US008329680B2
`
`(12) United States Patent
`Evans et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 8,329,680 B2
`*Dec. 11,2012
`
`(54) FORMULATION
`
`(75)
`
`Inventors: John R Evans, Macclesfield (GB);
`Rosalind U Grundy, Macclcsficld (GB)
`
`(73) Assignee: AstraZeneca AB, Sodertéilje (S3)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 338 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl.No.: 12/285,887
`
`(22)
`
`Filed:
`
`Oct. 15, 2008
`
`(65)
`
`Prior Publication Data
`
`US 2010/0152149 A1
`
`Jun. 17, 2010
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 10/872,784, filed on
`Jun. 22, 2004, now Pat. No. 7,456,160.
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 10, 2000
`Apr. 12, 2000
`
`(GB) ................................. .. 0000313.7
`(GB) ................................. .. 0008837.7
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31/56
`(52) U.S. Cl.
`...................................... .. 514/177; 514/178
`(58) Field of Classification Search ................ .. 514/177,
`514/178
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2,822,316 A
`2,983,649 A
`3,164,520 A
`
`2/1958 Richter et al.
`5/1961 Ercoli et al.
`1/1965 Huber
`
`3,541,209 A
`RE28,690 E
`4,048,309 A
`4,048,310 A
`4,212,863 A
`4,388,307 A
`4,659,516 A
`4,888,331 A
`5,095,129 A
`5,183,814 A
`5,484,801 A
`5,733,902 A
`5,929,030 A
`
`11/1970 Neumann et al.
`1/1976 Lchmann ct al.
`9/1977 Chen et al.
`9/1977 Chen et al.
`7/1980 Cornelius
`6/1983 Cavanak
`4/1987 Bowler et al.
`12/1989 Elger et al.
`3/1992 Ottow et al.
`2/1993 Dukes
`1/1996 Al-Razzak ct al,
`3/1998 Schneider
`7/1999 Hamied et al.
`
`(Continued)
`
`EP
`
`FOREIGN PATENT DOCUMENTS
`0138504
`4/1985
`
`(Continued)
`
`OTHER PUBLICATIONS
`
`The abstract of Wakeling et al., The Journal of Steroid Biochemistry
`and Molecular Biology, 1992,4311-3:173-177.*
`
`(Continued)
`
`Primary Examiner — San-Ming Hui
`(74) Attorney, Agent, or Firm — Finnegan, Henderson,
`Farabow, Garrett & Dunner LLP
`
`(57)
`
`ABSTRACT
`
`The invention relates to a novel sustained release pharmaceu-
`tical formulation adapted for administration by injection con-
`taining the compound 70L-[9-(4,4,5,5,5-pentafluoropentyl-
`sulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17[3-diol,
`more
`particularly to a formulation adapted for administration by
`injection containing the compound 7(x-[9-(4,4,5,5,5-pen-
`tafluoropentyl sulphinyl)nonyl] oestra-1 ,3 ,5 (1 0)-triene-3,
`17[3-diol in solution in a ricinoleate vehicle which addition-
`ally comprises at least one alcohol and a non-aqueous ester
`solvent wl1icl1 is miscible ir1 the ricinoleate vehicle.
`
`20 Claims, 2 Drawing Sheets
`
`50
`
`Jso
`
`wo
`
`-\NO0
`
`Fulvestrant(ngpermlplasma)
`
`—O—F1 Formulation F (Castor oil)
`— -A — F2 Miglyol 812-N
`- - 0- - - F3 Caslorlsesame oil 1:1
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 1
`
`

`

`US 8,329,680 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
`2001/0006963 A1
`7/2001 Lachnit-Fixson et al.
`
`FOREIGN PATENT DOCUMENTS
`0310542 A1
`4/1989
`EP
`0346014
`12/1989
`EP
`0819431
`3/1999
`EP
`0905143
`3/1999
`EP
`6241
`9/1968
`FR
`817241
`7/1959
`GB
`1126892
`9/1968
`GB
`1207571
`10/1970
`GB
`1569286
`6/1980
`GB
`43-27327
`11/1992
`JP
`09-208496
`12/1997
`JP
`10-203982
`4/1998
`JP
`10-152438
`6/1998
`JP
`11-501649
`2/1999
`JP
`11-158200
`6/1999
`JP
`549118
`3/1977
`SU
`676284
`7/1979
`SU
`W0 95/12383
`5/1995
`W0
`W0 96/19997
`7/1996
`W0
`W0 97/21440
`6/1997
`W0
`W0 97/37653
`10/1997
`W0
`W0 97/40823
`11/1997
`W0
`W0 98/11902
`3/1998
`W0
`W0 99/27906
`6/1999
`W0
`VVO 03/006064
`1/2003
`W0
`W0 W0 2011/012885
`2/2011
`ZA
`681014
`2/1968
`7.A
`682530
`4/1968
`
`OTHER PUBLICATIONS
`
`Anschel, “Losungsmittel und Losungsvermittler in Injektionen”,
`)harm, Ind., 1965, vol. 27 (1 la), pp. 781-787.
`. with
`.
`.
`Davis et al., “17-Alpha-Hydroxyprogesterone-Caproate:
`Chemically Pure Progesterone”, J. Clin. Endocrinol. and Metabo-
`lism, 1955, vol. 15, pp. 923-930.
`)ukes et al., “Antiuterotrophic effects of pure antioestrogen. ICI
`182,780, .
`.
`. the uterus in ovariectomized monkeys", J. Endocrinol-
`ogy, 1992, vol. 135, pp. 239-247.
`Dukes et al., “Antiuterotrophic effects of the pure antioestrogen ICI
`182, 780 .
`.
`. quantitative magnetic resonance imaging”; J. Endocri-
`nology. 1992, vol. 138, pp. 203-209.
`Iowell et al., “Pharmacokinetics, pharmacological and anti-tumour
`effects of the specific anti-oestrogen ICI 182780 in women with
`advanced breast cancer”, British Journal of Cancer, 1996, vol. 74, pp.
`300-308.
`{owell et al., “Response to a specific antioestrogen (ICI 182780) in
`tamoxifen-resistant breast cancer”, The Lancet, Jan. 7, 1995, pp.
`29-30.
`injections of
`intramuscular
`“Tolerability of
`al,
`\/Iackey et
`testosterone ester in oil vehicle”, Human Reproduction, vol. 10, No.
`4,pp,869-865,1995
`Martindale, 32nd Ed., “Alcohol”, Pharmaceutical Press. 1999, pp.
`1099-1 101.
`Martindale, 32nd Ed., “Benzoates” and “Benzyl Alcohol”; Pharma-
`ceutical Press, 1999, pp. 1102-1104.
`Martindale, 32nd Ed., “Caster Oil”; 32nd Ed., Pharmaceutical Press,
`1999, p. 1560.
`Migally, “Effect of Castor Oil and Benzyl Benzoate Used as aVehicle
`for Antiandrogens on the Adrenal Cortex”, Archives ofAndrology 2,
`1979 pp. 365-369.
`Osborne et al., “Comparison of the Effects of a Pure Steroidal
`Antiestrogen With Those of Tamoxifen in a Model of Human Breast
`Cancer”, Journal ofthe National Cancer, May 1995, vol. 87, No. 10,
`pp.746-750.
`Pcllcgrino, “Use of 17 (X Hydroxyprogcstcronc Caproatc in Threat-
`ened Abortion”, Current Therapeutic Research, vol. 4, No. 6, Jun.
`1962, pp. 301-305.
`.
`.
`Piver et al., “Medroxyprogesterone Acetate (Depo-Provera) vs .
`Women with Metastatic Endometrial Adenocarcinoma”, Cancer, vol.
`45, American Cancer Society, 1980, pp. 268-272.
`
`Remington’s Pharmaceutical Sciences, 18th ed., 1990, p. 219.
`Riffkin et al., “Castor Oil as aVehicle for Parenteral Administration
`of Steroid Hormones”, Journal of Pharmaceutical Sciences, vol. 53,
`No. 8, Aug. 1964, pp. 891-895.
`Robertson et al., “A partially-blind, randomised, multicentre study
`comparing the anti-tumor effects of single doses (50, 125 and250mg)
`of long-acting (LA)
`‘faslodex’ (ICI 182780 with tamoxifen in
`postmenopausal women with primary breast cancer prior to surgery”;
`Abstract 28, 22nd Armual San Antonio Breast Cancer Symposium:
`Dec. 8-11, 1999, San Antonio, Breast Cancer Research and Treat-
`ment 1999; 57 (1; special issue); p. 31.
`Sawada et al., “Estrogen Receptor Antagonist ICII82,780 Exacer-
`bates Ischemic Injury in Female Mouse”, Journal of Cerebral Blood
`Flow and Metabolism, vol. 20. No. 1, 2000, pp. 112-118.
`Vidal, Le Dictionnaire, “Benzo-Gynoestryl Retard”, 1998 p. 201.
`Vidal, Le Dictionnaire, “Gravibinan”, 1995, pp. 660-661.
`Vidal, Le Dictionnaire, “Parabolan”, 1997, p. 1245.
`Vidal, Le Dictionnaire, “Trophobolene”, 1997. pp. 1706-1707.
`Wakeling et al., “A Potent Specific Pure Antiestrogen with Clinical
`Potential”, Cancer Research, 1991, vol. 51, pp. 3867-3873.
`.
`.
`Waterton et al., “A Case of Adenomyosis in a Pigtailed Monkey .
`Treated with the Novel Pure Anti estrogen, ICI 182,780”; Laboratory
`Animal Science, 1993, vol. 43, No. 3, 1993, pp. 247-251.
`“Pharmaceutical dosage forms: Parenteral medications, vol. 1”, 2nd
`edition, edited by Avis, Lieberman and Lachman, 1992.
`The Merck Index, 12th Ed., Merck & Co., Inc., pp. xiv, 189-190,
`641-642 and 1715 (1996).
`Guerrini, et al., “Pharmacokinetics of probenecid in sheep", J Vet
`Pharmacol Ther., 128-135 (1985).
`Lavy, et al., “Pharmacokinetics of clindamycin HCI administered
`intravenously, intramuscularly and subcutaneously to dogs”, J Vet
`Pharmacol Ther., 22(4):261-265 (1999).
`Ismail, “Disposition kinetics of difloxacin after intravenous, intra-
`muscular and subcutaneous administration in calves”, Vet Res Com-
`mun., 31(4):467-476 (2007).
`Documents from the prosecution of European Application No.
`01900186.6(EP1 250 138) from Aug. 27, 2009 to Dec. 15,2011.
`Documents from the prosecution of European Application No.
`10180667.7 (EP 2 266 573) from Nov. 23, 2010 to Dec. 19, 2011.
`Documents from the prosecution of European Application No.
`10180661.0 (EP2 286 818) from Jan. 19. 2011 to Dec. 19. 2011.
`Declaration Under 35 U.S.C § 1.132 of Dr. Paul Gellert filed in Aug.
`2008 in U.S. Appl. No. 10/872,784.
`McLeskey et al., “Tamoxifen-resistant fibroblast growth factor-
`Lransfected MCF-7 cells are cross-resistant in vivo to the antiestrogen
`ICI 182,780 and two aromatase inhibitors,” Clin. Cancer Res, 4:69"-
`711(1998)
`JRF Robertson, et al., “Fulvestrant: pharmacokinetics and pharma-
`cology,” British Journal of Cancer, 90(1):S7-S10 (2004).
`John F. R. Robertson, “Fulvestrant (Faslodex®)—how to make a
`good drug better,” The Oncologist, 12:774-784 (2007).
`Search Report for European Pate11t Application No. 10180667.7
`dated Nov. 23, 2010.
`Search Report for European Patent Application No. 10180661.0
`dated Jan. 19,2011.
`Documents from the Opposition against European Patent Applica-
`tion No. 01900186.6 from Apr. 21, 2009 to Sep. 7, 2009.
`P.K. Gupta and G.A. Brazeau (eds). Injectable Drug Development.‘
`Techniques to Reduce Pain and Irritation. Chapters 11 & 17
`Interpharm Press, Denver, Colorado (1999).
`P.V. Lopatin, V. P Safonov, T. P. Litvinova and L. M. Yakimenko. Use
`ofnonaqueous solvents to prepare injection solutions. Pharm. Chem.
`J. 6:724-733 (1972).
`S. N ema, R.J. Washkuhn, and R.J. Brendel. Excipients and their use
`in injectable products. PDA J Pharm. Sci. Technol. 5 1: 166-71
`(1997).
`Physicians ’ Desk Reference (2 7th edition). 1277-1278, 13 50-1354,
`1391- 1392 Medical Economics Company, Oradell, NJ (1973).
`M. F. Powell, T. Nguyen, and L. Baloian. Compendium of excipients
`for parenteral formulations. PDA J'. Pharm. Sci. Technol. 522238-311
`[pp. 238-255 provided] (1998).
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 2
`
`

`

`US 8,329,680 B2
`Page 3
`
`R. G. Strickley. Parenteral formulations of small molecule therapeu-
`tics marketed in the United States (1999)—Part I. PDA JPharm. Sci.
`Techno]. 53:324-349 (1999).
`R. G. Strickley. Parenteral formulations of small molecule therapeu-
`tics marketed in the United States (1999)—Pa1tIIPDA JPharm. Sci.
`Techno]. 54:69-96 (2000).
`R. G. Strickley. Parenteral formulations of small molecule therapeu-
`tics marketed in the United States (1999)—Part I11. PDA J Pharm.
`Sci. Techno]. 54:152-169 (2000).
`Y.C. J. Wang and R. R. Kowal. Review of excipients and pH’s for
`parenteral products used in the United States. J Parenteral Drug
`Assoc. 34:452-462 (1980).
`U.S. Appl. No. 13/387,584, filed Jan. 27, 2012. Dimery et al.
`Buzdar, A. U, “Fulvestrant—A novel estrogen receptor antagonist
`for the treatment of advanced breast cancer,” Drugs of Today,
`44(9):679-692 (2008).
`“Comparison of fulvestrant (faslodex) 250 mg and 500 mg in
`postmenopausal Women with estrogen receptor-positive advanced
`
`breast cancer progressing or relapsing after previous endocrine
`therapy,” Clinicaltrials.gov (May 20, 2009) retrieved Jan. 24, 2012.
`Di Leo A., et al.. “Confirm: a phase III, randomized, parallel-group
`trial comparing fulvestrant 250 mg vs fulvestrant 500 mg in
`postmenopausal Women with estrogen receptor-positive advanced
`breast cancer.” Cancer Res., 69(24) Supp. 3, (2009).
`International Search Report for PCT Application No. PCT/GBl0/
`51228 (WO 2011/012885) mailed Dec. 20, 2012.
`International Preliminary Report on Patentability for PCT Applica-
`tion No. PCT/GB10/51228 (WO 2011/012885) mailed Dec. 20,
`2012.
`Documents from the prosecution of European Application No.
`01900186.6 (EP 1 250 138) dated Dec. 15, 2011.
`Documents from the prosecution of European Application No.
`019001866 (EP 1 250 138) dated Feb. 27, 2012.
`
`* cited by examiner
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 3
`
`

`

`U.S. Patent
`
`Dec. 11,2012
`
`Sheet 1 of2
`
`US 8,329,680 B2
`
`50
`
`40
`
`A
`
`—O— F1 Formulation F (Castor oil)
`— -A — F2 Miglyol 812-N
`- - 0- - -F3 Castorlsesame oil 1:1
`
`
`
`plasma) Fulvestrant(ngperml
`
`Time (d)
`
`Figure I
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 4
`
`

`

`U.S. Patent
`
`Dec. 11,2012
`
`Sheet 2 of2
`
`US 8,329,680 B2
`
`FLOW DIAGRAM OF MANUFACTURING
`
`Ingredients/Components
`
`process
`
`Flllvestram
`Alcohol
`
`Benzyl Alcohol
`
`STAGE 1: DISSOLUTION OF
`ACTIVE AGENT
`
`,
`
`Benzyl Benzoate
`
`T} STAGE 22 MIX
`
`STAGE 3: MAKE To
`
`—’
`
`I
`
`STAGE 4: STERILE FILTRATION
`
`(0.2 pm)
`INTO BULK RECEIVING VESSEL
`
`I
`
`STAGE 5; STERILE (0.2um)
`IN-LINE FILTRATION
`
`STALQ6: ASEPTIC FILLING,
`
`AND STOPPERING
`
`STAGi7: VISUAL
`
`INSP ECTION
`
`Figure 2
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 5
`
`

`

`US 8,329,680 B2
`
`1
`FORMULATION
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation Application of U.S.
`patent application Ser. No. 10/872,784, filed Jun. 22, 2004,
`now U.S. Pat. No. 7,456,160 which claims benefit of U.S.
`patent application Ser. No. 09/756,291, filed Jan. 9, 2001
`which claims the benefit of Great Britain Application No.
`0008837.7 filed Apr. 12, 2000 and Great Britain Application
`No. 0000313.7, filed Jan. 10, 2000, all of which are incorpo-
`rated herein by reference in their entireties.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`The invention relates to a novel sustained release pharma-
`ceutical formulation adapted for administration by injection
`containing the compound 70¢-[9-(4,4,5,5,5-pentafluoropen-
`tylsulphi11yl)nonyl]oestra-1,3,5(10)-triene-3,17|3-diol.
`2. Description of the Related Art
`Oestrogen deprivation is fimdamental to the treatment of
`many benign and malignant diseases of the breast and repro-
`ductive tract. In premenopausal women, this is achieved by
`the ablation of ovarian function through surgical, radiothera-
`peutic, or medical means, and, in postmenopausal won1en, by
`the use of aromatase inhibitors.
`
`An alternative approach to oestrogen withdrawal is to
`antagonise oestrogens with antioestrogens. These are drugs
`that bind to and compete for oestrogen receptors (ER) present
`in the nuclei of oestrogen-responsive tissue. Conventional
`nonstcroidal antiocstrogcns, such as tamoxifcn, compctc cfii-
`ciently for ER binding but their effectiveness is often limited
`by the partial agonism they display, which results in an
`incomplete blockade of oestrogen-mediated activity (Farr
`and Jordan 1984, May and Westley 1987).
`The potential for nonsteroidal antioestrogens to display
`agonistic properties prompted the search for novel com-
`pounds that would bind ER with high afiinity without acti-
`vating any of the normal transcriptional honnone responses
`and consequent manifestations of oestrogens. Such mol-
`ecules would be “pure” antioestrogens, clearly distinguished
`from tamoxifen-like ligands and capable of eliciting com-
`plete ablation ofthe trophic effects of oestrogens. Such com-
`pounds are referred to as Estrogen Receptor-Downregulators
`(E.R.D.). The rationale for the design and testing of novel,
`pure antioestrogens has been described in: Bowler et al 1989,
`Wakeling 1990a, 1990b, 1990c. Wakeling and Bowler 1987,
`1 988.
`
`Stcroidal analogues of ocstradiol, with an alkylsulphinyl
`side chain in the 70¢ position, provided the first examples of
`compounds devoid of oestrogenic activity (Bowler et al
`1989). One of these, 7a-[9-(4,4,5,5,5-pentafiuoropentyl sul-
`phinyl)nonyl]oestra-1,3,5-(10)triene-3,17B-diol
`wa s
`selected for intensive study on the basis of its pure oestrogen
`antagonist activity and significantly increased antioestro-
`genic potency over other available antioestrogens. In vitro
`findings and early clinical experience with 7(X-[9-(4,4,5,5,5-
`pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(l0)-triene-3,
`l7[3-diol have promoted interest in the development of the
`drug as a therapeutic agent for oestrogen-dependent indica-
`tions such as breast cancer and certain benign gynaecological
`conditions.
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`2
`allocated the international non-proprietary name fulvestrant,
`which is used hereinafter. When referring to fulvestrant we
`include pharmaceutically-acceptable salts thereof and any
`possible solvates of either thereof.
`Fulvestrant binds to ER with an afiinity similar to that of
`oestradiol and comple ely blocks the growth stimulatory
`action of oestradiol or1 human breast cancer cells in vitro; it is
`r11ore poter1t ar1d r11ore effective than tamoxifen in this respect.
`Fulvestrant blocks completely the uterotrophic action of
`oestradiol in rats, mice and monkeys, and also blocks the
`uterotrophic activity of tamoxifen.
`Because fulvestrant has none of the oestrogen-like stimu-
`latory activity that is characteristic of clinically available
`antioestrogens such as tamoxifen or toremifene, it may offer
`improved therapeutic activity characterised by more rapid,
`complete, or longer-lasting tumour regression; a lower inci-
`dence or rate of development of resistance to treatment; and a
`reduction of tumour invasiveness.
`
`In intact adult rats, fi.1lvestrant achieves maximum regres-
`sion of the uterus at a dose which does not adversely affect
`bone density or lead to increased gonadotrophin secretion. If
`also true in humans, these findings could be ofextreme impor-
`tance clinically. Reduced bone density limits the duration of
`oestrogen-ablative treatment for endometriosis. Fulvestrant
`does not block hypothalamic ER. Oestrogen ablation also
`causes or exacerbates hot flushes and other menopausal
`symptoms; fillvestrant will not cause such effects because it
`does not cross the blood-brain barrier.
`
`European Patent Application No. 0 138 504 discloses that
`certain steroid derivatives are effective antioestrogenic
`agents. The disclosure includes information relating to the
`preparation ofthe steroid derivatives. In particular there is the
`disclosure within Example 35 of the compound 70.-[9-(4,4,
`5,5,5 -pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-
`triene-3,17[3-diol, which compound is specifically named in
`claim 4. It is also disclosed that the compounds of that inven-
`tion may be provided for use in the form of a pharmaceutical
`composition comprising a steroid derivative of the invention
`together with a pharrnaceutically-acceptable diluent or car-
`rier. It is stated therein that the composition can be in a form
`suitable for oral or parenteral administration.
`Fulvestrant shows, along with other steroidal based com-
`pounds, certain physical properties which make formulation
`of these compounds difficult. Fulvestrant is a particularly
`lipophilic molecule, even when compared with other steroi-
`dal compounds, a11d its aqueous solubility is extremely low at
`around 10 ngml‘l (this is an estimate from a water/solvent
`mixture solute since measurements this low could not be
`
`achieved in a water only solute).
`Currently there are a number of sustained release inj ectable
`steroidal formulations which have been commercialised.
`
`Commonly these formulations use oil as a solvent and
`wherein additional excipients may be present. Below in Table
`1 are described a few commercialised sustained release
`
`60
`
`injectable formulations.
`In the formulations within Table 1 a number of different
`
`oils are used to solubilise the compound and additional
`excipients such as benzyl benzoate, benzyl alcohol and etha-
`nol have been used. Volumes of oil needed to solubilise the
`
`70L-[9-(4,4,5,5,5-Pentafluoropentylsulphinyl)no11yl]
`oestra-1,3-5(10)-triene-3,17[3-diol, or ICI 182,780, has been
`
`steroid active ingredient are low. Extended release is achiev-
`able for periods from 1 to 8 weeks.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 6
`
`

`

`9)
`
`US 8,329,680 B2
`
`TABLE 1
`
`OIL BASED LONG-ACTING INT {AMUSCULAR INJECTIONS
`
`-5
`
`PRODUCT NAME
`
`STEROID
`
`DOSE
`
`TYPE
`
`COMP’.
`
`SOURCE
`
`OIL
`
`BZBZ
`
`SUSTANON 100
`
`PROLUTON
`DEPOT
`TOCOGESTAN
`
`TROPHOBOLENE
`
`NORISTERAT
`
`BENZO-
`GYNOESTRYL
`PROGESTERONE-
`RETARD
`GRAVIBINAN
`
`30 mg
`60 mg
`
`Androgen
`
`Organon
`
`ABPI Data Sheet Arachis
`Comp. 1999
`
`60 mg
`100 mg
`250 mgml” Progestogen
`
`200 mg
`
`Progestogen
`
`ABPI Data Sheet Castor
`Schering
`Comp. 1999
`HC
`Theramax Dict. Vidal 1999
`
`Ethyl
`oleate
`
`up to 46%
`
`*40%
`
`Mixed
`
`Theramax Dict. Vidal 1997
`
`Olive
`
`45%
`
`50 mg
`250 mg
`1.3 mg
`50 mg
`80 mg
`
`200 mg
`
`Contraceptive
`
`Schering
`HC
`Roussel
`
`ABPI Data Sheet Castor
`Comp. 1999
`Dict. Vidal 1998
`
`Arachis
`
`5 mg
`
`Estradiol
`
`250 mgml’l Progestogen
`
`Pharlon
`
`Dict. Vidal 1999
`
`Castor
`
`5 mgml’1 Mixed
`250 mgml"
`
`Schering
`HC
`
`Dict. Vidal 1995
`
`Castor
`
`YES
`
`YES
`
`YES
`
`PARABOLAN
`DELESTROGEN
`
`DELALUTIN
`
`Androgen
`76 mg
`20 mgml’1 Estradiol
`40 mgml 1
`250 mgml'l Progestrogen
`
`"estosterone proprionate
`"estosterone
`ohenylproprionate
`"estosteroneisocaproate
`"estosterone decanoate
`Iydroxy progesterone
`exanoate
`Iydroxy progesterone
`enantate
`rogesterone
`ot-Tocopherol
`dstrapronicate
`Nandrolone undecanoate
`Iydroxyprogesterone
`ieptanoate
`Norethisterone
`oenanthoate
`Estradiol
`exahydrobenzoate
`{ydroxy progesterone
`caproate
`3stradiol17—[5—valerate
`Iydroxyprogesterone
`caproate
`Trenbolone
`Estradiol
`Valerate
`7-Hydroxy
`arogesterone
`PRODUCT NAME
`
`SUSTANON 100
`
`PROLUTON
`DEPOT
`TOCOGESTAN
`
`TROPIIOBOLENE
`
`NORISTERAT
`
`BENZO-
`GYNOESTRYL
`PROGESTERONE-
`RETARD
`GRAVIBINAN
`
`PARABOLAN
`DELESTROGEN
`
`DELALUTIN
`
`STEROID
`
`Testosterone proprionate
`Testosterone
`ahenylproprionate
`Testosterone isocaproate
`Testosterone decanoate
`Iydroxy progesterone
`iexanoate
`Iydroxy progcstcronc
`enantate
`’rogesterone
`OL-TOCOphC1‘Ol
`Estrapronicate
`Nandrolone undecanoate
`Iydroxyprogesterone
`ieptanoate
`Norethisterone
`oenanthoate
`istradiol
`iexahydrobenzoate
`Iydroxy progesterone
`caproate
`istradiol 17-[5-Valerate
`Iydroxyprogesterone
`caproale
`Trenbolone
`Estradiol
`Valerate
`7-Hydroxy
`arogesterone
`
`Negma
`BMS
`
`DMS
`
`BZOH
`
`0.1 ml
`
`Arachis
`Castor
`
`Castor
`
`Dict. Vidal 1997
`J. Pharm. Sci
`(1964) 53(8) 891
`J. Pharm. Sci.
`(1964) 53(8) 891
`EtOH
`DOSE
`
`78%
`58%
`YES
`
`DOSING
`
`1 m
`
`3 WCC{S
`
`1 or 2 m
`
`1 WCC{
`
`2 m
`
`<1 WCC{
`
`1 m
`
`15 to 30 ays
`
`1 m
`
`1 m
`
`8 WCC{S
`
`1 WCC{
`
`1 or 2 111
`
`1 WCC{
`
`1 or 2 m
`
`1-2 WCC{S
`
`1.5 m
`
`2 Wee<s
`
`75 mg
`20%
`40%
`YES
`
`45 mg
`2%
`2%
`up to 2%
`
`BZBZ = benzylbenzoate
`BZOH = benzylalcohol
`FTOI-I = ethanol
`Dict. Vidal = Dictionnaire Vidal
`"/0 are W/V and
`"approximate as measured directly from a single sample
`
`described which comprises 50 mg of fulvestrant, 400 mg of
`
`complicated by the high alcohol concentration. Therefore,
`
`benzyl alcohol and sufficient castor oil to bring the solution to
`
`there is a need to lower the alcohol concentration in fulVes-
`
`a Volume of 1 ml. Manufacture at a commercial scale of a 65
`
`trant formulations whilst preventing precipitation of fulVes-
`
`formulation as described in U.S. Pat. No. 5,183,814 will be
`
`trant from the formulation.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 7
`
`

`

`US 8,329,680 B2
`
`5
`SUMMARY OF THE INVENTION
`
`The invention relates to a novel sustained release pharma-
`ceutical formulation adapted for administration by injection
`containing the compound 701-[9-(4,4,5,5,5-pentafluoropen-
`tylsulphinyl)nonyl]oestra-1,3 ,5 (1 0)-triene-3 ,17|3-diol, more
`particularly to a formulation adapted for administration by
`injection containing the compound 7oL-[9-(4,4,5,5,5-pen-
`ta fluoropentylsulphinyl)nonyl]oestra -1,3 ,5 ( 10)-triene-3 ,
`17B-diol in solution in a ricinoleate vehicle which addition-
`ally comprises at least one alcohol and a non-aqueous ester
`solvent which is miscible in the ricinoleate vehicle.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`FIG. 1 shows the release profile in vivo of the four formu-
`lations from the second part of Table 4 below, and shows the
`effect ofthe fixed oil component on fulvestrant plasma profile
`over five days following intramuscular administration in rab-
`bits.
`
`FIG. 2 shows a process flow diagram associated with the
`Formulation Example.
`
`10
`
`15
`
`20
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`25
`
`Table 2 shows the solubility of fulvestrant in a number of
`different solvents.
`
`TABLE 2
`
`SOLUBILITY OF FULVESTRANT
`
`SOLVENT
`Water
`Arachis oil
`Sesame oil
`Castor oil
`Miglyol 810
`Miglyol 812
`Ethyl oleate
`Benzyl benzoate
`Isopropyl myristate
`Span 85 (surfactant)
`Ethanol
`Benzyl Alcohol
`
`SOLUBILITY
`(mgmrl at 25° C.)
`0.001
`0.45
`0.58
`20
`3.06
`2.72
`1.25
`6.15
`0.80
`3.79
`>200
`>200
`
`As can be seen fulvestrant is significantly more soluble in
`castor oil than any of the other oils tested. The greater solvat-
`ing ability of castor oil for steroidal compounds is known and
`is attributed to the high number of hydroxy groups of ricino-
`leic acid, which is the major constituent of the fatty acids
`within the triglycerides present in castor oil—see (Riffkin et.
`al. J. Pharm. Sci., (1964), 53, 891).
`However, even when using the best oil based solvent, cas-
`tor oil, we have found that it is not possible to dissolve
`fulvestrant in an oil based solvent alone so as to achieve a high
`enough concentration to dose a patient in a low volume injec-
`tion and achieve a therapeutically significant release rate. To
`achieve a therapeutically significant release rate the amount
`of fulvestrant needed would require the formulation volume
`to be large, at least 10 ml. This requires the doctor to inject an
`excessively large volume of formulation to administer a dose
`significantly high enough for human therapy.
`Currently guidelines recommend that no more than 5 mls
`of liquid is injected intramuscularly in a single injection.
`Pharmacologically active doses required for a 1 month long
`acting depot formulation of fulvestrant is around 250 mg.
`
`40
`
`45
`
`60
`
`65
`
`6
`Therefore, when dissolved injust castor oil, fulvestrant would
`need to be administered in at least 10 ml of castor oil.
`
`The addition of organic solvents in which fulvestra11t is
`freely soluble, and which are miscible with castor oil, may be
`used, such as an alcohol. With the addition of high concen-
`trations of an alcohol concentrations of >50 mgml"1 of ful-
`vestrant in a castor oil formulation is achievable, thereby
`giving an injection volumes of <5 ml—see Table 3 below. We
`have surprisingly found that the introduction of a non-aque-
`ous ester solvent which is miscible in the castor oil and an
`alcohol surprisingly eases the solubilisation of fulvestrant
`into a concentration of at least 50 mgml‘1—see Table 3
`below. The finding is surprising since the solubility of fulves-
`trant in non-aqueous ester solvents—see Table 2 above—is
`significantly lower than the solubility of fulvestrant in an
`alcohol. The solubility of fulvestrant is also lower in 11on-
`aqueous ester solvents than is the solubility of fulvestra11t in
`castor oil.
`
`Therefore, we present as a feature of the invention a phar-
`maceutical formulation comprising fulvestrant (preferably
`fulvestrant is present at 3-10% w/v, 4-9% w/v, 4-8% w/V,
`4-7% w/v, 4-6% w/V a11d 111ost preferably at about 5% w/V) in
`a ricinoleate vehicle, a pharmaceutically acceptable 11on-
`aqueous ester solvent, and a phannaceutically acceptable
`alcohol wherein the formulation is adapted for intramuscular
`administration and attaining a therapeutically significant
`blood plasma fulvestrant concentration for at lea st 2 weeks.
`Another feature of the invention is a pharmaceutical for-
`mulation comprising fulvestrant in which the formulation is
`adapted for intra-muscular injection into a human and which
`is capable after injection of attaining a therapeutically signifi-
`cant blood plasma fulvestrant concentration for at least 2
`weeks.
`Further features of the invention include a pharmaceutical
`formulation adapted for intra-muscular injection comprising
`fulvestrant, 30% or less weight of a pharmaceutically-accept-
`able alcohol per volume offormulation, at least 1% weight of
`a pharmaceutically-acceptable non-aqueous ester solvent
`miscible in a ricinoleate vehicle per volume of formulation
`a11d a suflicient amount of a ricinoleate vehicle so as to pre-
`pare a formulation which is capable after injection of attain-
`ing a therapeutically significant blood plasma fulvestrant
`concentration for at least 2 weeks.
`
`Further features of the invention include a pharmaceutical
`formulation adapted for intra-musc11lar injection comprising
`fulvestrant; 35% (preferably 30% and ideally 25%) or less
`weight of a pharmaceutically-acceptable alcohol per volume
`of formulation, at least 1% (preferably at least 5% or ideally
`10%) weight of a pharmaceutically-acceptable non-aqueous
`ester solvent miscible within a ricinoleate vehicle per volume
`offormulation and a sufficient amount of a ricinoleate vehicle
`
`so as to prepare a formulation of at least 45 mgml” of ful-
`vestrant.
`
`For the avoidance of any doubt when using the term %
`weight per volume of formulation for the constituents of the
`formulation we mean that within a unit volume of the formu-
`
`lation a certain percentage ofthe constituent by weight will be
`present, for example a 1% weigl1t per volu111e fon11ulation
`will contain within a 100 ml volume of formulation 1 g ofthe
`constituent. By way of further illustration
`
`% ofx by weight per
`volume of formulation
`
`weight ofx in 1 ml
`of formulation
`
`30%
`20%
`
`300 mg
`200 mg
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 8
`
`

`

`US 8,329,680 B2
`
`7
`-continued
`
`% ofx by weight per
`volume of formulation
`
`weigl1t ofx in 1 ml
`of formulation
`
`10%
`5%
`1%
`
`100 mg
`50 mg
`10 mg
`
`Preferred pharmaceutical formulations ofthe invention are
`as described above wherein:
`1 . The total volume ofthe formulation is 6 ml, or less, and the
`concentration of fulvestrant is at least 45 mgml‘1.
`2. The total amount of fulvestrant in the formulation is 250
`
`mg, or more, and the total volume of the formulation is 6
`ml, or less.
`3. The total amount offulvestrant in the formulationis 250 mg
`and the total volume of the formulation is 5-5.25 ml.
`
`It is appreciated that in the formulation an excess of for-
`mulation may be included to allow the attendant physician or
`care giver to be able to deliver the required dose. Therefore,
`when a 5 ml dose is required it would be appreciated that an
`excess of up to 0.25 ml, preferably up to 0.15 ml will also be
`present in the formulation. Typically the formulation will be
`presented in a vial or a prefilled syringe, preferably a prefilled
`syringe, containing a unit dosage of the formulation as
`described herein, these being further features ofthe invention.
`Preferred concentrations of a pharmaceutically-acceptable
`alcohol present in any of the above fonnulations are; at least
`3% w/v, at least 5% w/v, at least 7% w/v, at least 10% w/v, at
`least 11% w/v, at least 12% w/v, at least 13% w/v, at least 14%
`w/v, at least 15% w/v and, preferably, at least 16% w/v.
`Preferred maximal concentrations of pharmaceutically-ac-
`ceptable alcohol present in the formulation are 28% w/v or
`less, 22% w/v or less and 20% w/v or less. Preferred ranges of
`pharmaceutically-acceptable alcohol present i11 any of the
`above formulations are selected from any minimum or maxi-
`mum value described above and 3-35% w/v, 4-35% w/v,
`5.35% w/v, 5.32% w/v, 7.32% w/v, 10-30% w/v, 12-28%
`w/v, 15-25% w/v, 17-23% w/v, 18-22% w/v and ideally
`1 9-21% w/v.
`The phannaceutically-acceptable alcohol may consist of
`one alcohol or a mixture of two or more alcohols, preferably
`a mixture of two alcohols. Preferred pham1aceutically-ac-
`ceptable alcohols for parenteral administration are ethanol,
`benzyl alcohol or a mixture of both ethanol and benzyl alco-
`hol, preferably the ethanol and benzyl alcohol are present in
`the formulation in the same w/v amounts. Preferably the
`formulation alcohol contains 10% w/v ethanol and 10% w/v
`
`benzyl alcohol.
`The phar111aceutically-acceptable 11011-aqueous ester sol-
`vent may consist of one or a mixture of two or more pharrna-
`ccutically-acccptablc non-aqucous cstcr solvcnts, prcfcrably
`just one. A preferred pharrnaceutically-acceptable 11on-aque-
`ous ester solvent for parenteral administration is selected
`from benzyl benzoate, ethyl oleate, isopropyl myristate, iso-
`propyl palmitate or a mixture of any thereof.
`The ricinoleate vehicle should preferably be present in the
`formulation in a proportion ofat least 30% weight per volume
`ofthe formulation, ideally at least 40% or at least 50% weight
`per volume of formulation.
`It will be understood by the skilled person that the phar-
`maceutically-acceptable alcohol will be of a quality such that
`it will meet pharmacopoeial standards (such as are described
`in the US, British, European and Japanese pharmacopoeias)
`and as such will contain some water and possibly other
`organic solvents, for example ethanol in the US Pharma-
`
`10
`
`15
`
`20
`
`25
`
`35
`
`40
`
`45
`
`60
`
`65
`
`8
`copeia contains not less than 94.9% by volume and not more
`than 96.0% by volume of etha11ol when measured at 15.56° C.
`Dehydrated alcohol in the US Pharmacopeia contains not less
`than 99.5% ethanol by volume when measured at 15.56° C.
`Preferred concentrations of the pharmaceutically-accept-
`able non-aqueous ester solvent present in any of the above
`formulations are; at least 5% w/v, at least 8% w/v, at least 10%
`w/v, at least 11% w/v, at least 12% w/v, at least 13% w/v, at
`least 15% w/v, at least 16% w/v, at least 17% w/v, at least 18%
`w/v, at least 19% w/v and at least 20% w/v. Preferred maximal
`concentrations ofthe pharmaceutically-acceptable non-aque-
`ous ester solvent are; 60% w/v or less, 50% w/v or less, 45%
`w/v or less, 40% w/v orless, 35% w/v or less, 30% w/v orless
`and 25% w/v or less. A preferred concentration is 15% w/v.
`Preferr