00 ( 1H , q , J = 5 Hz ) , 7.22 ( 1H , ddd , J = 1 , 5.8 Hz ) , 7.64 ( 1H , dt, J = 2.8 Hz ) , 8.45 ( 1H , dd , An abiraterone acetate injectable ( IM depot) 90 % castor J = 2.5 Hz ) , 8.62 ( 1H , dd , J = 1.2 Hz ) . 5 oil , 10 % benzyl alcohol solution was prepared as follows: 700 mg of abiraterone acetate was weighed and placed in Example 2H . Preparation of Abiraterone Cypionate a 10 - mL serum vial with a crimped stopper. 8 mL of a 90 % castor oil / 10 % benzyl alcohol mixture was placed in a separate 10 - mL serum vial with a crimped stopper. The two 10 vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30 -minute liquid cycle . Following sterilization, the vials were moved to a laminar flow hood . CI, NEtz Then , 7 mL of the sterile 90 % castor oil / 10 % benzyl alcohol 15 solution was removed and added to the sterile abiraterone ?. CHCl3 acetate and the vial was re - stoppered and crimped closed . The abiraterone acetate was then dissolved by sonicating , vortexing, and placing the vials on a rotator. The final HO concentration of the sterile solution of abiraterone acetate Abiraterone 20 was 91 mg /ml . Example 3C . Preparation of Abiraterone Acetate 50 % Castor Oil , 50 % Benzyl Benzoate Solution 25 An abiraterone acetate injectable ( IM depot) 50 % castor oil , 50 % benzyl benzoate solution was prepared as follows: 980 mg of abiraterone acetate was weighed and placed in a 10 - mL serum vial with a crimped stopper. 8 mL of a 50 % castor oil / 50 % benzyl benzoate mixture was placed in a 30 separate 10 - mL serum vial with a crimped stopper. The two vials were then wrapped in aluminum foil and sterilized in an autoclave using a 30 -minute liquid cycle . Following Abiraterone Cypionate sterilization , the vials were moved to a laminar flow hood . Then , 7 mL of the sterile 50 % castor oil / 50 % benzyl celeAbiraterone cypionate was prepared using a procedure 35 benzoate mixture solution was removed and added to the sterile abiraterone acetate and the vial was re - stoppered and similar to the procedure for preparing abiraterone decanoate crimped closed . The abiraterone acetate was then dissolved ( Example 2C ) , except that 3 - cyclopentylpropanoyl chloride by sonicating , vortexing, and placing the vials on a rotator . was used instead of decanoyl chloride . LCMS m / z 474.4 The final concentration of the sterile solution of abiraterone (200 M + MHzH ); ' H) : NMR04 0.9-2.3 (CDC13 ( 36H, 200 , m MHz) , 4.62 ): (8H 1H , ' Hm NMR ) , 5.41 (CDC13( 1H , d , 40 acetate was 124 mg/ ml . J = 5 Hz ) , 6.00 ( 1H , q , J = 5 Hz ) , 7.22 ( 1H , ddd , J = 1 , 5.8 Hz ) , Example 3D . Preparation of Abiraterone Propionate 7.63 ( 1H , dt, J = 2.8 Hz ) , 8.45 ( 1H , dd, J = 2.5 Hz ) , 8.62 ( 1H , dd , J = 1.2 Hz ) . 90 % Castor Oil , 10 % Benzyl Alcohol Solution 45 An abiraterone propionate injectable ( IM depot ) 90 % Example 3. Preparation of Formulations of castor oil , 10 % benzyl alcohol solution was prepared as Abiraterone Prodrugs follows: 1,050 mg of abiraterone propionate was weighed and placed in a 10 - mL serum vial with a crimped stopper. 8 mL Example 3A . Preparation of Abiraterone Acetate 50 of a 90 % castor oil / 10 % benzyl alcohol mixture was placed Castor Oil Solution in a separate 10 - mL serum vial with a crimped stopper. The vehicle vial was then wrapped in aluminum foil and steril An abiraterone acetate injectable ( IM depot ) castor oil ized in an autoclave using a 30 -minute liquid cycle . Fol solution was prepared as follows : lowing sterilization , the vials were moved to a laminar flow 490 mg of abiraterone acetate was weighed and placed in 55 hood . Then, 8 mL of the sterile 90 % castor oil / 10 % benzyl a 10 - mL serum vial with a crimped stopper. 8 mL of castor alcohol solution was removed and added to the abiraterone oil was placed in a separate 10 - mL serum vial with a propionate and the vial was re -stoppered and crimped crimped stopper. The two vials were then wrapped in closed . The abiraterone propionate was then dissolved by aluminum foil and sterilized in an autoclave using a 30 -min sonicating , vortexing, and placing the vials on a rotator. The ute liquid cycle . Following sterilization, the vials were 60 final concentration of the sterile solution of abiraterone moved to a laminar flow hood . Then , 7 mL of the sterile propionate was 197 mg/ ml . castor oil was removed and added to the sterile abiraterone acetate and the vial was re - stoppered and crimped closed . Example 3E . Preparation of Abiraterone Propionate The abiraterone acetate was then dissolved by sonicating, 90 % Corn Oil , 10 % Benzyl Alcohol Solution vortexing , and placing the vials on a rotator. The final 65 concentration of the sterile solution of abiraterone acetate An abiraterone propionate injectable ( IM depot) 90 % corn was 70 mg /ml . oil , 10 % benzyl alcohol solution was prepared as follows : US 10,792,292 B2 77 78 1,050 mg of abiraterone propionate was weighed and crimped stopper. The vehicle vial was then wrapped in placed in a 10 - mL serum vial with a crimped stopper. 8 mL aluminum foil and sterilized in an autoclave using a 30 -min of a 90 % corn oil / 10 % benzyl alcohol mixture was placed in ute liquid cycle . Following sterilization , the vials were a separate 10 - mL serum vial with a crimped stopper. The moved to a laminar flow hood . Then , 10 mL of the sterile vehicle vial was then wrapped in aluminum foil and steril- 5 70 % corn oil / 10 % benzyl alcohol/ 20 % benzyl benzoate ized in an autoclave using a 30 -minute liquid cycle . Fol solution was removed and added to the abiraterone decano lowing sterilization , the vials were moved to a laminar flow ate and the vial was re - stoppered and crimped closed . The hood . Then , 8 mL of the sterile 90 % corn oil / 10 % benzyl abiraterone decanoate was then dissolved by sonicating , alcohol solution was removed and added to the abiraterone vortexing , and placing the vials on a rotator. The final propionate and the vial was re -stoppered and crimped 10 concentration of the sterile solution of abiraterone decanoate closed . The abiraterone propionate was then dissolved by was 209 mg /ml . sonicating , vortexing, and placing the vials on a rotator. The final concentration of the sterile solution of abiraterone Example 31. Preparation of Abiraterone Decanoate propionate was 168 mg /ml . ( ~ 240 Mg / Ml ) 70 % Corn Oil , 10 % Benzyl Alcohol, 15 20 % Benzyl Benzoate Solution Example 3F . Preparation of Abiraterone Decanoate 90 % Castor Oil , 10 % Benzyl Alcohol Solution An abiraterone decanoate injectable ( IM depot ~ 240 mg/ ml ) 70 % corn oil , 10 % benzyl alcohol, 20 % benzyl An abiraterone decanoate injectable ( IM depot) 90 % benzoate solution was prepared as follows: castor oil , 10 % benzyl alcohol solution was prepared as 20 3,125 mg of abiraterone decanoate was weighed and follows: placed in a 20 - mL serum vial with a crimped stopper. 60 mL 1,260 mg of abiraterone decanoate was weighed and of a 70 % corn oil / 10 % benzyl alcohol / 20 % benzyl benzoate placed in a 10 - mL serum vial with a crimped stopper. 8 mL mixture was placed in a separate 100 - mL serum vial with a of a 90 % castor oil / 10 % benzyl alcohol mixture was placed crimped stopper. The vehicle vial was then wrapped in in a separate 10 - mL serum vial with a crimped stopper. The 25 aluminum foil and sterilized in an autoclave using a 30 -min vehicle vial was then wrapped in aluminum foil and steril ute liquid cycle . Following sterilization , the vials were ized in an autoclave using a 30 -minute liquid cycle . Fol moved to a laminar flow hood . Then , 10 mL of the sterile lowing sterilization , the vials were moved to a laminar flow 70 % corn oil / 10 % benzyl alcohol/ 20 % benzyl benzoate hood . Then , 8 mL of the sterile 90 % castor oil / 10 % benzyl solution was removed and added to the abiraterone decano alcohol solution was removed and added to the abiraterone 30 ate and the vial was re - stoppered and crimped closed . The decanoate and the vial was re - stoppered and crimped closed . abiraterone decanoate was then dissolved by sonicating , The abiraterone decanoate was then dissolved by sonicating, vortexing, and placing the vials on a rotator. The final vortexing, and placing the vials on a rotator . The final concentration of the sterile solution of abiraterone decanoate concentration of the sterile solution of abiraterone decanoate was 242 mg /ml . was 160 mg / ml . 35 Example 3J . Preparation of Abiraterone Isocaproate Example 3G . Preparation of Abiraterone Decanoate 90 % Corn Oil , 10 % Benzyl Alcohol Solution 90 % Corn Oil , 10 % Benzyl Alcohol Solution An abiraterone isocaproate injectable ( IM depot) 90 % An abiraterone decanoate injectable ( IM depot) 90 % corn 40 corn oil , 10 % benzyl alcohol solution was prepared as oil , 10 % benzyl alcohol solution was prepared as follows: follows : 1,260 mg of abiraterone decanoate was weighed and 1190 mg of abiraterone isocaproate was weighed and placed in a 10 - mL serum vial with a crimped stopper. 8 mL placed in a 10 - mL serum vial with a crimped stopper. 8 mL of a 90 % corn oil / 10 % benzyl alcohol mixture was placed in of a 90 % corn oil / 10 % benzyl alcohol mixture was placed in a separate 10 - mL serum vial with a crimped stopper. The 45 a separate 10 - mL serum vial with a crimped stopper. The vehicle vial was then wrapped in aluminum foil and steril vehicle vial was then wrapped in aluminum foil and steril ized in an autoclave using a 30 -minute liquid cycle . Fol ized in an autoclave using a 30 -minute liquid cycle . Fol lowing sterilization , the vials were moved to a laminar flow lowing sterilization , the vials were moved to a laminar flow hood . Then , 8 mL of the sterile 90 % corn oil / 10 % benzyl hood . Then , 6.4 mL of the sterile 90 % corn oil / 10 % benzyl alcohol solution was removed and added to the abiraterone 50 alcohol solution was removed and added to the abiraterone decanoate and the vial was re - stoppered and crimped closed . isocaproate and the vial was re - stoppered and crimped The abiraterone decanoate was then dissolved by sonicating, closed . The abiraterone isocaproate was then dissolved by vortexing , and placing the vials on a rotator. The final sonicating , vortexing, and placing the vials on a rotator. The concentration of the sterile solution of abiraterone decanoate final concentration of the sterile solution of abiraterone was 170 mg / ml . 55 isocaproate was 158 mg/ ml . Example 3H . Preparation of Abiraterone Decanoate Example 4A . Solubility Testing of Abiraterone ( ~ 200 Mg / MI ) 70 % Corn Oil , 10 % Benzyl Alcohol , Prodrugs 20 % Benzyl Benzoate Solution 60 The solubilities of various abiraterone prodrugs were An abiraterone decanoate injectable ( IM depot ~ 200 tested as follows. The results are shown in Table 2 . mg /ml ) 70 % corn oil , 10 % benzyl alcohol , 20 % benzyl For each solvent studied , a sufficient quantity of prodrug benzoate solution was prepared as follows: was weighed into a separate glass vial and 1-2 ml of solvent 2,500 mg of abiraterone decanoate was weighed and was added . The resultant suspension was sonicated and placed in a 20 - mL serum vial with a crimped stopper. 60 mL 65 vortexed . If the prodrug was completely dissolved , more of a 70 % corn oil / 10 % benzyl alcohol / 20 % benzyl benzoate prodrug was added until an excess of material was observed . mixture was placed in a separate 100 - mL serum vial with a If there was a large excess of undissolved prodrug, addi US 10,792,292 B2 79 80 tional diluent could be added . The total mass and volume TABLE 2A used were recorded . Each vial was tightly capped and wrapped with foil to protect it from light as necessary . The vials were placed on a laboratory rotator in a 25 ° C. Solubility Studies of Abiraterone Decanoate in Different Vehicles incubator ( or at any other temperature that was required ). 5 The samples were allowed to equilibrate for a minimum of Equilibrium 1 day before assessing solubility . A later second time point, Formulation saturation solubility typically at about 1 week , was also taken to confirm the solubility of each prodrug. Corn Oil Benzyl Alcohol Benzyl Benzoate ( RT , mg/ ml ) At the appropriate time point, the vials were removed 10 from the incubator. A small amount of supernatant from each 100 % 63 vial was transferred into a microcentrifuge tube containing 90 % 10 % 79 a 0.22 or 0.45 um filter. The tube was centrifuged at 10,000 80 % 20 % 94 95 % 5 % 108 rpm until all of the liquid passed through the filter to the 15 bottom of the tube. Alternatively, samples were filtered 90 % 10 % 170 using a 0.22 or 0.45 um syringe filter. The filtered liquid was 85 % 5 % 10 % 148 assayed using HPLC . Samples were diluted as necessary so 70 % 10 % 20 % 240 that the sample concentrations were bracketed by the stan dards . 20 As can be seen from this study, the combination of benzyl TABLE 2 alcohol and benzyl benzoate can significantly enhance the solubility of abiraterone decanoate in corn oil . See also Solubilities of Abiraterone Prodrugs . FIGS . 13A and 13B . Abiraterone Prodrug Solubility (mg / ml ) 25 Additional experiments also show that the inclusion of Vehicle Acetate Propionate Butanoate Decanoate benzyl benzoate lowers viscosity and Glide Force of oil vehicles . It is expected that such oil vehicles can be advan Castor oil 74 154 36 188 Castor oil , 10 % 112 188 52 190 tageously used in formulating the abiraterone prodrugs benzyl alcohol 30 herein to provide a lower viscosity and lower Glide Force Castor oil , 10 % 91 — — — benzyl benzoate abiraterone prodrug formulation when desired . Castor oil , 50 % 148 — The Glide Force testing was carried out with tensile and benzyl benzoate compression testing machine ( e.g. Lloyd press or equiva Sesame oil 27 86 17 130 lent) , NEXYGEN Plus materials testing software , or equiva Cottonseed oil 27 85 17 152 35 Corn oil 56 134 30 183 lent Load cell 250N . 5 - mL Luer - Lok Syringe ( e.g. Becton , Corn oil , 10 % 223 277 Dickinson and Company /BD , P / N 309646 ) , or equivalent 23 benzyl alcohol gauge , 1.5 inch length , thin wall , Precision Glide Needle ( e.g. Becton , Dickinson and Company /BD , P / N 305194 ) , or Abiraterone Prodrug Solubility (mg /ml ) equivalent 27 gauge , 1.5 inch length , regular wall , Precision Cypi Iso Hepta Hexa Penta 40 Glide Needle ( e.g. Becton , Dickinson and Company / BD , Vehicle onate caproate noate noate noate P / N 301629 ), or equivalent . Castor oil 48 120 124 173 89 Table 2B shows the viscosity of various oil vehicles, Castor oil , 10 % 108 160 171 188 121 benzyl alcohol without additives, or with 10 % benzyl alcohol , 20 % benzyl Corn oil 70 103 124 133 81 45 benzoate , or a combination of 10 % benzyl alcohol and 20 % Corn oil , 10 % 121 183 189 204 146 benzyl benzoate. See also FIG . 13C . benzyl alcohol TABLE 2B The parenteral formulations must be sterilized before administration . This can be achieved by a variety of tech- 50 Viscosity (Pa * s ) of Various Oils with Additives niques including heat sterilization ( for example, dry heat or 20% Benzyl moist heat ), radiation sterilization ( for example , gamma ray Benzoate with sterilization ), filtration sterilization ( for example, 0.22 10 % Benzyl 20% Benzyl 10 % Benzyl micrometer membrane filters ), or gaseous sterilization ( for Solvent None Alcohol Benzoate alcohol example, formaldehyde or ethylene oxide gas ) . 55 Corn Oil 0.0550 0.0386 0.0371 0.0267 Sesame Oil 0.0594 0.0409 0.0395 0.0277 Example 4B . Solubility, Viscosity , and Glide Force Peanut Oil 0.0671 0.0458 0.0434 0.0302 Cottonseed 0.0591 0.0408 0.0396 0.0280 Testings of Abiraterone Decanoate Formulations or Oil Oil Vehicles Miglyol 0.0259 0.0193 0.0204 0.0154 60 812 This example tests properties of various abiraterone decanoate formulations and oil vehicles . First , further solubility studies show solubility advantages Tables 2C and 2D show Glide Force ( N ) of various oil of abiraterone decanoate formulation 70 % Corn oil , 10 % vehicles , without additives, or with 10 % benzyl alcohol , benzyl alcohol, 20 % benzyl Benzoate . See Table 2A below . 65 20 % benzyl benzoate , or a combination of 10 % benzyl The abiraterone decanoate used for the studies in Table 2A alcohol and 20 % benzyl benzoate , using 23 Gauge Needle or was obtained from Example 6A . 27 Gauge Needle , respectively. See also FIGS . 13D and 13E . US 10,792,292 B2 81 82 TABLE 2C out the length of the study and analyzed for both prodrug and abiraterone. The results of the rat study are provided in Table Glide Force ( N ) of Various Oils with Additives, 23 Gauge Needle 3 and FIG . 1 . 20% Benzyl Benzoate with 5 TABLE 3 10 % Benzyl 20 % Benzyl 10% Benzyl Solvent None Alcohol Benzoate alcohol Group Mean Plasma Pharmacokinetic Parameters for Abiraterone Following IM Injection of Various Formulations Corn Oil 13.4 8.7 8.0 7.5 of Abiraterone or Abiraterone Acetate in Rats. Sesame Oil 12.4 9.7 8.7 6.1 Peanut Oil 14.6 12.9 10.9 6.6 10 Tmax Cmax AUClast Cottonseed 11.9 10.8 10.1 5.7 Group Animal ( hr) ( ng /mL ) ( ng * hr /mL ) Oil Miglyol 12.4 6.7 6.5 4.1 1 N 5 5 5 812 Mean 39.2 21.6 934 SD 35.3 26.1 332 15 CV % 90.2 121 35.5 2 N 5 5 5 TABLE 2D Mean 8.00 3.84 329 SD 0.00 2.40 71.6 CV % 0.00 62.6 21.8 Glide Force ( N ) of Various Oils with Additives, 27 Gauge Needle 3 N 5 5 4 Mean 2.60 13.3 163 20 % Benzyl 20 Benzoate with SD 1.34 16.0 174 10% Benzyl 20 % Benzyl 10% Benzyl CV % 51.6 120 107 Solvent None Alcohol Benzoate alcohol 4 N 3 3 0 Mean 1.67 1.43 Corn Oil 91.5 66.4 53.0 48.5 SD 0.577 0.261 Sesame Oil 92.6 68.0 63.2 46.1 Peanut Oil 85.6 74.0 58.2 49.2 25 Group 1 : abiraterone acetate solution in castor oil ( 70 mg/ ml ) ; Group 2 : abiraterone acetate suspension , sodium phosphate buffer, 0.1 % Tween ( 70 Cottonseed 99.3 68.4 63.8 45.0 mg /ml ); Oil Group 3 : abiraterone suspension in castor oil ( 62.5 mg/ ml ); Miglyol 46.8 35.4 37.7 27.2 Group 4 : abiraterone suspension , sodium phosphate buffer, 0.1 % Tween ( 62.5 mg/ ml ) 812 30 The data from the rat study indicate that formulations containing abiraterone acetate preformed significantly better Example 5 than the formulations containing abiraterone. Additionally, the formulation of Group 1 , which contained abiraterone Blood Plasma Pharmacokinetics of Abiraterone in acetate in solution , performed better than the formulation of Rats and Dogs Following Administration of 35 Group 2 , which contained abiraterone acetate in suspension Formulations of Abiraterone Prodrugs versus solution . Example 5A . PK Studies of Abiraterone and FIG . 1 depicts the mean plasma concentrations versus Abiraterone Acetate in Rats and Dogs time profiles of abiraterone in rats following IM injection of the abiraterone acetate formulation into the thigh muscle of Several formulations were considered in the initial rat 40 five male rats at a dose of 35 mg/ kg . Blood samples for the study. These formulations consisted of abiraterone acetate as evaluation of systemic exposure after abiraterone acetate IM a solution in castor oil or as a suspension in sodium depot administration were collected at 1 , 2 , 4 , 8 , 24 , 48 , 72 phosphate buffer, 0.1 % Tween and abiraterone suspension in and 168 hours post - administration and analyzed for abirater castor oil or as an aqueous mixture of sodium phosphate 45 one as well as abiraterone acetate . In this study, the abi buffer, 0.1 % Tween . The manufacturing of these long - acting raterone acetate castor oil solution formulation was com IM formulations follows the general process of placing the pared with abiraterone acetate aqueous suspension drug in one vial and the solubilizing solution in a second vial formulation and abiraterone aqueous and castor oil suspen and sterilizing each of the vials . Once the components are sions. sterilized , they are mixed together under sterile conditions to 50 Initially , we attempted to administer abiraterone intramus produce the final product. Sterilization is done separately cularly to rats as a suspension consisting of vegetable oils because the drug could possibly degrade during the steril and aqueous . Surprisingly , very low blood plasma levels ization process when the drug is in solution . Additionally, were achieved with abiraterone itself ( See FIG . 1 ) . Also , this sterilization process was selected over filtration steril 55 surprisingly, the use of abiraterone acetate in aqueous sus ization due to the viscosity of the oils or the suspension pension resulted in low blood plasma levels ( See FIG . 1 ) . nature of two of the formulations. Conversely, a vegetable oil solution of abiraterone acetate An additional study was done using dogs as the animal gave not only the highest blood plasma levels but also the model instead of rats . Four formulations were taken into this longest extended blood plasma concentrations of abiraterone study and they included a solution of abiraterone acetate in 60 in rats when injected intramuscularly ( See FIG . 1 ) . an aqueous system ( given IV ) and solutions of abiraterone The abiraterone acetate castor oil IM depot solution acetate in castor, 90 % castor oil and 10 % benzyl alcohol , or formulation showed superior plasma concentrations of abi abiraterone acetate in 50 % castor oil and 50 % benzyl raterone compared with the abiraterone and abiraterone benzoate . acetate aqueous and castor oil suspensions over the 168 - hour The above formulations were administered to either rats 65 period . or dogs as an IV injection or as IM injections to the hind The results of the dog study are provided in Table 4 and leg ( s ) of each animal . Plasma samples were pulled through FIG . 2 . US 10,792,292 B2 83 84 TABLE 4 Group Mean Plasma Pharmacokinetic Parameters for Abiraterone Following IV and IM Injection of Abiraterone Acetate in Dogs . AUCiast AUCINE Dose T.?? ???? Cmax ( hr * ng AUCiast' ( hr * ng / AUCINE t1 / 2 Group (mg / kg ) Animal ( hr) (ng mL/ ) Dose mL) Dose mL Dose ( hr ) % F 1 10 N 9 9 9 9 9 9 9 9 Mean 0.0830 8560 856 5920 592 5990 599 4.64 SD 0.00 2170 217 1590 159 1630 163 1.33 CV % 0.00 25.4 25.4 26.9 26.9 27.3 27.3 28.6 2 19 N 3 3 3 3 3 3 3 3 3 Mean 56.0 60.0 2.89 8910 469 8990 473 78.4 86.2 SD 13.9 14.4 0.684 1830 96.3 1790 94.2 10.2 9.58 CV % 24.7 23.7 23.7 20.5 20.5 19.9 19.92 13.1 11.1 3 27 N 3 3 3 3 3 3 3 3 3 Mean 56.0 97.7 3.26 14900 551 15000 555 87.3 85.7 SD 13.9 39.2 1.45 3940 146 3940 146 3.73 2.11 CV % 24.7 40.1 40.1 26.5 26.5 26.3 26.3 4.27 2.46 4 38 N 3 3 3 3 3 3 3 3 3 Mean 21.3 153 4.04 12400 327 12500 329 66.0 61.7 SD 23.1 33.5 0.882 3350 88.2 3370 88.6 13.4 28.8 CV % 108 21.8 21.8 26.9 26.9 27.0 27.0 20.2 46.7 Group 1 : IV administration of abiraterone acetate solution ( 33 % aq HP -beta - cyclodextrin ) dosed at 10 mg /kg ; Group 2 : IM administration of abiraterone acetate solution in castor oil ( 66 mg/ ml ) dosed at 21 mg /kg ; Group 3 : M administration of abiraterone acetate solution in castor oil with 10 % zyl alcohol ( 91 mg /ml ) dosed at 30 mg /kg ; Group 4 : M administration of abiraterone acetate solution in castor oil with 50 % benzyl benzoate ( 124 mg/ ml ) dosed at 42 mg/ kg . 25 The data from the dog study indicate that abiraterone predicted 600 mg IM dose of abiraterone acetate adminis acetate given as a solution in castor oil (with or without tered every two weeks should be compared to the current benzyl alcohol) produced measurable blood levels out to 504 1,000 mg / day oral dose of Zytiga® ( which would be 14,000 hours. Additionally, although the formulation with benzyl mg for a two - week dosing period ). The higher bioavailabil benzoate produced measurable levels of abiraterone acetate , 30 ity of the IM delivery together with the elimination of the the formulation was found to be irritating to the dogs at the food effect will lead to lower patient variability which injection site ; one or two dogs were licking and biting at the together with higher and less frequent plasma trough levels injection site and developed an open wound . This caused a should lead to better efficacy ( ref Cmin > 8.4 ng /ml associated significant decrease in the fraction of prodrug absorbed from with improved prostate - specific antigen response and these animals and a significant decrease in the average 35 improved progression - free survival in castration - resistant fraction absorbed ( 61.7 % ) in this dose group . The absolute prostate cancer patients ) ( Carton et al . , Eur. J. Can . 72:54 , bioavailabilities for these formulations were found to range 2017 ) . between 61.7 and 86.2 % . FIG . 2 depicts the mean plasma concentrations versus time profiles of abiraterone in dogs following IM injection 40 Example 5B . PK Studies of Abiraterone Propionate of various abiraterone acetate formulations into the thigh and Abiraterone Decanoate in Dogs muscle of male dogs ( three dogs for each formulation ) at doses of 19 , 27 , and 38 mg/ kg . Blood samples for the This is a Single - Dose Bioavailability Study of Several evaluation of systemic exposure after abiraterone acetate IM Abiraterone Pro - drugs ( Propionate and Decanoate ) given as depot administration were collected at 0.5 , 1 , 2 , 3 , 4 , 5 , 8 , 24 , 45 Intramuscular Injections ( IM ) and intravenous injections to 48 , 60 , 120 , 168 , 336 , and 504 hours post - administration and Beagle Dogs . analyzed for abiraterone as well as abiraterone acetate . The formulations and dosages used for this study are as The abiraterone acetate IM depot solution formulations in follows: castor oil , castor oil /benzyl alcohol, and castor oil/ benzyl 1 ) Intramuscular ( IM ) ; Abiraterone propionate 197 benzoate showed extended plasma concentrations of abi- 50 mg /mL solution in 10 % Benzyl alcohol / 90 % Castor oil , raterone over the 504 - hour period. dosed at 41 mg/ kg ; An IV administration of abiraterone acetate was included 2 ) Intramuscular ( IM ) ; Abiraterone propionate 168 in this study ( dose of 10 mg /kg ) to measure the bioavail mg/ mL solution in 10 % Benzyl alcohol / 90 % Corn oil , ability of the IM depot formulations . The bioavailabilities dosed at 41 mg /kg ; were determined to be 86.2 % ; 85.7 % and 61.7 % . 55 3 ) Intramuscular ( IM ) ; Abiraterone decanoate 160 mg /mL Computer -modeling was used to predict the human phar solution in 10 % Benzyl alcohol / 90 % Castor oil ; dosed macokinetic profile of abiraterone prodrugs administered IM at 50 mg /kg ; to humans based on data obtained from the IM rat and dog studies. The modeling predicted that an IM dose of 600 mg 4 ) Intramuscular ( IM ) ; Abiraterone decanoate 170 mg /mL to 2,000 mg of abiraterone acetate administered to human 60 solution in 10 % Benzyl alcohol / 90 % Corn oil ; dosed at subjects every two to four weeks would produce the desired 50 mg /kg ; plasma pharmacokinetic profile in human subjects ( that is , 5 ) Intravenous ( IV ) ; Abiraterone propionate 0.57 mg/ mL bioavailability of greater than 80 % , Cmin value of abirater solution in 40 % HP - b - CD / 25 mM Na phosphate ( pH one greater than 1.0 ng /ml to 8.4 ng /ml , e.g. , greater than 1 7.4 ) dosed at 1 mg/ kg ; and ng /ml , greater than 2 ng /ml , greater than 4 ng / ml, or greater 65 6 ) Intravenous ( IV ) ; Abiraterone decanoate 0.37 mg /mL than 8.4 ng /ml , and Cmax value of abiraterone of approxi solution in 40 % HP - b - CD / 25 mM Na phosphate (pH mately 10 ng /ml to 400 ng /ml for at least two weeks ) . The 7.4 ) , dosed at 1.2 mg /kg . US 10,792,292 B2 85 86 Table 5 below summarizes the study design : were manually selected . Lambda z profiles that did not meet the guidelines stated above excluded the AUCINF , 11/29 CL / F , TABLE 5 and Vz / F parameters for that animal profile with an asterisk and excluded the results from summary descriptive statis Experimental Study Design 5 tics . Dose Dose The AUC INF value was calculated as : AUCiast + (Ciastaz ). Level Conc . # of CL / F was calculated as : Dose per dosing interval/ ( AUCINE ) Group Test Article Route (mg / kg ) * (mg / mL ) Animals and Vz / F was calculated as : Dose per dosing interval / 1 Abiraterone Propionate IV 1 0.57 6 (AUCINF * NZ ). Terminal 11/2 was calculated as : ln ( 2 ) /az . If in 40 % HP -beta 10 cyclodextrin the lambda z interval was not at least 2 - fold greater than the 2 Abiraterone Decanoate IV 1.2 0.37 6 calculated half - life , the half - life value was flagged as unre in 40 % HP - beta liable with an asterisk and excluded from descriptive statis cyclodextrin tics . 3 Abiraterone Propionate IM 41 197 3 in 90 % castor oil / 10 % 15 Mean plasma concentration versus time data are presented benzyl alcohol with standard deviation ( SD ) and percent coefficient of 4 Abiraterone Propionate IM 41 168 3 variation ( CV % ) and reported to three significant figures . in 90 % corn oil / 10 % benzyl alcohol PK parameter values are presented with mean , SD , and CV 5 Abiraterone Decanoate IM 50 160 3 % . Individual T ??? values were reported to two significant in 90 % castor oil / 10 % benzyl alcohol 20 figures, while all other values and descriptive statistics are 6 Abiraterone Decanoate IM 50 170 3 reported to three significant figures. in 90 % corn oil / 10 % Individual animal and group mean PK parameters for the benzyl alcohol pro -drugs and abiraterone, following IV administration , are presented in Table 6 and Table 7. Individual animal and Equivalent* dose is Pro Abiraterone - drug concentration active dose . was 0.82 mg/ kg for IV administration and 35 mg/ kg 25 group mean PK parameters for the pro - drugs and abirater for IM administration one, following IM administration , are presented in Table 8 and Table 9. Group mean plasma concentration versus time All animals were dose via IV administration . Following a profiles, following administration to dogs , are plotted in washout period of 72 hours , all dogs were dosed via IM FIG . 5 through FIG . 10 . route . Doses were based on an assumed body weight of 10 30 Results from IV Administration : kg . Following IV administration , blood was collected at Following IV administration of abiraterone decanoate 0.083 , 0.1667 , 0.25 , 0.5 , 0.75 , 1 , 2 , 4 , 6 , 8 , and 24 hours post ( pro - drug ), a mean CL value of 8.88 mL /min /kg was cal dose administration . Following IM administration , blood culated for the prodrug , which was considered low clear was collected at 0.5 , 1 , 2 , 3 , 4 , 5 , 8 , and 12 hours and 1 , 2 , ance . Using a dose value of 0.84 mg /kg ( assuming 100 % 3 , 5 , 7 , 14 , 21 , 28 , 35 , 42 , 49 , 56 ( decanoate only ) and 63 35 conversion of the prodrug to abiraterone) the mean CL / F ( decanoate only ) days post dose administration ( time of value was 97.8 mL /min /kg for abiraterone. The mean Vz collection to approximate the time of dose administration ). value was 0.659 L /kg for the pro -drug and the mean Vz / F Blood was processed to plasma and the resulting plasma value 13.0 L /kg for abiraterone . The mean t1 / 2 value for the samples were analyzed for the prodrug and abiraterone . prodrug and abiraterone was 0.86 hours and 1.5 hours, Following IV administration of abiraterone propionate, 40 respectively. animals only had 1 or 2 quantifiable plasma concentrations, Exposure to abiraterone propionate was only observed in as such , no reliable pharmacokinetic parameters could be the first 2 time points after dose administration , as such no assessed . reliable PK parameters could be calculated . Following IV Pharmacokinetic analyses were performed on plasma administration of abiraterone propionate (pro - drug ), the concentration versus time data using Phoenix WinNonlin ( v 45 mean CL / F value for abiraterone was 114 mL /min /kg , with 8.1 ) non - compartmental analysis function ( linear trapezoi a mean Vz/ F value of 20.8 L /kg . The mean t12 value for dal rule for AUC calculations ) . Nominal dose values and abiraterone was 2.1 hours . sampling times were used for calculations . For the purpose While the abiraterone Cmax value was almost 4 - fold of PK calculations, any concentration reported as “ BLQ” higher following IV administration of abiraterone propi was set equal to zero . 50 onate , the AUC values were comparable (within 2 - fold ), Cmax and the corresponding Tmax values were determined suggesting marginal differences between the pro - drugs. by direct assessment of the concentration versus time data . Results from IM Administration : All AUC calculations were performed using the linear Following IM administration of the two decanoate for trapezoidal rule . mulations, mean abiraterone Tmax value was 5.0 days for As data permitted , the terminal elimination rate constant 55 either of the two formulations and the mean decanoate T ,??? ( lambda z , az ) was calculated . The value of az was deter values ranged between 0.11 and 0.26 days between the mined by the slope of the regression line of the natural log formulations. The mean pro - drug and abiraterone exposures transformed concentrations versus time with the following ( as evidenced by Cmar and AUC values ) were within 2 - fold constraints : between the 2 formulations. The terminal elimination phase Data points should be randomly distributed around a 60 for the prodrug did not achieve a stable negative slope single straight line ; beyond the Day 7 time points, as such no additional dispo At least three data points post the Cmax should be used in sition parameters could be assessed . For abiraterone, the the regression ; mean t1 / 2 value ( terminal t1 / 2 ) was 23 and 24 days following The correlation coefficient ( R2 ) of regression should administration in the 2 vehicles. Estimates of the absolute be > 0.80 ; 65 bioavailability for abiraterone are calculated using the mean To optimize the reliability of the identified terminal phase AUCINF values following IV administration ( 145 h * ng /mL ) ( az ) , where possible , the data points used to define the az and IM administration ( corrected for dose and time US 10,792,292 B2 87 88 units = 104 h * ng /mL for Group 5 and 134 h * ng /mL for Group and extent ( F ) of bioavailability of abiraterone after IM 6 ) . The bioavailability was 72 and 92 % for Group 5 and 6 , administration to dogs was estimated by deconvolution ; respectively. values of K01 and F were assumed to be equivalent in man . The predicted PK parameters ( CL , Vss , K01 and F ) were mulationsFollowing, mean IM administrationabiraterone T , of thevalues two rangedpropionate between for 5 used to simulate plasma concentration- time profiles in man max after IM administration with various prescribed dose regi 0.56 or 0.61 days and the mean propionate Tmax values mens ( assuming linear kinetics of abiraterone .) The model ranged between 0.11 and 0.26 days ( 2.3 and 6.2 hours ) ing predicted that an IM dose of as low as 120 mg abirater between the formulations . The mean pro - drug and abirater one decanoate every two weeks can achieve a one exposures ( as evidenced by Cmax and AUC values ) were therapeutically effective abiraterone plasma concentration in within 2 - fold between the 2 formulations. Excluding the 10 human with a Cmin value of abiraterone at steady state Day 7 time point (no values beyond Day 7 ) , the mean t1 / 2 greater than about 8 ng /ml , with a Cmax value of abiraterone values for the pro - drug were between 0.98 and 1.7 days at steady state of about 14 ng /ml . The modeling also following administration of the 2 different vehicles . For predicted that an IM dose of abiraterone decanoate is abiraterone, the mean t1 / 2 value was 1.8 and 4.5 days suitable for once a month or once in more than a month following administration in the 2 vehicles . Estimates of the 15 dosing regimen in human , which can provide a therapeuti absolute bioavailability for abiraterone are calculated using cally effective abiraterone plasma concentration . For the mean AUCINF , values following IV administration ( 127 example , an IM dose of about 350 mg abiraterone decanoate h * ng /mL ) and IM administration ( corrected for dose and once in 4 weeks is sufficient to provide a Cmin value of time units = 105 h * ng /mL for Group 3 and 94.1 h * ng /mL for abiraterone at steady state greater than about 8 ng /ml . Cmax Group 4 ) . The bioavailability was 83 and 74 % for Group 3 20 value of abiraterone at steady state generally is dose pro and 4 , respectively. portional. See also FIG . 11A , FIG . 11B , FIG . 11C , and FIG . Tables 6-9 and FIGS . 5-10 provide a summary of the PK 11D . In light of this disclosure, in some cases , the dosing studies of this example . regimen can also include an initial dosing period with a Computer -modeling was also used to predict the human higher dosing frequency or with a different abiraterone pharmacokinetic profile of abiraterone decanoate adminis 25 medication to achieve certain exposure of abiraterone in a tered IM to humans based on data obtained from the rat and treated subject, which is then followed by a once a month ( or dog studies . Pharmacokinetic ( PK ) modelling and simula in more than a month ) dosing regimen as described herein . tions were carried out using a fully - validated version ( 8.1 ) of For example , in some cases , the dosing regimen can include WinNonlin Phoenix . Linear PK ( exponential) models were an initial IM doses of abiraterone decanoate once in two fitted to the plasma concentration - time profiles of abirater 30 weeks, e.g. , for about 2-3 doses, which is then followed by one following IV administration of abiraterone ( acetate or a once in a month administration of abiraterone decanoate . decanoate formulations) to rats and dogs . The derived PK Computer modeling predicted that such dosing regimen can parameters of clearance ( CL ) and distribution volume ( Vss ) achieve a Cmin value of abiraterone at steady state greater were predicted in man by allometric scaling . The rate ( K01 ) than about 8 ng /ml during the treatment period . TABLE 6 Group Mean Abiraterone or Abiraterone Decanoate Plasma PK Parameters Following IV Administration of 1.2 mg /kg Abiraterone Decanoate in Dogs ( N = 6 )

Analyte Vz or CL or Dose Tmax , Cmax AUC0-8 AUC last AUCINF Vz / F CL / F t1/ 2 (mg /kg ) (h ) ( ng /mL ) ( h * ng /mL ) ( h * ng /mL ) ( h * ng /mL ) ( L /kg ) (mL /min /kg ) ( h )

Abiraterone Mean 0.833 57.2 135 143 145 13.0 97.8 1.54 0.83 SD 0.129 5.78 21.7 28.0 26.9 2.86 17.6 0.202 CV % 15.5 10.1 16.0 19.6 18.5 22.0 18.0 13.1 Abiraterone Mean 0.0833 1890 2250 2260 2260 0.659 8.88 0.858 Decanoate SD 0.00 220 143 141 142 0.0329 0.577 0.0202 1.2 CV % 0.00 11.6 6.35 6.26 6.27 5.00 6.50 2.36

TABLE 7 Group Mean Abiraterone or Abiraterone Propionate Plasma PK Parameters Following IV Administration of 1 mg/ kg Abiraterone Propionate in Dogs ( N = 6 ) Analyte Vz or CL or Dose Cmax AUC0-8 AUClast AUCINF Vz / F CL / F t / 2 (mg /kg ) Imax( h ) ( ng /mL ) ( h * ng /mL ) ( h * ng /mL ) ( h * ng /mL ) ( L /kg ) (mL /min /kg ) ( h ) Abiraterone Mean 0.0833 222 112 126 127 20.8 114 2.11 0.86 SD 0.00 30.8 11.9 14.1 14.2 2.53 12.9 0.142 CV % 0.00 13.9 10.7 11.2 11.2 12.2 11.3 6.76 Abiraterone Mean 0.0833 27.1 Propionate SD 0.00 5.47 1.2 CV % 0.00 20.2 US 10,792,292 B2 89 90 TABLE 8 Individual Animal and Group Mean Abiraterone or Abiraterone Decanoate Plasma PK Parameters Following IM Administration of 41 mg / kg Abiraterone Decanoate in Dogs Tmax ???? AUC0-28 AUClast AUCINE Vz / F CL / F t1 / 2 Analyte Group ( d ) ( ng /mL ) ( d * ng mL/ ) ( d * ng /mL ) ( d * ng /mL ) ( L /kg ) (mL /min / kg ) ( d ) Abiraterone 5 N 3 3 3 3 2 2 2 2 Mean 5.0 5.66 99.2 141 178 6560 138 23 SD 0.0 1.25 13.3 19.8 21.9 1170 17.0 1.3 CV % 0.00 22.1 13.4 14.1 12.3 17.8 12.3 5.53 Abiraterone 6 N 3 3 3 3 2 2 2 2 Mean 5.0 8.99 135 184 229 5330 107 24 SD 0.0 0.760 14.1 4.28 28.0 300 13.0 4.3 CV % 0.00 8.45 10.5 2.33 12.2 5.62 12.2 17.8 Abiraterone 5 N 3 3 3 3 0 0 0 0 Decanoate Mean 0.26 4.15 16.6 30.0 SD 0.21 0.673 1.72 8.07 CV % 81.2 16.2 10.3 26.9 Abiraterone 6 N 3 3 3 3 0 0 0 0 Decanoate Mean 0.11 6.61 21.9 35.9 SD 0.024 2.70 6.12 1.40 CV % 21.8 40.9 27.9 3.89

TABLE 9 Individual Animal and Group Mean Abiraterone or Abiraterone Propionate Plasma PK Parameters Following IM Administration of 50 mg/kg Abiraterone Propionate in Dogs ( N = 3 ) Tmax ???? AUC0-28 AUCjast AUCINE Vz / F CL / F t2 Analyte Group ( d ) ( ng /mL ) ( d * ng /mL ) ( d * ng /mL ) ( d * ng /mL ) ( L / kg ) (mL /min /kg ) ( d ) Abiraterone 3 Mean 0.556 22.8 215 217 219 1050 112 4.53 SD 0.419 1.55 19.1 19.9 19.6 219 10.5 0.949 CV % 75.5 6.79 8.88 9.20 8.92 20.9 9.38 21.0 Abiraterone 4 Mean 0.611 74.9 198 190 196 467 124 1.81 SD 0.347 29.0 12.0 14.5 11.7 36.8 7.45 0.135 CV % 56.8 38.7 6.05 7.60 5.98 7.88 6.00 7.44 Abiraterone 3 Mean 0.111 7.15 15.7 13.0 14.9 6870 1980 1.71 Propionate SD 0.0485 1.02 3.08 2.82 3.29 1570 481 0.502 CV % 43.7 14.3 19.6 21.7 22.1 22.9 24.3 29.3 Abiraterone 4 Mean 0.104 31.6 28.6 28.0 29.0 2110 1000 0.983 Propionate SD 0.0953 18.4 5.67 5.97 5.29 937 181 0.264 CV % 91.6 58.3 19.8 21.3 18.2 44.4 18.0 26.9

Example 6A . Large Scale Preparation of 45 Abiraterone Decanoate from Decanoic Acid

( 1.2 eq ) OH EDCI , Et3N ( 1.5 eq ), DMAP , DCM

HO Abiraterone Mol . Wt : 349.5 US 10,792,292 B2 91 92 -continued

Abiraterone Decanoate Mol . Wt : 503.76

To a suspension of Abiraterone ( 381.9 g , 1.09 mol ) in The white solid obtained in this example was also char dichloromethane ( 3500 mL ) was added triethylamine ( 165 acterized by X - Ray Powder Diffraction (XRPD ) and Dif g , 1.64 mol ) and a catalytic amount of DMAP ( 13.35 g , ferential Scanning Calorimetry ( DSC ) . XRPD was con 0.109 mol ) . Decanoic acid ( 225 g , 1.31 mol ) as a solution in 20 ducted with Bruker's D8 Discover X - rat diffractometer, with dichloromethane ( 500 mL ) was added to the suspension , Theta \theta vertical goniometer, using Vantec -500 as detec followed by EDCI ( 293 g , 1.53 mol ) and the reaction then tor. Standard conditions : voltage 40 kV , current 40 mA , agitated for 19 h at 20-25 ° C. radiation , Cu , temperature , ambient, X - ray source exit slit 10 wt % aq NaH2PO4 ( 4000 mL ) was then added and the size , 0.5 mm pinhole , snout collimator, 0.5 mm , sample reaction was agitated for 20 min . The organic layer was 25 holder, ground quartz plate . Operating conditions: detector separated and extracted with 10 wt % aq NaH2PO4 ( 2000 distance, 30 cm , Chi integration range , 4-40 degree 20 , mL ) and brine ( 2000 mL ) . The organic layer was solvent count time , 120 seconds/ frame, # of frames: 3 , Theta 1 exchanged with acetonitrile ( 4750 mL ) and concentrated to position , 4 degree , Theta 2 position , 4 degree , Frame width , 3100 g keeping temperature of bath < 40 ° C. The suspension 12 , scan axis , coupled . Software used include GADDs was diluted with acetonitrile ( 900 g ) . The solids were 30 software , General Area Detector Diffraction System , version isolated by filtration to afford 510 g of crude abiraterone 4.1.50 ; and DIFFRAC.EVA , version 4.0 . DSC was per decanoate . formed with TA Instruments Q2000 ( Thermal Advantage V 510 g of the crude abiraterone decanoate was dissolved in 5.0.0 qualified ) , with a sample size of 2-10 mg , heating acetone ( 4000 mL ) at 40 ° C. The solution was filtered range from 25 ° C. to 250 ° C. at a heating rate of 10 ° C./min . through a filter paper. The filtrate was transferred to a 12 L 35 Representative XRPD and DSC spectra are shown in FIGS . 3 - neck flask , diluted to 5100 g and reheated to 40 ° C. to form 12A - 12B . A thermogravimetric analysis ( TGA ) was also a solution . The solution was cooled slowly to 20 ° C. to form performed on this sample. TGA was performed with TA a suspension . This was diluted with water ( 1020 mL ) and Instruments TGAQ500 ( Thermal Advantage V5.2.5_quali agitated at RT overnight. The solid was filtered and the flask fied ), with a sample size of 5-20 mg , heating range from 25 ° was rinsed with the filtrate and transferred to filter funnel. 40 C. to 150 ° C. at a heating rate of 10 ° C./min . A representative The wet cake was transferred to drying tray and dried at TGA trace is shown in FIG . 12C . 40-45 ° C. in vacuum oven overnight to obtain 457.1 g ( 90 % yield ) as white solid . ' H NMR ( CDC13 , 400 MHz) : dy 8.62 Example 6B . Preparation of Abiraterone Decanoate ( d , 1H , J = 1.9 Hz ) , 8.31 ( dd , 1H , J = 4.9 , 1.6 Hz ) , 7.64 (dt , 1H , Salts J = 7.9 , 1.9 Hz ) , 7.21 ( ddd, 1H , J = 8.0 , 4.9 , 0.8 Hz ) , 6.01-5.97 45 ( m , 1H ) , 5.44-5.40 ( m , 1H ) , 4.68-4.58 ( m , 1H ) , 2.39-2.23 Preparation of Abiraterone Decanoate Oxalate Salt ( m , 3H ) , 2.27 ( t, 2H , J = 7.6 Hz ) , 2.12-2.00 ( m , 3H ) , 1.91 A solution of Abiraterone Decanoate ( 374 g , 744 mmoles ) 1.54 ( m , 10H ) , 1.49 (dt , 1H , J = 11.9 , 5.1 Hz ) , 1.35-1.23 ( m , dissolved in isopropyl acetate to 5200 g and taken in a 12 L 12H ) , 1.20-1.07 ( m , 2H ) , 1.08 ( s , 3H ) , 1.05 ( s , 3H ) , 0.88 ( t, reactor. Oxalic acid ( 18.0 g ) was charged and agitated for 2 3H , J = 6.8 Hz ) . Elemental Analysis, theoretical ( corrected 50 h . The suspension was warmed to 72 ° C. and agitated for 2 for 0.055 % moisture level ): C , 81.0 % , H , 9.8 % , N , 2.8 % ; h . After cooling to 60 ° C. , oxalic acid ( 20 g ) and isopropyl found : C , 81.1 % , H , 10.2 % , N , 2.8 % . acetate ( 1000 g ) were charged . Heating was continued at 60 ° The abiraterone decanoate obtained in this example was C. for 30 min . More oxalic acid ( 20 g ) and isopropyl acetate determined to have a purity of 99.7 % by weight using a ( 600 g ) were charged and heating was continued at 60 ° C. HPLC method . For HPLC analysis, abiraterone decanoate 55 After 30 min more oxalic acid ( 15.7 g ) and isopropyl acetate samples were prepared in methanol at a concentration of ( 600 g ) were charged . Reaction temperature was increased 0.05 mg/ mL ( for assay analysis ) or 5 mg/ mL ( for impurity to 72 ° C. and heating was maintained for 18 h . analysis ). The HPLC conditions are the following: HPLC The reaction was then cooled to RT and further to 5-10 ° column : Halo C8 ( 2.7 um , 100x3.0 mm ) ; injection volume : C. and the slurry was agitated for 2 h at the same tempera 5 uL ; Column Temperature: 40 ° C .; Sample Temperature : 60 ture. The solids were filtered and rinsed with cold isopropyl ambient; Detection : 210 nm ; Mobile Phase : 25 mM Ammo acetate ( 520 mL ) . The wet cake was transferred to drying nium Acetate , pH 8.0 (MPA ) and 95/5 acetonitrile / tetrahy trays and dried in vacuum oven at 45-50 ° C. until constant drofuran ( MPB ) ; Flow Rate : 0.6 ml /min ; Gradient: starting weight of 410 g (92.8 % yield ) . HPLC of the ABIRATER with 65/35 MPA /MPB , in 35 minutes , reaching to 100 % ONE DECANOATE oxalate showed a purity of 99.62A % . MPB , hold at 100 % MPB until 40 minutes , at 40.10 minute , 65 ' H NMR ( CDC13 , 400 MHz ) : d4 12.62 ( brs, 2H ) , 8.84 ( d , back to 65/35 MPA /MPB , and hold at 65/35 MPA / MPB until 1H , J = 1.8 Hz ) , 8.69 ( d , 1H , J = 5.5 , 1.1 Hz ) , 8.24 ( dt, 1H , end at 45 minutes . J = 8.3 , 1.7 Hz ) , 7.75 (dt , 1H , J = 8.2 , 5.5 ) , 6.32-6.29 ( m , 1H ) , US 10,792,292 B2 93 94 5.44-5.39 ( m , 1H ) , 4.68-4.58 ( m , 1H ) , 2.42-2.31 ( m , 3H ) , abiraterone decanoate ) was dosed intramuscularly at 90 2.28 ( t , 2H , J = 7.5 Hz ) , 2.20-2.00 ( m , 3H ) , 1.93-1.47 ( m , mg/ kg in Male Cynomolgus Monkeys ( n = 3 ) . 11H ) , 1.38-1.11 ( m , 14H ) , 1.10 ( s , 6H ) , 0.88 ( t, 3H , J = 6.9 An IV dose of Abiraterone Decanoate ( 0.4 mg/ ml solution Hz ) . in 40 % HP -beta - cyclodextrin 25 mM Na phosphate buffer Preparation of Abiraterone Decanoate HC1 Salt 5 (pH 7.4 ) dosed at 1.2 mg /kg ( Average n = 3 ) was used as A solution of Abiraterone Decanoate ( 20 mmol) in EtOAc comparison . For the IV dose , blood samples were taken at 0 ( 140 mL ) was treated with 2 M HCl / ether ( 12 mL ; 24 mmol; hr, 0.083 hr, 0.17 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hr, 4 hr, 1.2 eq . ) . The suspension was heated at 50 ° C. overnight; then 8 hr, and 24 hr. The results are shown in Table 10A and FIG . cooled to 0-5 ° C. for 2 h . The solids filtered reasonably fast 14A . and it was rinsed with EtoAc to obtain 7.97 g ( 14.76 mmol ; 10 74 % yield ) of ABIRATERONE DECANOATE HCl salt as white solid . ' H NMR ( CDC13 , 400 MHz ) : d . 8.70 ( d , 1H , TABLE 10A J = 1.6 Hz ) , 8.58 ( dd , 1H , J = 1.6 , 5.6 Hz ) , 8.34 ( dt, 1H , J = 8.3 , Monkey IV PK parameters (arithmetic mean ) 1.6 Hz ) , 7.84 ( dd , 1H , J = 8.3 , 5.6 Hz ) , 6.37-6.33 ( m , 1H ) , 5.44-5.39 ( m , 1H ) , 4.68-4.58 ( m , 1H ) , 4.43-2.31 ( m , 3H ) , 15 Cmax AUCinf 2.27 ( t , 2H , J = 7.5 Hz ) , 2.20-2.00 ( m , 3H ) , 1.92-1.45 ( m , Tmax ( h ) (ng /mL ) ( ng : hmL) t1 /2 ( h ) 13H ) , 1.36-1.23 ( m , 13H ) , 1.21-1.10 ( m , 2H ) , 1.09 ( s , 3H ) , Abiraterone 0.083 2450 2860 2.27 1.08 ( s , 3H ) , 0.88 ( t, 3H , J = 6.9 Hz ) . Decanoate Preparation of Abiraterone Decanoate Benzene Sulfonic Salt Abiraterone 0.83 123 376 2.59 A solution of ABIRATERONE DECANOATE ( 0.57 20 mmnol ) in ethyl acetate ( 10 ml ) was treated with benzene Single Dose PK studies were carried out by injection of sulfonic acid ( 0.72 mmol. The resulting solid ABIRATER the abiraterone decanoate formulation ( 90 % Corn Oil , 10 % ONE DECANOATE benzene sulfonate salt ( 0.72 mmol ) Benzyl Alcohol , 192 mg /ml iraterone decanoate ) intra was isolated by filtration ( 74 % yield ). ' H NMR ( CDC13 , 400 muscularly at 90 mg /kg in Male Cynomolgus Monkeys MHz ) : d 8.87 ( d , 1H , J = 1.7 Hz ) , 8.81 ( brd , 1H , J = 5.6 Hz ) , 25 ( n = 3 ). The abiraterone decanoate formulation was injected 8.32 ( dt, 1H , J = 8.1 , 1.4 Hz ) , 7.97-7.92 ( m , 2H ) , 7.86 ( dd , intramuscularly with split between 2 injections into the thigh 1H , J = 8.1 , 5.6 Hz ) , 7.41-7.36 ( m , 3H ) , 6.36-6.32 ( m , 1H ) , on each hind leg , using 27 - Gauge needle . Blood samples 5.44-5.38 ( m , 1H ) , 4.68-4.56 ( m , 1H ) , 2.59-2.30 ( m , 3H ) , were taken at O hr, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 8 hr, 24 2.27 ( t , 2H , J = 7.5 Hz ) , 2.17-2.00 ( m , 4H ) , 1.91-1.54 ( m , hr, 48 hr, 72 hr, 120 hr, 168 hr, 336 hr, 504 hr, 672 hr, 840 10H ) , 1.47 ( dt, 1H , J = 12.1 , 4.7 Hz ) , 1.35-1.22 ( m , 15H ) , 30 1.20-1.10 ( m , 1H ) , 1.08 ( s , 3H ) , 1.06 ( s , 3H ) , 0.88 ( t, 3H , hr, 1008 hr, 1176 hr, 1344 hr. Plasma concentration of J = 7.2 Hz ). Abiraterone Decanoate and Abiraterone were determined . Preparation of Abiraterone Decanoate p - Toluene Sulfonate The results are shown in Table 10B and FIG . 14B . Salt A solution of ABIRATERONE DECANOATE ( 0.57 35 TABLE 10B mmnol) in ethyl acetate ( 10 ml ) was treated with p - Toluene Monkey single Dose PK parameters sulfonic acid ( 0.72 mmol. The resulting solid ABIRATER ( geometric mean ; Tmax is the median ) ONE DECANOATE p - Toluene sulfonate salt was isolated by filtration ( 64 % yield ). ' H NMR ( CDC13 , 400 MHz ) : dy Tmax Cmax AUC t12 8.85 ( d , 1H , J = 1.7 Hz ) , 8.81 ( brd, 1H , J = 5.6 Hz ) , 8.31 ( dt, 40 ( days ) ( ng /mL ) ( ng · days /mL ) (days ) F ( % ) 1H , J = 8.4 , 1.6 Hz ) , 7.85 ( dd , 1H , J = 8.3 , 5.8 Hz ) , 7.82 ( dt, Abiraterone 0.74 11 69.6 10 0.8 1H , J = 8.3 , 1.6 Hz ) , 7.18 ( d , 2H , J = 8.0 Hz ) , 6.36-6.31 ( m , Decanoate 1H ) , 5.45-5.39 ( m , 1H ) , 4.69-4.57 ( m , 1H ) , 2.57-2.30 ( m , Abiraterone 6.3 10 156 16 14 6H ) , 2.28 ( t, 2H , J = 7.5 Hz ) , 2.19-2.00 ( m , 4H ) , 1.93-1.54 ( m , 10H ) , 1.46 ( dt, 1H , J = 4.8 , 1.20 Hz ) , 1.36-1.10 ( m , 16H ) , 45 The progesterone, cortisol, and testosterone levels were 1.08 ( s , 3H ) , 1.06 ( s , 3H ) , 0.88 ( t , 3H , J = 6.9 Hz ) . also analyzed in this single dose PK study. As shown in FIG . Preparation of Abiraterone Decanoate Phosphate Salt 14C , following the single dose IM injection , a long duration A solution of ABIRATERONE DECANOATE ( 1.0 of CYP17A1 inhibition was achieved as evidenced by the mmmol) in isopropyl acetate ( 10 ml ) was treated with sustained increase of progesterone level and reduction of phosphoric acid ( 69.6 mg , 0.61 mmol) . The resulting solid 50 cortisol and testosterone level . The reduction in testosterone ABIRATERONE DECANOATE phosphate salt was iso level is modest as the monkeys in this study were non lated by filtration ( 0.39 g , 65 % yield ) . 1H NMR ( CDC13 , 400 castrated . MHz ) : du 9.75 ( Brs , 4H ) , 8.60 ( Brs , 2H ) , 8.00 ( Brd , 1H , Multiple Dose PK studies were also carried out . In this J = 7.7 ) , 7.65 ( Brs , 1H ) , 6.17 ( Brs , 1H ) , 5.37 ( Brs , 1H ) , 4.59 study, multiple doses ( each dose is 90 mg /kg ) of the abi ( Brs , 1H ), 2.45-2.16 ( m , 6H ) , 2.09-1.78 ( m , 5H ) , 1.73-1.44 55 raterone decanoate formulation ( 90 % Corn Oil , 10 % Benzyl ( m , 9H ) , 1.35-1.21 ( m , 16H ) , 1.03 ( s , 3H ) , 0.95 ( s , 3H ) , 0.88 Alcohol, 192 mg /ml abiraterone decanoate ) were injected ( t , 3H , J = 6.9 Hz ) . intramuscularly in Male Cynomolgus Monkeys ( n = 3 ) at Day 0 , Day 7 and Day 35. Each dose of the abiraterone decanoate Example 7. Studies of Abiraterone Decanoate in formulation was injected intramuscularly with split between Rats and Monkeys and Allometric Scaling and 60 2 injections into the thigh on each hind leg , using 27 - Gauge Prediction of Plasma Profile in Human needle . Blood samples were taken at 0 hr, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 8 hr, 24 hr, 48 hr, 72 hr, 120 hr, 168 hr, 192 Example 7A . Studies of Abiraterone Decanoate in hr, 216 hr, 240 hr, 288 hr, 336 hr, 504 hr, 672 hr, 840 hr, 864 Monkeys hr, 888 hr, 912 hr, 960 hr, 1008 hr, 1176 hr, 1344 hr, 1512 65 hr, 1680 hr. Plasma concentration of Abiraterone Decanoate In the monkey PK studies , abiraterone decanoate formu and Abiraterone were determined . The results were shown in lation ( 90 % Corn Oil , 10 % Benzyl Alcohol , 192 mg/ ml FIG . 14E . US 10,792,292 B2 95 96 Example 7B . Studies of the Impact of Benzyl TABLE 11B Benzoate on Abiraterone Exposure in Monkeys Rat Single IM dose PK parameters This example compares the pharmacokinetic behaviours Tmax ???? AUC t1 / 2 F of IM injections of two different abiraterone decanoate 5 ( days ) (ng /mL ) ( ng days /mL ) ( days ) ( % ) formulations : Abiraterone 0.46 1.3 25 33 0.8 Formulation 1 , Abiraterone Decanoate in 90 % Corn oil Decanoate 10 % , benzyl alcohol, with the concentration of abi Abiraterone 11 1.19 53 23 22 raterone decanoate of 207 mg/ ml 10 Multiple Dose PK studies were also carried out . In this Formulation 2 — Abiraterone Decanoate in 70 % Corn Oil , study, multiple doses ( each dose is 90 mg/ kg ) of the abi 10 % benzyl alcohol, 20 % benzyl benzoate, with the raterone decanoate formulation ( 90 % Corn Oil , 10 % Benzyl concentration of abiraterone decanoate of 209 mg /ml . Alcohol, 172 mg /ml abiraterone decanoate ) were injected Formulations 1 and 2 were intramuscularly dosed into 15 intramuscularly in Male rats ( n = 5 ) at Day 0 , Day 7 and Day male cynomolgus monkeys ( n = 1 ) at 100 mg/ kg . The injec 35. Each dose of the abiraterone decanoate formulation was tions were given at day 0 , day 7 and day 14. Blood samples injected intramuscularly into the thigh on hind leg , using were taken at O hr, 1 hr , 2.5 hr, 5 hr, 7.5 hr, 10 hr, 24 hr, 48 27 -Gauge needle . Blood samples were taken at 0 hr, 0.5 hr, hr, 72 hr, 120 hr and 168 hr post each injection . Plasma 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 8 hr, 24 hr, 48 hr, 72 hr, 120 hr, abiraterone concentrations are shown in FIG . 14F . 20 168 hr, 192 hr, 216 hr, 240 hr, 288 hr, 336 hr, 504 hr, 672 hr, As shown in FIG . 14F , IM injection of Formulation 2 840 hr, 864 hr, 888 hr, 912 hr, 960 hr, 1008 hr, 1176 hr, 1344 unexpectedly provided significantly higher abiraterone hr, 1512 hr, 1680 hr. Plasma concentration of Abiraterone plasma concentrations in monkeys compared to IM injection Decanoate and Abiraterone were determined . The results are of Formulation 1 at the same dose . This trend was also shown in FIG . 15C . confirmed by parallel studies at different dosing levels . 25 Example 7D . Allometric Scaling and Prediction of Plasma Profile of Abiraterone in Man Example 7C . Studies of Abiraterone Decanoate in Rats This pharmacokinetic ( PK ) analysis deals with the mod 30 elling of plasma concentrations of abiraterone following In the rat PK studies, abiraterone decanoate formulation single intravenous ( IV ) and intramuscular ( IM ) administra ( 90 % Corn Oil , 10 % Benzyl Alcohol , 172 mg /ml abiraterone tion of abiraterone to rats, dogs and monkeys . PK param decanoate ) was dosed intramuscularly at 90 mg /kg in male eters were derived from the PK model after IV dosing and rats ( n = 5 ). 35 IM dosing in rats , dogs and monkeys to predict, by means of An IV dose of Abiraterone Decanoate ( 0.4 mg /ml solution deconvolution and allometric scaling, the plasma profile of in 40 % HP - beta - cyclodextrin 25 mM Na phosphate buffer abiraterone in man after IM dosing of abiraterone decanoate . ( pH 7.4 ) dosed at 1.2 mg/ kg ( Average n = 5 ) was used as Abiraterone decanoate was administered IV ( 1.2 mg /kg ) comparison . For the IV dose , blood samples were taken at 0 and IM ( 90 mg /kg ) to rats and monkeys ; each animal hr , 0.083 hr, 0.17 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hr, 4 hr, 40 receivedadministered IV IVand ( 1.2 IM mg doses / kg ) and. Abiraterone IM ( 50 mg / decanoate kg ) to dogs wasand 8 hr, and 24 hr. The results are shown in Table 11A and FIG . IM ( 87 mg / kg ) to dogs . Following single IV administration 15A . in rats, dogs and monkeys and single intramuscular admin istration in dogs , plasma samples were taken up 24 h . TABLE 11A 45 Following single IM administration in rats , dogs and mon keys, plasma samples were taken up to 1344 h . The PK Rat IV PK parameters results were reported herein . Pharmacokinetic Modelling : Tmax Cmax AUCinf Pharmacokinetic models ( one and two - compartment with ( h ) (ng /mL ) ( ng : h/ mL ) t1/ 2 ( h ) 50 zero - order input were fitted (with or without weighting of 1 / C predicted ) to the plasma concentration profiles of abi Abiraterone 0.083 1800 1020 3.2 raterone in individual animals , following single intravenous Decanoate administration of abiraterone to rats, dogs and monkeys Abiraterone 0.167 55.1 75.6 1.5 using WinNonlin Phoenix Version 8.2 . The modelling was 55 based on the assumptions of linear ( dose -proportional ) and Single Dose PK studies were carried out by injection of time - invariant kinetics and that there was complete conver the abiraterone decanoate formulation ( 90 % Corn Oil , 10 % sion of the abiraterone decanoate pro - drug to abiraterone . Benzyl Alcohol , 172 mg /ml abiraterone decanoate ) intra The function ( representing one - compartment disposition muscularly at 90 mg /kg in Male rats ( n = 5 ) . The abiraterone 60 withfunction zero -(order representing absorption two ) was -compartment WinNonlin disposition Model 2 and with the decanoate formulation was injected intramuscularly into the zero - order absorption ) was WinNonlin Model 10. Weighting thigh on hind leg , using 27 -Gauge needle . Blood samples was included , dependent on the pattern of residuals ( residual taken at O hr, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 8 hr, 24 hr , Y versus predicted concentration or time ) and precision of 48 hr, 72 hr, 120 hr, 168 hr, 336 hr, 504 hr, 672 hr, 840 hr , the estimated parameters. The appropriate model was 1008 hr, 1176 hr, 1344 hr. Plasma concentration of Abirater- 65 selected based on : ( i ) visual inspection of the model fit to the one Decanoate and Abiraterone were determined . The data ( ii ) the lowest value of Akaike Information Criterion results are shown in Table 11B and FIG . 15B . ( AIC ) and ( iii ) precision of the estimated parameters ( CV ) . US 10,792,292 B2 97 98 Systemic clearance ( CL ) and apparent volume of distribu the IM depot ) half - life after IM dosing in rats , dogs and tion (Vss ) were derived from the exponential functions. monkeys was 325 , 319 and 325 h , respectively . Deconvolution : Therefore , the parameters of CL ( 73 L / h ), Vss ( 437 L ) , The rate and extent of input from an intramuscular K01 ( 0.00213 h- ! ) and F ( 56 % ) were used to simulate the administration was simulated by deconvolution using Win- 5 plasma profile in man . See Table 12B , FIGS . 16A and 16B . Nonlin Phoenix Version 8.2 . Deconvolution is based on linear systems analysis and is defined by the convolution TABLE 12B integral: G ( t) = R ( t) * H ( t) . G ( t) is the measured plasma con Predicted parameters of abiraterone in centration profile after intramuscular dosing, H (t ) is repre man following intramuscular sented by the exponential function described in Section 3.2 10 administration of abiraterone decanoate * and R ( t) , the rate of input from the IM depot over time , is derived by deconvolution of the above expression . The slope Parameter Estimate of the input rate versus time generates the input rate constant CL ( L / h ) 73 Vss ( L ) 437 ( K.1 ) . Integration of input rate versus time generates the 15 K01 ( / h ) 0.00213 cumulative input function and an estimate of absolute bio t1 /2 ( h ) 325 availability F ( % ) 56 Allometric Scaling to Man : * Predictions assume a one- compartment disposition with first -order absorption model and The plasma concentration profile in man after intramus linear kinetics in man . cular dosing was simulated based on the predictions of CL 20 Following once monthly ( i.e. , every 4 weeks ) intramus and Vss ( to describe the disposition of abiraterone ), and rate cular dose of abiraterone at 1000 mg to man , the predicted and extent of input ( absorption ) into systemic circulation Cmin value was 5 ng /mL at steady state. See FIG . 16C . The ( bioavailability ). The disposition of abiraterone in animals inventors believe that human bioavailability of the once derivedwas characterised from the exponential by the PK model parameters. CL and Vin( CL manand wereVss ), 25 monthly intramuscular administration at this dosing level predicted from CL and Vss in animals by an allometric can be higher than the 56 % used for the prediction in FIG . approach . Vs = a : W * where a is the intercept, W is body 16C and approaching complete bioavailability. Assuming weight and x is the allometric exponent; then , log Vss =xºlog complete bioavailability , the inventors believe that follow W + log a ( derived from a log - log plot of body weight versus ing once monthly intramuscular dose of abiraterone at 1000 V SS in the 3 species ). CL in man was derived by the 30 mgsteady to manstate , .the See predicted FIG . 16D Cmin . value would be 9.3 ng/ mL at data - driven method of Tang [ ]; i.e. CLman /kg = 0.407 CL Conclusion : monkeys / kg . The rate and extent of input was derived by Volume of distribution (Vss ) in man ( 437 L ) was predicted deconvolution . by allometry with adequate correlation between rats, dogs Results : 35 and monkeys . Vss indicates extensive tissue distribution in A bi - exponential function was considered to best repre man . Systemic clearance ( CL ) in man ( 73 L / h ) was predicted sent the plasma concentration -time profiles of abiraterone by allometry in monkeys. CL in man was not appreciably following single intravenous administration to rats , dogs and different to hepatic blood flow . Rate of absorption (absorp monkeys, respectively. Plasma clearance ( CL ) of abirater tion half - life of 325 h ) and bioavailability ( F of 56 % ) was one was 11414 , 6469 and 2578 mL /h /kg in rats, dogs and 40 predicted from deconvolution of intramuscular and intrave monkeys, respectively. Apparent of volume of distribution at nous data . Following once in four weeks intramuscular dose steady state ( Vss) of abiraterone was 22313 , 14205 and 5732 of abiraterone decanoate at 1000 mg to man , the predicted mL /kg in rats , dogs and monkeys, respectively . See Table Cmin was 5 ng /mL at steady state . 12 A below . 45 Example 8. Studies of Abiraterone Isocaproate and TABLE 12A Decanoate in Dogs Summary of PK parameters of abiraterone in rats , dogs and monkeys following intravenous and The objective of this study was to compare the pharma intramuscular administration of abiraterone decanoate cokinetics ( PK ) of two different esters of abiraterone ( iso 50 caproate and decanoate ) from intramuscular ( IM ) formula CL Vss K01 F tions following single administration to beagle dogs relative Species (mL / h /kg ) (mL / kg ) ( / h ) ( % ) to a single intravenous ( IV ) formulation of abiraterone Rats 11414 22313 0.00213 19 isocaproate used to enable calculation of absolute bioavail Dogs 6469 14205 0.00217 56 ability of the isocaproate ester . Monkeys 2578 5732 0.00213 14 55 Naïve male beagle dogs were obtained from Marshall Bioresources, North Rose , N.Y. for use in this study. The Allometric scaling predicted CL ( from monkeys only animals were 6-7 months old and weighed 7.0-7.9 kilograms given the very high values of CL in rats and dogs ) and VSS at the time of first dose administration . ( from rats, dogs and monkeys ) in man of 73 L / h and 437 L , Two groups of three male dogs / group underwent standard respectively . The predicted Vs in man was appreciably 60 evaluations such as body weight, clinical observations, and greater than total body water volume ( 42 L ) , indicating blood collection for PK . One group of three dogs were dosed extensive tissue distribution . The predicted CL in man was on Day 1 via IV with abiraterone isocaproate ( Test article # 1 , not appreciably different to hepatic blood flow ( 80 L / h ). abiraterone isocaproate in 40 % HP -beta -cyclodextrin ). Fol Deconvolution of the IM profiles with the IV profiles lowing a minimum washout of 72 hours , all six dogs were provided estimations of the rate and extent of bioavailability 65 dosed via IM . The three dogs that received the IV dose of of abiraterone . IM bioavailability in rats , dogs and monkeys abiraterone isocaproate were given the abiraterone iso was 19 , 56 and 14 % , respectively. The input ( release from caproate IM preparation ( Test article # 2 , abiraterone iso US 10,792,292 B2 99 100 caproate in 90 % corn oil / 10 % benzyl alcohol) and the lowing IM administration ( Table 13B and FIG . 17B ) , remaining three dogs were dosed with abiraterone decanoate although it should be noted that there was high variability in IM preparation ( Test article # 3 , abiraterone decanoate in exposure parameters (Cmax and AUC values ) as CV % 90 % corn oil / 10 % benzyl alcohol ) . Doses were based on an values ranged between 60 to 70 % . Following IM adminis assumed body weight of 10 kg , which could impact the 5 trationabiraterone, mean and Tmax the isocaproatevalues were prodrug 1.7 and , respectively 0.19 days. Thefor calculated CL ( or CL / F ) , Vz ( or Vz / F ) values , and the mean Cmax values were 20.2 and 106 ng /mL for abiraterone bioavailability assessment. The study design is summarized and the isocaproate prodrug, respectively . The mean AUClast , in the following table : values were 266 and 281 day * ng /mL for abiraterone and the isocaproate prodrug, respectively. The mean t?2 values were 10 9.3 and 7.4 days for abiraterone and the isocaproate prodrug , Study Test Dose Dose Dose Conc * Dose Volume Number of respectively. Group Article Route ( mg / kg ) (mg /mL ) (mL / kg ) Animals Estimates of the absolute bioavailability for abiraterone 1 # 1 IV 1.0 0.3 3.3 were calculated using the mean AUC INF values following 2 # 2 IM 77 158 0.49 ?? 0.78 mg /kg IV abiraterone isocaproate administration ( 206 3 # 3 IM 87 155 0.56 15 h * ng /mL , or 131 h * ng /mL when corrected for dose ) and 60 * Concentration of Prodrug . mg /kg IM administration of abiraterone isocaproate (cor rected for dose and time units = 114 h * ng /mL ). The estimated Blood was collected predose and following IV adminis abiraterone bioavailability from the isocaproate ester was tration, at 0.083 , 0.1667 , 0.25 , 0.5 , 0.75 , 1 , 2 , 4 , and 24 hours calculated at 87 % , although these data should be interpreted post dose administration . Blood was collected just prior to 20 with caution since the dose was based on an assumed body dosing and following IM administration , at 0.5 , 1 , 2 , 3 , 4 , 5 , weight of 10 kg. 8 , and 24 hours and 2 , 3 , 5 , 7 , 14 , 21 , 28 , 35 , and 49 days Single -Dose Pharmacokinetics of Abiraterone and Abi post dose administration ( time of collection to approximate raterone Decanoate Following IM Administration of Abi the time of dose administration ). Blood was processed to raterone Decanoate : plasma and the resulting plasma samples were analyzed for 25 Evidence of systemic exposure to abiraterone and abi the prodrug and abiraterone . raterone decanoate was observed in all treated dogs follow Pharmacokinetic analyses were performed on plasma ing IM administration ( Table 13B and FIG . 17C ) . The concentration versus time data using Phoenix WinNonlin ( v variability in abiraterone exposure parameters ( Cmax and 8.1 ) non - compartmental analysis function ( linear trapezoi AUC values ) was between 60 to 70 % , while the decanoate dal rule for AUC calculations ) . See e.g. , Example 5B . 30 exposure parameters had low variability with CV % values Results: Single - Dose Pharmacokinetics of Abiraterone of < 27 % . Following IM administration , the mean T max, and Abiraterone Isocaproate Following IV Administration of values were 5.7 and 0.71 days for abiraterone and the 1 mg/ kg Abiraterone Isocaproate : decanoate prodrug, respectively . The mean Cmar values were Evidence of systemic exposure to abiraterone and abi 7.82 and 45.0 ng /mL for abiraterone and the decanoate raterone isocaproate was observed in all treated dogs fol 35 prodrug, respectively . The mean AUCiast values were 176 lowing IV administration ( Table 13A and FIG . 17A ). Fol and 298 day * ng /mL for abiraterone and the decanoate lowing IV administration of abiraterone isocaproate ( pro prodrug, respectively. The mean t / 2 values were 14 and 6.7 drug ), a mean CL value of 62.8 mL /min /kg was calculated days for abiraterone and the decanoate prodrug, respectively. for the prodrug , which was considered high clearance . Using Estimates of the absolute bioavailability for abiraterone are a dose value of 0.78 mg/ kg ( assuming 100 % conversion of 40 calculated using the mean AUC INF values following 0.86 the prodrug to abiraterone ) the mean CL / F value was 63.3 mg/ kg IV administration of abiraterone decanoate ( 145 mL /min /kg for abiraterone . The mean Vz value was 1.91 h * ng /mL , or 169 h * ng /mL when corrected for dose ) and 60 L /kg for the pro - drug and the mean Vz / F value 4.22 L /kg for mg /kg IM administration ( corrected for dose and time abiraterone . The mean t / 2 value for the prodrug and abi units = 70.4 h * ng /mL ). The estimated abiraterone bioavail raterone was 0.350 hours and 0.773 hours, respectively . 45 ability was calculated at 42 % , although these data should be Single - Dose Pharmacokinetics of Abiraterone and Abi interpreted with caution since the dose was based on an raterone Isocaproate Following IM Administration of Abi assumed body weight of 10 kg . The comparison of mean raterone Isocaproate : abiraterone plasma concentration profile following IM Evidence of systemic exposure to abiraterone and abi administration of abiraterone isocaproate or abiraterone raterone isocaproate was observed in all treated dogs fol decanoate is shown in FIG . 17D . TABLE 13A Summary Abiraterone or Abiraterone Isocaproate Plasma PK Parameters Following IV Administration in Dogs.

T Dose max ???? AUC0-4 AUC last AUCINE Vz or Vz / F CL or CL / F t12 Analyte (mg /kg ) ( h ) (ng /mL ) ( h * ng /mL ) ( h * ng /mL ) ( h * ng /mL ) ( L /kg ) (mL /min /kg ) ( h ) Abiraterone 0.78 N 3 3 3 3 3 3 3 3 Mean 0.17 165 159 206 206 4.22 63.3 0.773 SD 0.0 17.2 3.48 12.5 12.5 0.125 3.85 0.0653 CV % 0.00 10.5 2.18 6.08 6.09 2.97 6.08 8.45 Isocaproate 1.0 N 3 3 3 3 3 3 3 Mean 0.083 751 269 269 269 1.91 62.8 0.350 SD 0.0 158 40.0 40.0 40.0 0.349 8.61 0.0228 CV % 0.00 21.0 14.9 14.9 14.9 18.3 13.7 6.52 US 10,792,292 B2 101 102 TABLE 13B Summary Abiraterone or Abiraterone Prodrug Plasma PK Parameters Following IM Administration in Dog Imax Cmax AUC last AUCINF Vz / F CL / F t / 2 Group Analyte ( d ) (ng /mL ) ( d * ng /mL ) ( d * ng /mL ) ( L /kg ) (mL /min / kg ) ( d ) 2 Isocaproate N 3 3 3 3 3 3 Mean 0.19 106 281 285 3640 238 7.40 SD 0.12 67.2 186 188 1950 114 1.36 CV % 61.9 63.5 66.1 65.9 53.6 47.8 18.4 2 Abiraterone N 3 3 3 3 3 3 3 Mean 1.7 20.2 266 275 3910 201 9.31 SD 1.2 13.2 192 197 2060 105 0.845 CV % 69.3 65.4 72.2 71.6 52.7 52.4 9.07 3 Decanoate N 3 3 3 3 3 3 3 Mean 0.71 45.0 295 299 2850 207 6.68 SD 0.51 12.0 50.2 51.4 426 38.0 0.723 CV % 71.3 26.6 17.0 17.2 15.0 18.4 10.8 3 Abiraterone N 3 3 3 3 3 3 3 Mean 5.7 7.82 157 176 10900 386 13.8 SD 1.2 4.48 105 121 9600 350 0.466 CV % 20.4 57.3 67.1 68.8 88.1 90.5 3.37

Conclusion of Example 8 : It can be appreciated that variations to the present invention Evidence of systemic exposure to abiraterone was would be readily apparent to those skilled in the art, and the observed in all treated dogs following dose administration . present invention is intended to include those alternatives . Comparison of the mean Tmax and Cmax values suggest that 25 Further, because numerous modifications will readily occur the isocaproate prodrug is more rapidly absorbed , with to those skilled in the art, it is not desired to limit the shorter T ???, values and higher Cmax values relative to the invention to the exact construction and operation illustrated decanoate prodrug. Mean abiraterone AUC values appeared and described , and accordingly, all suitable modifications to be less than 2 - fold higher following IM administration of and equivalents may be resorted to , falling within the scope the isocaproate pro -drug when compared to the decanoate 30 of the invention . prodrug. The long half -life values observed following IM We claim : administration relative to those values observed following 1. A compound of Formula I , or a pharmaceutically IV administration suggests that the prodrug has a slow acceptable salt thereof, release / absorption profile when administered via the IM route . There was some evidence that abiraterone half - life 35 appeared to be longer following the decanoate administra Formula I tion , which is likely due to the slower absorption of the decanoate prodrug. Each reference referred to within this disclosure is hereby incorporated in its respective entirety . 40 As used herein , the term “ about ” modifying an amount related to the disclosure refers to variation in the numerical quantity that can occur , for example, through routine testing H and handling; through inadvertent error in such testing and handling ; through differences in the manufacture, source , or 45 purity of ingredients /materials employed in the disclosure ; and the like . As used herein , “ about " a specific value also R1 includes the specific value , for example, about 10 % includes 10 % . Whether or not modified by the term “ about ” , the wherein Rl is R10,0 - R10, or NHR10 , claims include equivalents of the recited quantities. In one 50 10 embodiment, the term “ about ” means within 20 % of the wherein R is selected from : reported numerical value . a C8-30 alkyl; a C7-30 alkenyl; a C7-30 alkynyl; an alkyl With respect to aspects of the disclosure described as a substituted with a cycloalkyl, which has a total number genus, all individual species are individually considered of carbons between 5 and 16 ; an alkyl substituted with separate aspects of the disclosure. If aspects of the disclosure 55 a phenyl, which has a total number of carbons between are described as " comprising ” a feature, embodiments also 7 and 16 ; a cycloalkyl optionally substituted with one are contemplated " consisting of " or " consisting essentially or more alkyl, which has a total number of carbons of” the feature . between 5 and 16 ; and All of the various aspects , embodiments , and options described herein can be combined in any and all variations. 60 Having now described a few embodiments of the inven tion , it should be apparent to those skilled in the art that the foregoing is merely illustrative and not limiting, having been presented by way of example only. Numerous modifications and other embodiments are within the scope of one of 65 ordinary skill in the art and are contemplated as falling 2. The compound of claim 1 , or a pharmaceutically within the scope of the invention and any equivalent thereto . acceptable salt thereof, wherein Rl is a C3-16 alkyl. US 10,792,292 B2 103 104 3. The compound of claim 1 , or a pharmaceutically subject in need thereof a therapeutically effective amount of acceptable salt thereof, wherein R is an alkyl having the the pharmaceutical composition of claim 5 . formula (CH2 ) n — CH3, wherein n is an integer selected 13. The method of claim 12 , wherein the administering is from 7 , 8 , 9 , 10 , 11 , or 12 . an intramuscular injection , intradermal injection , or subcu 4. The compound of claim 1 , or a pharmaceutically 5 taneous injection . acceptable salt thereof, wherein Rl is an alkyl having the 14. The method of claim 12 , wherein the pharmaceutical formula ( CH2) -CH ; or composition is administered to the subject with or without food . 15. The method of claim 12 , wherein the one or more 10 disorders are selected from prostate cancer , breast cancer , ovarian cancer, bladder cancer , hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovary syndrome, Cushing's syndrome, Cushing's disease, classical or non classical congenital adrenal hyperplasia , precocious puberty , 15 hirsutism , and combinations thereof. 5. A pharmaceutical composition comprising the com 16. The method of claim 12 , wherein the one or more pound of claim 1 , or a pharmaceutically acceptable salt disorders is a sex hormone - dependent benign or malignant thereof, and a pharmaceutically acceptable carrier. disorder selected from castration resistant prostate cancer 6. A pharmaceutical composition comprising abiraterone and castration sensitive prostate cancer . decanoate having the formula of: 20 17. The method of claim 12 , wherein the one or more disorders is a sex hormone -dependent benign or malignant disorder selected from metastatic castration resistant pros tate cancer and metastatic castration sensitive prostate can cer . 25 18. The method of claim 12 , wherein the subject is treated with a gonadotropin - releasing hormone analog and /or bilat eral orchiectomy À 19. The method of claim 12 , further comprising admin istering to the subject a corticosteroid . 30 20. The method of claim 12 , further comprising admin istering to the subject prednisone, prednisolone, and / or methylprednisolone . or a pharmaceutically acceptable salt thereof , and a phar 21. The method of claim 12 , wherein the pharmaceutical maceutically acceptable carrier . composition is administered to the subject once a week or 7. The pharmaceutical composition of claim 6 , formulated 35 once in more than a week . for intramuscular injection , intradermal injection , or subcu 22. The method of claim 12 , wherein the administering taneous injection. provides ( a ) a blood plasma concentration of abiraterone 8. The pharmaceutical composition of claim 6 , wherein above 1.0 ng /ml for a period of at least two weeks ; ( b ) a the pharmaceutically acceptable carrier comprises a phar single dose or steady state Cmax of abiraterone between maceutically acceptable oil and optionally a further phar- 40 about 10 ng / ml and about 400 ng /ml ; or ( c ) both ( a ) and ( b ) . maceutically acceptable solvent. 23. A pharmaceutical composition comprising a therapeu 9. The pharmaceutical composition of claim 8 , wherein tically effective amount of abiraterone decanoate having the the pharmaceutically acceptable oil comprises a triglyceride , formula of: and the further pharmaceutically acceptable solvent, if pres ent, comprises an alcohol , ester, and / or acid solvent. 45 10. The pharmaceutical composition of claim 9 , wherein the pharmaceutically acceptable oil is selected from veg etable oil , castor oil , corn oil , sesame oil , cottonseed oil , peanut oil , poppy seed oil , tea seed oil , and soybean oil , and the further pharmaceutically acceptable solvent, if present, 50 H comprises benzyl alcohol , benzyl benzoate , or a combina tion thereof. 11. The pharmaceutical composition of claim 6 , which comprises the abiraterone decanoate or pharmaceutically 55 acceptable salt thereof in an amount sufficient to provide a a pharmaceutically acceptable oil , and a pharmaceutically therapeutically effective blood plasma concentration of abi acceptable solvent, wherein the abiraterone decanoate is in raterone , or a blood plasma concentration of abiraterone of its basic form , which is present at a concentration of about about 1 ng /ml or higher, for a period of at least two weeks , 25 mg/ ml to about 500 mg /ml , wherein the pharmaceutical after a single administration to a subject having one or more 60 composition is formulated for intramuscular injection , intra disorders selected from a sex hormone -dependent benign or dermal injection , or subcutaneous injection, wherein the malignant disorder, a syndrome due to androgen excess , and pharmaceutical composition comprises the abiraterone a syndrome due to glucocorticoid excess . decanoate in an amount of about 50 mg to about 2,000 mg . 12. A method of treating one or more disorders selected 24. The pharmaceutical composition of claim 23 , wherein from a sex hormone - dependent benign or malignant disor- 65 the pharmaceutically acceptable oil comprises a triglyceride, der, a syndrome due to androgen excess , and a syndrome due and the pharmaceutically acceptable solvent comprises an to glucocorticoid excess , comprising administering to a alcohol , ester, and / or acid solvent. US 10,792,292 B2 105 106 25. The pharmaceutical composition of claim 24 , wherein in a pharmaceutically acceptable carrier to form a mixture ; pharmaceutically acceptable oil comprises a vegetable oil , and optionally castor oil , corn oil , sesame oil , cottonseed oil , peanut oil , poppy seed oil , tea seed oil , or soybean oil , the pharmaceu b ) sterilizing the mixture formed in a ) . tically acceptable solvent comprises benzyl alcohol and / or 5 benzyl benzoate, and wherein the abiraterone decanoate is present at a concentration of about 50 mg/ mL to about 300 29. The method of claim 28 , wherein the mixing com mg /mL . prises mixing a crystalline form of abiraterone decanoate in 26. A method of treating prostate cancer , comprising the pharmaceutically acceptable carrier, wherein the crys administering to a subject in need thereof the pharmaceutical talline form is characterized by an X - Ray Power Diffraction composition of claim 23 via intramuscular injection , intra 10 dermal injection , or subcutaneous injection , once a month or spectrum having one or more of the following peaks : 4.6 , once in more than a month . 6.9 , 8.7 , 17.5 , 18.3 , 18.6 , 19.1 , 19.6 , and 20.8 , degrees 2 27. The method of claim 26 , wherein the pharmaceutical theta, + 0.2 ° ; a Differential Scanning Calorimetry pattern composition is administered via intramuscular injection . having an endothermic peak with an onset temperature at 28. A method for preparing an abiraterone decanoate 15 about 69.0 ° C .; or a combination thereof. formulation suitable for parenteral administration to a sub ject having a sex hormone- dependent benign or malignant 30. The method of claim 28 , wherein the pharmaceuti disorder, a syndrome due to androgen excess , and a syn cally acceptable carrier comprises a pharmaceutically drome due to glucocorticoid excess , comprising : acceptable oil and a pharmaceutically acceptable solvent, a ) mixing abiraterone decanoate, which has the formula 20 wherein the pharmaceutically acceptable oil comprises a of: vegetable oil , castor oil , corn oil , sesame oil , cottonseed oil , peanut oil , poppy seed oil , tea seed oil , or soybean oil , the pharmaceutically acceptable solvent comprises benzyl alco 25 hol or benzyl benzoate , and wherein the abiraterone decano ate is present at a concentration of about 50 mg /mL to about À 300 mg/ mL .