US007456l60B2
`
`(12) United States Patent
`Evans et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 7,456,160 B2
`*NOV. 25, 2008
`
`(54) FORMULATION
`
`(75)
`
`Inventors: John R Evans, Macclesfield (GB);
`Rosalind U Grundy, Macclcsficld (GB)
`
`(73) Assignee: AstraZeneca AB, Sodertalje (S3)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 873 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl.No.: 10/872,784
`
`(22)
`
`Filed:
`
`Jun. 22, 2004
`
`2,983,649 A
`3,164,520 A
`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
`
`5/1961 Ercoli et 211.
`1/1965 Huber
`11/1970 Neumann et al.
`1/1976 Lehmann et 211.
`9/1977 Chen et 211.
`9/1977 Chen et 211.
`7/1980 Cornelius
`6/1983 Cavanak
`4/1987 Bowler et 211.
`12/1989 Elger et al.
`
`(Continued)
`FOREIGN PATENT DOCUMENTS
`
`EP
`
`0 138 504
`
`4/1985
`
`(Continued)
`OTHER PUBLICATIONS
`
`(65)
`
`Prior Publication Data
`
`US 2005/0043285 A1
`
`Feb. 24, 2005
`
`Anschel, “Losungsmittel und Losungsvermittler in Injektionen”,
`Pharm, Ind., 1965, vol. 27 (1 la), pp. 781-787.
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 09/756,291, filed on
`Jan. 9, 2001, now Pat. No. 6,774,122.
`
`(Continued)
`
`Primary Examiner—San-ming Hui
`(74) Attorney, Agent, or Firm—Morgan, Lewis & Bockius
`LLP
`
`(30)
`
`Foreign Application Priority Data
`
`(57)
`
`ABSTRACT
`
`Jan. 10, 2000
`Apr. 12,2000
`
`(GB)
`(GB)
`
`............................... .. 00003l3.7
`............................... .. 0008837.7
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31/56
`(52) U.S. Cl.
`..................................... .. 514/177; 514/178
`(58) Field of Classification Search ..................... .. None
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`2,822,316 A
`
`2/1958 Richter et al.
`
`The invention relates to a novel sustained release pharmaceu-
`tical formulation adapted for administration by inj cction con-
`taining the compound 7oL—[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,
`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.
`
`12 Claims, 1 Drawing Sheet
`
`40
`
`
`
`Fulvastranl(ngpermlplasma)
`
`-+- F1 Formulatlan F (Caslor all)
`— + — F2 Mlglyol 812-N
`- -1- - - FJ Caslnrlsesama ol|1:1
`
`
`
`Time (d)
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 1
`
`

`
`US 7,456,160 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`5,095,129 A
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`5,733,902 A
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`
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`
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`FR
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`JP
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`SU
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`W0
`W0
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`ZA
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`
`0310542 A1
`0 346 014
`0819431 A1
`0905143 A2
`6241
`817241
`1 126 892
`1 207 571
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`10-152438
`11-501649
`11-158200
`549118
`676284
`W0 95/12383
`W0 96/19997
`W0 97/21440
`W0 97/37653
`W0 97/40823
`W0 98/11902
`681014
`682530
`
`4/1989
`12/1989
`3/1999
`3/1999
`9/1968
`7/1959
`9/1968
`10/1970
`10/1970
`6/1980
`11/1992
`12/1997
`4/1998
`6/1998
`2/1999
`6/1999
`3/1977
`7/1979
`5/1995
`7/1996
`6/1997
`10/1997
`11/1997
`3/1998
`2/1968
`4/1968
`
`OTHER PUBLICATIONS
`
`. with
`.
`.
`Davis et al., “17-Alpha-Hydroxyprogesterone-Caproate:
`Chemically Pure Progesterone”, J. Clin. Endocrinol. And Metabo-
`lism, 1955, vol. 15, pp. 923-930.
`Dukes et al., “Antiuterotrophic effects of the pure antioestrogen ICI
`182, 780 .
`.
`. quantitative magnetic resonance imaging”; J. Endocri-
`nology. 1992, V01. 138, pp. 203-209.
`Dukes et al., “Antiuterotrophic effects ofpure antioestrogen. ICI 182,
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`.
`. the uterus in ovariectomized monkeys”, J. Endocrinology,
`1992, vol. 135, pp. 239-247.
`Howell 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, V01. 74, pp.
`300-308.
`Martindale, 32nd Ed., “Alcohol”, Pharmaceutical Press. 1999. pp.
`1099-1101.
`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 ofCaster Oil and Benzyl Benzoate Used as aVehicle
`for Antiandrogens on the Adrenal Cortex”, Archives ofAndrology 2,
`1979, pp. 365-369.
`Pellegrino, “Use of 17 01 Hydroxyprogesterone Caproate in Threat-
`ened Abortion”, Current Therapeutic Research, vol. 4, No. 6, Jun.
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`
`.
`.
`Piver et al., “Medroxyprogesterone Acetate (Depo—Provera) vs .
`Women with \/letastatic Endometrial Adenocarcinoma”, Cancer, Vol.
`45, American Cancer Society, 1980, pp. 268-272.
`Riffl<in 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.
`Sawada et al., “Estrogen Receptor Antagonist ICII82,780 Exacer-
`batcs Ischcmic Injury in Female Mousc”, 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 witl1 Clinical
`Potential", Cancer Research, 1991, vol. 51, pp. 3867-3873.
`.
`.
`Waterton et al., “A Case ofAde11omyosis i11 a Pigtailed Monkey .
`Treated with the Novel Pure Antiestrogen, ICI 182,780”; Laboratory
`Animal Science, 1993, vol. 43, No. 3, 1993, pp. 247-251.
`Mackey et
`al,
`“Tolerability of
`intramuscular
`injections of
`testosterone ester in oil vehicle”, Human Reproduction, vol. 10. No.
`4, pp. 869-865, 1995.
`Howell et al., “Response to a specific antioestrogen (ICI 182780) in
`tamoxifen-resistant breast cancer”, The Lancet, Jan. 7, 1995, pp.
`29-30.
`Osborne et al., “Comparison of the Effects of a Pure Steroidal
`Antiestrogen With Those of Tamoxifen in a Model of Human Breast
`Cancer”, Journal of the National Cancer, May 1995, vol. 87, No. 10,
`pp. 746-750.
`Robertson et al., “A Partially-Blind, Randomised, Multicentre Study
`Comparing the Anti-Tumor Effects of Single Doses (50, 125 and
`250MG) of Long-Acting (LA)
`‘Faslodex’
`(ICI 182,780 with
`Tamoxifin in Postmenopausal Women with Primary Breast Cancer
`Prior to Surgery”; Abstract 28, 22nd Annual San Antonio Breast
`Cancer Symposium: Dec. 8-11, 1999, San Antonio, Breast Cancer
`Research and Treatment 1999; 57 (1; special issue); p. 31.
`Remington’s Pharmaceutical Sciences, 18th ed., 1990, p. 219.
`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. Nema, R.J. Washkuhn, and R.J. Brendel. Excipients and their use
`in injectable products. PDA J. Pharm. Sci. Technol. 51:166-71
`(1997).
`Physicians’ Desk Reference (27th edition). 1277-1278, 1350-1354,
`1391-1392 Medical Economics Company, Oradcll, NJ (1973).
`M. F. Powell, T. Nguyen, and L. Baloian. Compendium of excipients
`for parenteral formulations. PDA J. Pharm. Sci. Technol. 521238-311
`[pp. 238-255 provided] (1998).
`R. G. Strickley. Parenteral formulations of small molecule therapeu-
`tics marketed in the United States (1999) -Part I. PDA J. Pharm. Sci.
`Technol. 53:324-349 (1999).
`R. G. Strickley. Parenteral formulations of small molecule therapeu-
`tics marketed in the United States (1999)—Pa1tIIPDA J. Pharm. Sci.
`Technol. 54:69-96 (2000).
`R. G. Strickley. Parenteral formulations of small molecule therapeu-
`tics marketed in the United States (1999)—Part III. PDA J. Pharm.
`Sci. Technol. 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. .1. Parenteral Drug
`Assoc. 34:452-462 (1980).
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 2
`
`

`
`U.S. Patent
`
`Nov. 25, 2008
`
`US 7,456,160 B2
`
`
`
`._.oSumo.H.._o_.a__:Eo“.E..Io.l.
`
`fr:0aEumomto.mmonu....0...
`
`
`
`2&3_o>_m__2EILTu
`
`:3oE_.p
`
`2.
`
`on
`
`(eLuse|d |u1 Jed 6u)1uensa/xgng
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 3
`
`

`
`US 7,456,160 B2
`
`1
`FORMULATION
`
`This is a Continuation of application Ser. No. 09/756,291,
`filed Jan. 9, 2001 now U.S. Pat. No. 6,744,122.
`
`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, more
`particularly to a formulation adapted for administration by
`injection containing the compound 70t—[9—(4,4,5,5,5—pen—
`tafluoropcntylsulphinyl)nonyl]oestra-1,3 ,5 ( 10)-tricnc-3 ,
`17[3-diol i11 solution i11 a ricinoleate vel1icle wl1icl1 addition-
`ally comprises at least one alcohol and a non-aqueous ester
`solvent which is miscible in the ricinoleate vehicle.
`
`Oestrogen deprivation is fundamental 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 women, 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
`nonsteroidal antioestrogens, such as tamoxifen, compete efli-
`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 (Furr
`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 affinity without acti-
`vating any of the normal transcriptional hormone 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 of the 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 i11: Bowler et al 1989,
`Wakeling 1990a, 1990b, 1990c. Wakeling and Bowler 1987,
`1 988.
`
`Steroidal analogues of oestradiol, 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, 70¢-[9-(4,4,5,5,5-pentafiuoropentyl sul-
`phinyl)nonyl]oestra-1,3,5-(10)triene-3,17[3-diol
`was
`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(10)-triene-3,
`17B-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.
`
`7ot-[9-(4,4,5,5,5-Pentalluoropentylsulphinyl)no11yl]
`oestra-1,3-5(10)-triene-3,17[3-diol, or ICI 182,780, has been
`allocated the international non-proprietary name fulvestrant,
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`60
`
`65
`
`2
`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 aflinity similar to that of
`oestradiol and completely blocks the growth stimulatory
`action of oestradiol on human breast cancer cells in vitro; it is
`more potent and more effective than tamoxifen i11 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 invasivcncss.
`
`In intact adult rats, fulvestrant 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; fulvestrant 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 7ot—[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 tl1at 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, and 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 excipie11ts may be present. Below ir1 Table
`1 are described a few co111111ercialised sustained release
`
`inj ectable 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
`
`steroid active ingredient are low. Extended release is achiev-
`able for periods from 1 to 8 weeks.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 4
`
`

`
`9)
`
`-5
`
`US 7,456,160 B2
`
`TABLE 1
`
`OIL BASED LONG-ACTING INTRAMUSCULAR INJECTIONS
`
`PRODUCT NAME
`
`ST EROID
`
`DOSE
`
`TYPE
`
`COMP’.
`
`SOURCE
`
`OIL
`
`BzBz BzOH
`
`EtOH
`
`DOSE DOSING
`
`SUSTANON 100
`
`PROLUTON
`DEPOT
`
`TOCOGESTAN
`
`TROPHOBOLENE
`
`Testosterone
`pro Jrionate
`Testosterone
`pheny -
`pro arionate
`Tes os erone
`isocaproate
`Tes os erone
`decanoate
`
`{y roxy
`aroges erone
`exanoate
`{y roxy
`aroges erone
`enanta e
`
`roges erone
`or-Tocopherol
`Estrapronicate
`Nandrolone
`lmdecanoate
`
`60 mg
`
`60 mg
`
`100 mg
`
`250 mgml’1
`
`200 mg
`
`50 mg
`250 mg
`1.3 mg
`50 mg
`
`80 mg
`
`30 111g
`
`And.roge11
`
`Organon
`
`Arachis
`
`0.1 1111
`
`1 1111
`
`3 Weeks
`
`ABPI Data
`Sheet
`Comp. 1999
`
`Progestogen
`
`Schering
`HC
`
`ABPI Data
`Sheet
`Comp. 1999
`Progestogen Theramax Dict. Vidal
`1999
`
`up to
`46%
`
`*40%
`
`Castor
`
`Ethyl
`oleate
`
`1 Week
`
`1 or
`2 ml
`
`2 ml
`
`<1 Week
`
`Mixed
`
`Theramax Dict. Vidal
`1997
`
`Olive
`
`45%
`
`1 ml
`
`15 to 30
`days
`
`Castor
`
`YES
`
`1 ml
`
`8 weeks
`
`Arachis
`
`1 ml
`
`1 week
`
`200 mg
`
`Contra—
`ccptivc
`
`Schering
`HC
`
`5 mg
`
`Estradiol
`
`Roussel
`
`250 mgml"
`
`Progestogen Pharlon
`
`ABPI Data
`Shcct
`Comp. 1999
`Diet. Vidal
`1998
`
`Dict.Vidal
`1999
`
`Castor
`
`YES
`
`5 mgml’1 Mixed
`
`Schering Dict.Vidal
`1995
`
`Castor
`
`YES
`
`250 mgml’l
`
`HC
`
`1 Week
`
`1 or
`2 ml
`
`1-2
`1 or
`2 ml Weeks
`
`{ydroXy-
`arogesterone
`eptanoate
`Norethisterone
`ocnanthoatc
`
`Estradiol
`heXahydr0-
`benzoate
`
`NORISTERAT
`
`BENZO-
`GYNOESTRYL
`
`GRAVIBINAN
`
`PROGESTERONE- Hydroxy
`RETARD
`progesterone
`caproate
`Estradiol
`17-[5-Valerate
`Hyd.roXy-
`progesterone
`caproate
`Trenbolone
`
`PARABOLAN
`
`76 mg
`
`Androgen
`
`Negma
`
`Dict. Vidal
`1997
`
`.T.Pha1m.
`Sci
`(1964)
`53(8) 891
`.T.Pha1m.
`Sci.(1964)
`53(8) 891
`
`Arachis
`
`75 mg
`
`45 mg
`
`1.5 ml 2 Weeks
`
`Castor
`
`78%
`58%
`
`20%
`40%
`
`2%
`2%
`
`Castor
`
`YES
`
`YES
`
`up to
`2%
`
`DELESTROGEN
`
`Estradiol
`valerate
`
`20 mgml’1 Estradiol
`40 mgml’1
`
`BMS
`
`DELALUTIN
`
`17-Hydroxy
`progesterone
`
`250 mgml’1
`
`Progestrogen DMS
`
`BZBZ = benzylbenzoate
`BZOH = benzylalcohol
`EtOH = ethanol
`Dict. Vidal = Dictionnaire Vidal
`% are W/V and
`
`*approXimate as measured directly from a single sample
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 5
`
`

`
`US 7,456,160 B2
`
`6
`alcohol. The solubility of fulvestrant is also lower in 11on-
`aqueous ester solvents than is the solubility of fulvestra11t in
`castor oil.
`
`5
`described which comprises 50 mg of fulvestrant, 400 mg of
`benzyl alcohol and sufficient castor oil to bring the solution to
`a volume of 1 ml. Manufacture at a commercial scale of a
`formulation as described in U.S. Pat. No. 5,183,814 will be
`complicated by the high alcohol concentration. Therefore,
`there is a need to lower the alcohol concentration in fulves-
`
`trant formulations whilst preventing precipitation of fulves-
`trant from the formulation.
`
`Table 2 shows the solubility of fulvestrant in a number of 1
`different solvents.
`
`TABLE 2
`
`SOLUBILITY OF FULVESTRANT
`
`SOLVENT
`Water
`Arachis oil
`Sesame oil
`Castor oil
`Miglyol 810
`Miglyol 812
`Ethyl oleate
`Benzyl benzoate
`lsopropyl Inyristate
`Spain 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. Phann. Sci., (1964), 53, 891).
`However, even when using the best oil based solve11t, 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 bc large, at least 10 ml. This rcquircs the doctor to inject an
`excessively large volume of formulation to administer a dose
`significantly high cnough for human thcrapy.
`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.
`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 fulvestrant is
`freely soluble, and which are to miscible with castor oil, may
`be used, such as an alcohol. With the addition of high con-
`centrations of an alcohol concentrations of >50 n1gm1‘1 of
`fulvestrant 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 11on-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 n1gml’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
`
`Therefore, we present as a feature of the invention a phar-
`5 maceutical fonnulation 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 and most 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 least 2 weeks.
`Another feature of the invention is a pharmaceutical for-
`mulation comprising fulvestrant in which the formulation is
`adapted for intramuscular 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.
`
`15
`
`20
`
`25
`
`Further features of the invention include a pharmaceutical
`formulation adapted for intramuscular 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
`and a sulficient amount of a ricinoleate vehicle so as to pre-
`pare a formulatio11 which is capable after injection of attain-
`ing a therapeutically significant blood plasma fulvestrant
`concentration for at lea st 2 weeks.
`
`Further features of the invention include a pharmaceutical
`formulation adapted for intramuscular injection comprising
`fulvestrant; 35% (preferably 30% and ideally 25%) or less
`weight of a pharmaceutically-acceptable alcohol per volume
`of formulation, at lea st 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 ofa ricinoleate vehicle
`
`40
`
`so as to prepare a formulation of at least 45 mgml"1 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
`45 present, for example a 1% weight per volume formulation
`will contain within a 100 ml volume of formulation 1 g ofthe
`constituent. By way of further illustration
`
`50
`
`55
`
`% ofx by weight per
`volume offorinulalion
`
`weight ofx in
`1 H11 offonnulation
`
`30%
`20%
`10%
`5%
`1%
`
`300 mg
`200 mg
`100 mg
`50 mg
`10 mg
`
`Preferred pharmaceutical formulations ofthe invention are
`50 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”.
`2. The total amount of fulvestrant in the formulation is 250
`
`65
`
`mg, or more, and the total volume of the formulation is 6
`ml, or less.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 6
`
`

`
`US 7,456,160 B2
`
`8
`and 25% w/v or less. A preferred concentration is 15% w/v.
`Preferred ranges of pharrnaceutically-acceptable non-aque-
`ous ester solvent present in any of the above formulations are
`selected from any minimum or maximum value described
`above and preferably are; 5-60% w/v, 7-55% w/v, 8-50% w/v,
`10-50% w/v, 10-45% w/v, 10-40% w/v, 10-35% w/v, 10-30%
`w/v, 10-25% w/v, 12-25% w/v, 12-22% w/v, 12-20% w/v,
`12-18% w/v, 13-17% w/v and ideally 14-16% w/v. Preferably
`the ester solvent is benzyl benzoate, most preferably at about
`15% w/v.
`
`It will be understood by the skilled person that the phar-
`maceutically-acceptable non-aqueous ester solvent will be of
`a quality that it will meet pharmacopoeial standards (such as
`described in the US, British, European and Japanese pharma-
`copoeias).
`Preferred combinations of pharmaceutically-acceptable
`alcohol and pharmaceutically-acceptable non-aqueous ester
`solvent in the formulation are set out below:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`7
`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 ofa 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 pham1aceutically-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 iii any of the
`above formulations are selected from any minimum or maxi-
`mum value described above and preferably are; 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 19-21% 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 phannaceutically-acceptable non-aqueous ester sol-
`vent may consist of one or a mixture of two or more pharma-
`ceutically-acceptable non-aqueous ester solvents, preferably
`just one. A preferred pharmaceutically-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-
`copeia contains not less than 94.9% by volume and not more
`than 96.0% by volume ofethanol 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 1 9% w/v and at least 20% w/v. Preferred maximal
`concentrations ofthe pharmaceutically-acceptable 11on-aque-
`ous ester solvent are; 60% w/v or less, 50% w/v or less, 45%
`w/v or less, 40% w/v or less, 35% w/v or less, 30% w/v or less
`
`Pharmaceutically-acceptabl e
`alcohol(% w/v)
`10-30
`
`17-23
`
`3-35, 4-35, 5-35, 5-32, 7-32,
`5 10-30,12-28, 15-25,17-23,
`18-22 and ideally 19-
`3-35, 4-35, 5-35, 5-32, 7-32,
`10-30, 12-28, 15-25, 17-23,
`18-22 and ideally 19-21.
`ethanol and benzyl alcohol, most
`preferably each at about 10%
`
`40
`
`’l1a.rn1aceutically-
`acceptable non-aqueous
`ester (% w/v)
`5-60, 7-55, 8-50,10-50, 10-45,
`0-40, 10-35,10-30,
`0-25, 12-25,12-22,
`2-20,12-18,13-17 and
`ideally 14-16.
`5-60, 7-55, 8-50,10-50, 10-45.
`0-40, 10-35,10-30,
`0-25, 12-25, 12-22,
`2-20,12-18,13-17 and
`ideally 14-16.
`0-35
`
`2-18
`
`enzyl benzoate, 111ost
`vreferably at about 15%
`
`45
`
`50
`
`60
`
`65
`
`By the use of the term ricinoleate vehicle we mean a11 oil
`which has as a proportion (at least 20%, 30%, 40%, 50%,
`60%, 70%, 80%, 90% or 95% w/v) of its composition as
`triglycerides of ricinoleic acid. The ricinoleate vehicle may
`be a synthetic oil or conveniently is castor oil, ideally of
`pharmacopoeial standards, as described above.
`We have surprisingly found that the above formulations of
`the invention provide, after intramuscular injection, satisfac-
`tory release of fulvestrant over an extended period of time.
`This finding is indeed surprising for the following reasons.
`1 . Previously tested by the applicants have been intra-muscu-
`lar injections of fillvestrant in the form of an aqueous
`suspension. We have found extensive local tissue irritation
`at the injection site as well as a poor release profile. It is
`believed that the tissue irritation/inflammation was due to
`
`the presence of fulvestrant in the form of solid particles.
`The release profile appeared to be determined by the extent
`of inflan1rnation/irritation present at the injection site and
`this was variable and diflicult to control. Also the fulves-
`
`trant release rate was not sufficiently high to be clinically
`significant.
`2. Our findings from studies using “C labelled benzyl alcohol
`show that it dissipates rapidly from the injection site and is
`removed from the body within 24 hours of administration.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 7
`
`

`
`US 7,456,160 B2
`
`10
`amounts of alcohol and benzyl benzoate but in which the oil
`is changed. The data also shows solubility of fulvestrant after
`removal of the alcohols.
`
`TABLE 4
`
`Solubility comparisons of fulvestrant in oil based
`formulations with and without alcohols
`
`Fulvestrant Solubility mg
`ml’1 @ 25° c.
`
`Complete
`vehicle
`81.2
`86.8
`70.1
`
`45.7
`40.2
`
`Vehicle minus
`alcohols
`12.6
`1.7
`4.4
`
`0.7
`<0.2
`
`Formulationla)
`Castor oil based
`Miglyol 812-N based
`Sesame seed/
`Castor oil (1:1) based
`Sesame seed oil based
`Arachis oil based
`
`(‘"‘)Complete Vehicle Formulations comprised ethanol [96%](10%), benzyl
`alcohol (10%) and benzyl benzoate (15%) made to volume with the stated
`oil. Excess fulvestrant was added to each solvent mixture and solubility
`determined.
`
`10
`
`15
`
`20
`
`25
`
`Effect of formulation on precipitation of fulvestrant at the
`injection site
`
`9
`It would be expected that ethanol will dissipate at least as
`quickly, if not more rapidly, from the injection site.
`It is known that benzyl benzoate is metabolised by conju-
`gation to glycine to form hippuric acid by the human liver and
`excreted into the urine—Martindale: The Extra Pharmaco-
`
`poeia 32'” edition page 1 103, and, therefore, it is unlikely that
`benzyl benzoate, when used, is present at the injection site
`during the whole of the extended release period.
`We have found that despite the rapid elimination of the
`additional solubilising excipients, i.e. the alcohol and phar-
`maceutically-acceptable non-aqueous ester solvent, from the
`formulation vehicle and the site of injection after injection of
`the formulation, extended release at therapeutically signifi-
`cant levels of fillvestrant over an extended period can still
`achieved by the formulation of the invention.
`By use of the term “therapeutically significant levels” we
`mean that blood plasma concentrations of at least 2.5 ngml‘1,
`ideally at least 3 ngml‘1, at least 8.5 ngml‘1, a11d up to 12
`ngml"l of fulvestrant are achieved in the patient. Preferably
`blood plasma levels should be less than 15 ngm1‘1.
`By use ofthe term “extended release” we mean at least two
`weeks, at least three weeks, and, preferably at least four
`weeks of continuous release of fulvestrant is achieved. In a
`
`preferred feature extended release is achieved for 36 days.
`Preferably extended release of fulvestrant is for at least 2-5
`weeks and more preferably for the following periods (weeks)
`2.5-5, 2.5-4, 3-4, 3.5-4 and most preferably for at least about
`4 weeks.
`
`It will be understood that the attendant physician may wish
`to administer the intramuscular injection as a divided dose,
`i.e. a 5 ml formulation is sequentially administered in two
`separate injections of 2.5 ml, this i