(12) United States Patent
`Evans et al.
`
`(54) FORMULATION
`
`(75)
`
`Inventors: John R Evans, Macclesfield (GB);
`Rosalind U Grundy, Macclesfield (GB)
`
`(73) Assignee: AstraZeneca AB, Sodertalje (SE)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/756,291
`
`(22) Filed:
`
`Jan. 9, 2001
`
`(65)
`
`Prior Publication Data
`
`US 2001/0020016 Al Sep. 6, 2001
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 10, 2000
`Apr. 12, 2000
`
`(GB) ............................................. 0000313
`(GB) ............................................. 0008837
`
`Int. Cl.7 ................................................ A61K 31/56
`(51)
`(52) U.S. Cl. ........................................ 514/177; 514/178
`(58) Field of Search .................................. 514/177, 178
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
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`12/1989 Elger et al.
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`3/1992 Ottow et al.
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`2/1993 Dukes
`1/1996 Al-Razzak et al.
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`5,733,902 A
`3/1998 Schneider
`7/1999 Hamied et al.
`5,929,030 A
`
`FOREIGN PATENT DOCUMENTS
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006774122B2
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,774,122 B2
`Aug. 10, 2004
`
`EP
`FR
`GB
`GB
`GB
`GB
`SU
`SU
`WO
`WO
`WO
`WO
`WO
`WO
`ZA
`ZA
`
`0 346 014
`6241
`817241
`1 126 892
`1 207 571
`1 569 286
`549118
`676284
`WO 95/12383
`WO 96/19997
`WO 97/21440
`WO 97/37653
`WO 97/40823
`WO 98/11902
`681014
`682530
`
`12/1989
`9/1968
`7/1959
`9/1968
`10/1970
`6/1980
`3/1977
`7/1979
`5/1995
`7/1996
`6/1997
`10/1997
`11/1997
`3/1998
`2/1968
`4/1968
`
`OTHER PUBLICATIONS
`
`Remington's Pharmaceutical Sciences, 18th ed., 1990, p.
`219.*
`
`(List continued on next page.)
`
`Primary Examiner---Sreeni Padmanabhan
`Assistant Examiner-San-ming Hui
`(74) Attorney, Agent, or Firm-Morgan, Lewis & Bockius
`LLP
`
`(57)
`
`ABSTRACT
`
`The invention relates to a novel sustained release pharma(cid:173)
`ceutical formulation adapted for administration by injection
`containing the compound 7a-[9-(4,4,5,5,5-
`pentafiuoropentylsulphiny l)nonyl ]oestra -1,3,5( 1 O)-triene-3,
`17~-diol, more particularly to a formulation adapted for
`administration by injection containing the compound 7a-[9-
`( 4,4,5 ,5,5-pentafiuoropentylsulphinyl)nony1 ]oestra-1,3,5
`(10)-triene-3,17~-diol in solution in a ricinoleate vehicle
`which additionally comprises at least one alcohol and a
`non-aqueous ester solvent which is miscible in the ricino(cid:173)
`leate vehicle.
`
`EP
`
`0 138 504
`
`4/1985
`
`9 Claims, 1 Drawing Sheet
`
`I
`
`, ....
`I : ~.
`t
`.. , ..
`
`.. ,
`
`'
`
`'
`
`............
`
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`
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`... ....... .....
`
`~
`-.,
`'',
`'', ..
`.....•..... :::-. -:-. ., ~ .... ~:..: ·• :: .:: .::_· ._ ....
`
`-+-F1 Formulation F (Cutor ollj
`- -4- - F2 Mlglyol 812·N
`•• ·• • · F3 Ca1torlS.aam• oll 1:1
`
`-~.:.:.:.····
`
`40
`
`I 30
`
`.s.
`
`~ 10
`
`I
`I
`I
`I
`
`I
`
`", :•
`
`.. a. e -:; 20
`:
`: .. ~...
`i l; •.
`I
`,
`•!
`: !
`::
`•!
`
`0.5
`
`1.5
`
`2.5
`Time(d)
`
`3.5
`
`4
`
`4.5
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 1
`
`

`
`US 6,774,122 B2
`Page 2
`
`OIBER PUBLICATIONS
`
`Davis et al., "17-Alpha-Hydroxyprogesterone-Caproate ...
`with Chemically Pure Progesterone", J. Clin. Endocrinol.
`And Metabolism, 1955, vol. 15, pp. 923-930.
`Dukes et al., "Antiuterotrophic effects of the pure antioestro(cid:173)
`gen ICI 182, 780 ... quantitative magnetic resonance
`imaging"; J. Endocrinology, 1992, vol. 138, pp. 203-209.
`Dukes et al., "Antiuterotrophic effects of pure antioestrogen.
`ICI 182,780 ... the uterus in ovariectromized monkeys", J.
`Endocrinology, 1992, vol. 135, pp. 239-247.
`Howell et al., "Pharmacokinetics, pharmacological and anti(cid:173)
`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.
`Martindale, 32nd Ed., "Alcohol", Pharmaceutical Press,
`1999, pp. 1099-1101.
`Martindale, 32nd Ed., "Benzoates" and "Benzyl Alcohol";
`Pharmaceutical Press, 1999, pp. 1102-1104.
`Martindale, 32nd Ed., "Caster Oil"; 32nd Ed., Pharmaceu(cid:173)
`tical Press, 1999, p. 1560.
`Migally, "Effect of Castor Oil and Benzyl Benzoate Used as
`a Vehicle for Antiandrogens on the Adrenal Cortex",
`Archives of Andrology 2, 1979 pp. 365-369.
`Pellegrino, "Use of 17 a Hydroxyprogesterone Caproate in
`Threatened 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 Adenocarci(cid:173)
`noma", Cancer, vol. 45, American Cancer Society, 1980, pp.
`268-272.
`Riffkin et al., "Castor Oil as a Vehicle for Parenteral Admin(cid:173)
`istration of Steroid Hormones", Journal of Pharmaceutical
`Sciences, vol. 53, No. 8, Aug. 1964, pp. 891-895.
`Sawada et al., "Estrogen Receptor Antagonist ICII82,780
`Exacerbates Ischemic Injury in Female Mouse", Journal of
`Cerebral Blood Flow and Metabolism, vol. 20. No. 1, 2000,
`pp. 112-118.
`
`Vidal, Le Dictionnaire, "Benzo-Dynoestryl Retard", 1998 p.
`201.
`
`Vidal, Le Dictionnaire, "Gravibinan", 1995, pp 660--661.
`
`Vidal, Le Dictionnaire, "Parabolan", 1997, p. 1245.
`
`Vidal, Le Dictionnaire,
`1706-1707.
`
`"Trophobolene", 1997, pp.
`
`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 Antiestrogen, ICI
`182,780"; Laboratory Animal Science, 1993, vol. 43, No. 3,
`1993, pp. 247-251.
`
`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 Ste(cid:173)
`roidal 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, Multi(cid:173)
`centre Study Comparing The Anti-Tumor Effects of Single
`Doses (50, 125 and 250MG) of Long-Acting (LA) 'Faslo(cid:173)
`dex' (ICI 182,780 With Tamoxifin in Postmenopausal
`Women with Primary Breast Cancer Prior to Surgery";
`Abstract 28, 22nd Annual San Antonio Breast Cancer Sym(cid:173)
`posium: Dec. 8-11, 1999, San Antonio, Breast Cancer
`Research and Treatment 1999; 57 (1; special issue); p. 31.
`
`Mackey et al, "Tolerability of intramuscular injections of
`testosterone ester in oil vehicle", Human Reproduction, vol.
`10, No. 4, pp., 869-865, 1995.
`
`* cited by examiner
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 2
`
`

`
`U.S. Patent
`
`Aug. 10, 2004
`
`US 6,774,122 B2
`
`z
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`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 3
`
`

`
`US 6,774,122 B2
`
`1
`FORMULATION
`
`The invention relates to a novel sustained release phar(cid:173)
`maceutical formulation adapted for administration by injec(cid:173)
`tion containing the compound 7 a-[9-( 4,4,5,5,5-
`pentafiuoropenty lsulphiny l)nony 1 ]oestra -1,3,5( 1 O)-triene-3,
`17~-diol, more particularly to a formulation adapted for
`administration by injection containing the compound 7a-[9-
`( 4,4,5 ,5,5-pentafiuoropentylsulphinyl)nony1 ]oestra-1,3,5
`(10)-triene-3,17~-diol in solution in a ricinoleate vehicle
`which additionally comprises at least one alcohol and a
`non-aqueous ester solvent which is miscible in the ricino(cid:173)
`leate vehicle.
`Oestrogen deprivation is fundamental to the treatment of
`many benign and malignant diseases of the breast and
`reproductive tract. In premenopausal women, this is
`achieved by the ablation of ovarian function through 20
`surgical, radiotherapeutic, or medical means, and, in post(cid:173)
`menopausal 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) 25
`present in the nuclei of oestrogen-responsive tissue. Con(cid:173)
`ventional nonsteroidal antioestrogens, such as tamoxifen,
`compete efficiently for ER binding but their effectiveness is
`often limited by the partial agonism they display, which 30
`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(cid:173)
`pounds that would bind ER with high affinity without 35
`activating any of the normal transcriptional hormone
`responses and consequent manifestations of oestrogens.
`Such molecules would be "pure" antioestrogens, clearly
`distinguished from tamoxifen-like ligands and capable of 40
`eliciting complete ablation of the trophic effects of oestro(cid:173)
`gens. Such compounds are referred to as Estrogen Receptor(cid:173)
`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 45
`and Bowler 1987, 1988.
`Steroidal analogues of oestradiol, with an alkylsulphinyl
`side chain in the 7a position, provided the first examples of
`compounds devoid of oestrogenic activity (Bowler et al 50
`1989). One of these, 7a-[9-(4,4,5,5,5-pentafiuoropentyl
`sulphinyl)nonyl ]oestra-l,3,5-(lO)triene-3,17~-diol was
`selected for intensive study on the basis of its pure oestrogen
`antagonist activity and significantly increased antioestro(cid:173)
`genic potency over other available antioestrogens. In vitro
`findings and early clinical experience with 7a-[9-( 4,4,5,5,
`5-pen tafi uoropenty lsulp hin y 1)nony1 ]oes tra-1,3-5( 1 O)(cid:173)
`triene-3,17~-diol have promoted interest in the development
`of the drug as a therapeutic agent for oestrogen-dependent
`indications such as breast cancer and certain benign gynae(cid:173)
`cological conditions.
`7 a-[ 9-( 4,4,5 ,5 ,5-Pentafi uoropen ty lsulphin y l)nony 1]
`oestra-1,3-5(10)-triene-3,17~-diol, or ICI 182,780, has been
`allocated the international non-proprietary name fulvestrant,
`which is used hereinafter. When referring to fulvestrant we
`
`55
`
`2
`include pharmaceutically-acceptable salts thereof and any
`possible solvates of either thereof.
`Fulvestrant binds to ER with an affinity 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 in this
`respect. Fulvestrant blocks completely the uterotrophic
`action of oestradiol in rats, mice and monkeys, and also
`10 blocks the uterotrophic activity of tamoxifen.
`Because fulvestrant has none of the oestrogen-like stimu(cid:173)
`latory activity that is characteristic of clinically available
`antioestrogens such as tamoxifen or toremifene, it may offer
`15 improved therapeutic activity characterised by more rapid,
`complete, or longer-lasting tumour regression; a lower inci(cid:173)
`dence or rate of development of resistance to treatment; and
`a reduction of tumour invasiveness.
`In intact adult rats, fulvestrant achieves maximum
`regression 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 of
`extreme importance clinically. Reduced bone density limits
`the duration of oestrogen-ablative treatment for endometrio(cid:173)
`sis. 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 of the steroid derivatives. In particular there is
`the disclosure within Example 35 of the compound 7a-[9-
`( 4,4,5 ,5,5-pentafiuoropentylsulphinyl)nony1 ]oestra-1,3,5
`(10)-triene-3,17~-diol, which compound is specifically
`named in claim 4. It is also disclosed that the compounds of
`that invention may be provided for use in the form of a
`pharmaceutical composition comprising a steroid derivative
`of the invention together with a pharmaceutically-acceptable
`diluent or carrier. 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
`compounds, certain physical properties which make formu(cid:173)
`lation of these compounds difficult. Fulvestrant is a particu-
`larly lipophilic molecule, even when compared with other
`steroidal compounds, and its aqueous solubility is extremely
`low at around 10 ngml- 1 (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 inject-
`able steroidal formulations which have been commercial(cid:173)
`ised. Commonly these formulations use oil as a solvent and
`wherein additional excipients may be present. Below in
`60 Table 1 are described a few commercialised sustained
`release 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
`65 ethanol have been used. Volumes of oil needed to solubilise
`the steroid active ingredient are low. Extended release is
`achievable for periods from 1 to 8 weeks.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 4
`
`

`
`US 6,774,122 B2
`
`4
`
`3
`
`TABLE 1
`
`OIL BASED LONG-ACTING INTRAMUSCULAR INJECTIONS
`
`PRODUCT NAME STEROID
`
`DOSE
`
`TYPE
`
`COMP'.
`
`SUSTANON 100
`
`PRO LUTON
`DEPOT
`TOCOGESTAN
`
`NORISTERAT
`
`Testosterone proprionate
`Testosterone
`phenylproprionate
`Testosterone isocaproate
`Testosterone decanoate
`Hydroxy progesterone
`hexanoate
`Hydroxy progesterone
`enantate
`Progesterone
`a-Tocopherol
`TROPHOBOLENE Estrapronicate
`Nandrolone undecanoate
`Hydroxyprogesterone
`heptanoate
`Norethisterone
`oenanthoate
`BENZO-
`Estradiol
`hexahydrobenzoate
`GYNOESTRYL
`PROGESTERONE- Hydroxy progesterone
`RETARD
`ca pro ate
`Estradiol 17-1)-valerate
`GRAVIBINAN
`Hydroxyprogesterone
`ca pro ate
`Trenbolone
`Estradiol
`vale rate
`17-Hydroxy
`progesterone
`
`PARABOLAN
`DELESTROGEN
`
`DELALUTIN
`
`30 mg
`60 mg
`
`Androgen
`
`Organ on
`
`60 mg
`100 mg
`250 mgml-1 Progestogen
`
`200 mg
`
`Progestogen
`
`Sc he ring
`HC
`Theramax
`
`50 mg
`250 mg
`1.3 mg
`50 mg
`80 mg
`
`Mixed
`
`Theramax
`
`200 mg
`
`Contraceptive
`
`mg
`
`Estradiol
`
`Sc he ring
`HC
`Roussel
`
`250 mgml-1 Progestogen
`
`Pharlon
`
`mgml-1 Mixed
`250 mgml-1
`
`Sc he ring
`HC
`
`Androgen
`76 mg
`20 mgml-1 Estradiol
`40 mgml-1
`250 mgm1-1 Progestrogen
`
`Negma
`EMS
`
`OMS
`
`PRODUCT NAME SOURCE
`
`OIL
`
`BzBz
`
`BzOH
`
`EtOH
`
`DOSE
`
`DOSING
`
`SUSTANON 100
`
`PRO LUTON
`DEPOT
`
`TOCOGESTAN
`
`NORISTERAT
`
`PARABOLAN
`
`DELESTROGEN
`
`Castor
`
`Ethyl
`oleate
`Olive
`
`Castor
`
`Arachis
`
`Castor
`
`Castor
`
`Arachis
`
`Castor
`
`ABPI Data Arachis
`Sheet
`Comp. 1999
`ABPI Data
`Sheet
`Comp. 1999
`Diet. Vidal
`1999
`TROPHOBOLENE Diet. Vidal
`1997
`ABPI Data
`Sheet
`Comp. 1999
`BENZO-
`Diet. Vidal
`1998
`GYNOESTRYL
`PROGESTERONE Diet. Vidal
`-RETARD
`1999
`GRAVIBINAN
`Diet. Vidal
`1995
`Diet. Vidal
`1997
`J.Pharm
`Sci
`(1964)
`53(8) 891
`J.Pharm.
`Sci.(1964)
`53(8) 891
`
`0.1 ml
`
`1 ml
`
`3 weeks
`
`1 or
`2ml
`
`1 week
`
`2ml
`
`<1 week
`
`1 ml
`
`1 ml
`
`15 to 30
`days
`8 weeks
`
`1 ml
`
`1 week
`
`1 or
`2ml
`1 or
`2ml
`1.5 ml
`
`1 week
`
`1-2
`weeks
`2 weeks
`
`up to
`46%
`
`*40%
`
`45%
`
`YES
`
`YES
`
`YES
`
`75 mg
`
`45 mg
`
`78%
`58%
`
`20%
`40%
`
`2%
`2%
`
`YES
`
`YES
`
`up to
`2%
`
`DELALUTIN
`
`Castor
`
`BzBz ~ benzylbenzoate
`BzOH ~ benzylalcohol
`EtOH ~ ethanol
`Diet. Vidal ~ Dictionnaire Vidal
`% are w/v and * approximate as measured directly from a single sample
`
`60
`
`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 65
`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(cid:173)
`trant from the formulation.
`
`Table 2 shows the solubility of fulvestrant in a number of
`different solvents.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 5
`
`

`
`US 6,774,122 B2
`
`5
`
`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
`(mgml- 1 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
`solvating ability of castor oil for steroidal compounds is
`known and is attributed to the high number of hydroxy
`groups of ricinoleic 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,
`castor 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
`injection and achieve a therapeutically significant release
`rate. To achieve a therapeutically significant release rate the 30
`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.
`Therefore, when dissolved in just castor oil, fulvestrant 40
`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 miscible with castor oil, may
`be used, such as an alcohol. With the addition of high
`concentrations of an alcohol concentrations of >50 mgml- 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 non-aqueous ester solvent which is miscible in the castor
`oil and an alcohol surprisingly eases the solubilisation of 50
`fulvestrant into a concentration of at least 50 mgml- 1-see
`Table 3 below. The finding is surprising since the solubility
`of fulvestrant in non-aqueous ester solvents-see Table 2
`above-is significantly lower than the solubility of fulves(cid:173)
`trant in an alcohol. The solubility of fulvestrant is also lower 55
`in non-aqueous ester solvents than is the solubility of
`fulvestrant in castor oil.
`Therefore, we present as a feature of the invention a
`pharmaceutical 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 and most preferably at
`about 5% w/v) in a ricinoleate vehicle, a pharmaceutically
`acceptable non-aqueous ester solvent, and a pharmaceuti(cid:173)
`cally acceptable alcohol wherein the formulation is adapted
`for intra-muscular administration and attaining a therapeu- 65
`tically significant blood plasma fulvestrant concentration for
`at least 2 weeks.
`
`6
`Another feature of the invention is a pharmaceutical
`formulation 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
`significant 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-
`10 acceptable alcohol per volume of formulation, at least 1 %
`weight of a pharmaceutically-acceptable non-aqueous ester
`solvent miscible in a ricinoleate vehicle per volume of
`formulation and a sufficient amount of a ricinoleate vehicle
`so as to prepare a formulation which is capable after
`injection of attaining a therapeutically significant blood
`15 plasma fulvestrant concentration for at least 2 weeks.
`Further features of the invention include a pharmaceutical
`formulation adapted for intra-muscular injection comprising
`fulvestrant; 35% (preferably 30% and ideally 25%) or less
`weight of a pharmaceutically-acceptable alcohol per volume
`20 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 vol(cid:173)
`ume of formulation and a sufficient amount of a ricinoleate
`vehicle so as to prepare a formulation of at least 45 mgml- 1
`25 of fulvestrant.
`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
`formulation a certain percentage of the constituent by weight
`will be present, for example a 1 % weight per volume
`formulation will contain within a 100 ml volume of formu(cid:173)
`lation 1 g of the constituent. By way of further illustration
`
`35
`
`% of x by weight per volume of
`formulation
`
`weight of x in 1 ml of formulation
`
`30%
`20%
`10%
`5%
`1%
`
`300 mg
`200 mg
`100 mg
`50 mg
`10 mg
`
`Preferred pharmaceutical formulations of the invention
`45 are as described above wherein:
`
`1. The total volume of the 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 of fulvestrant in the formulation is 250
`mg and the total volume of the formulation is 5-5.25 ml.
`
`It is appreciated that in the formulation an excess of
`formulation may be included to allow the attendant physi(cid:173)
`cian 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
`60 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 pre filled syringe, containing a unit dosage of the
`formulation as described herein, these being further features
`of the invention.
`Preferred concentrations of a pharmaceutically(cid:173)
`acceptable alcohol present in any of the above formulations
`are; at least 3% w/v, at least 5% w/v, at least 7% w/v, at least
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 6
`
`

`
`US 6,774,122 B2
`
`8
`Preferred combinations of pharmaceutically-acceptable
`alcohol and pharmaceutically-acceptable non-aqueous ester
`solvent in the formulation are set out below:
`
`Pharmaceutically-acceptable
`alcohol (% w/v)
`
`Pharmaceutically-acceptable non-aqueous
`ester (% w/v)
`
`10-30
`
`17-23
`
`5-60, 7-55, 8-50, 10-50, 10-45, 10-40,
`10-35, 10-30, 10-25, 12-25, 12-22,
`12-20, 12-18, 13-17 and ideally 14-16.
`5-60, 7-55, 8-50, 10-50, 10-45, 10-40,
`10-35, 10-30, 10-25, 12-25, 12-22,
`12-20, 12-18, 13-17 and ideally 14-16.
`10-35
`
`12-18
`
`7
`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-acceptable alcohol present in the formu(cid:173)
`lation are; 28% w/v or less, 22% w/v or less and 20% w/v
`or less. Preferred ranges of pharmaceutically-acceptable
`alcohol present in any of the above formulations are selected
`from any minimum or maximum 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, 10
`17-23% w/v, 18-22% w/v and ideally 19-21 % w/v.
`The pharmaceutically-acceptable alcohol may consist of
`one alcohol or a mixture of two or more alcohols, preferably
`a mixture of two alcohols. Preferred pharmaceutically(cid:173)
`acceptable alcohols for parenteral administration are 15
`ethanol, benzyl alcohol or a mixture of both ethanol and
`benzyl alcohol, preferably the ethanol and benzyl alcohol are
`present in the formulation in the same w/v amounts. Pref(cid:173)
`erably the formulation alcohol contains 10% w/v ethanol
`and 10% w/v benzyl alcohol.
`The pharmaceutically-acceptable non-aqueous ester sol(cid:173)
`vent may consist of one or a mixture of two or more
`pharmaceutically-acceptable non-aqueous ester solvents,
`preferably just one. A preferred pharmaceutically-acceptable
`non-aqueous ester solvent for parenteral administration is 25
`selected from benzyl benzoate, ethyl oleate, isopropyl
`myristate,isopropyl palmitate or a mixture of any thereof.
`The ricinoleate vehicle should preferably be present in the
`formulation in a proportion of at least 30% weight per
`volume of the formulation, ideally at least 40% or at least 30
`50% weight per volume of formulation.
`It will be understood by the skilled person that the
`pharmaceutically-acceptable alcohol will be of a quality
`such that it will meet pharmacopoeia! standards (such as are
`described in the US, British, European and Japanese 35
`pharmacopoeias) and as such will contain some water and
`possibly other organic solvents, for example ethanol in the
`US Pharmacopeia contains not less than 94.9% by volume
`and not more than 96.0% by volume of ethanol when
`measured at 15.56° C. Dehydrated alcohol in the US Phar- 40
`macopeia contains not less than 99.5% ethanol by volume
`when measured at 15.56° C.
`Preferred concentrations of the pharmaceutically(cid:173)
`acceptable non-aqueous ester solvent present in any of the
`above formulations are; at least 5% w/v, at least 8% w/v, at 45
`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 of the pharmaceutically(cid:173)
`acceptable non-aqueous ester solvent are; 60% w/v or less, 50
`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 and 25% w/v or less. A preferred
`concentration is 15% w/v. Preferred ranges of
`pharmaceutically-acceptable non-aqueous ester solvent
`present in any of the above formulations are selected from 55
`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% 60
`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
`pharmaceutically-acceptable non-aqueous ester solvent will
`be of a quality that it will meet pharmacopoeia! standards 65
`(such as described in the US, British, European and Japanese
`pharmacopoeias).
`
`3-35, 4-35, 5-35, 5-32,
`7-32, 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.
`benzyl benzoate, most preferably at about
`ethanol and benzyl alcohol,
`20 most preferably each at about 15%
`10%
`
`By the use of the term ricinoleate vehicle we mean an 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
`pharmacopoeia! standards, as described above.
`We have surprisingly found that the above formulations of
`the invention provide, after intra-muscular injection, satis(cid:173)
`factory release of fulvestrant over an extended period of
`time.
`This finding is indeed surprising for the following rea(cid:173)
`sons.
`
`1. Previously tested by the applicants have been intra(cid:173)
`muscular injections of fulvestrant 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 inflammation/irritation
`present at the injection site and this was variable and
`difficult to control. Also the fulvestrant release rate was
`not sufficiently high to be clinically significant.
`2. Our findings from studies using 14C labelled benzyl
`alcohol show that it dissipates rapidly from the injection
`site and is removed from the body within 24 hours of
`administration.
`
`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
`conjugation to glycine to form hippuric acid by the human
`liver and excreted into the urine-Martindale: The Extra
`Pharmacopoeia 32nd edition page 1103, 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
`pharmaceutically-acceptable non-aqueous ester solvent,
`from the formulation vehicle and the site of injection after
`injection of the formulation, extended release at therapeu(cid:173)
`tically significant levels of fulvestrant over an extended
`period can still achieved by the formulation of the invention.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 7
`
`

`
`US 6,774,122 B2
`
`10
`
`9
`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
`, and up
`to 12 ngml- 1 of fulvestrant are achieved in the patient.
`Preferably blood plasma levels should be less than 15
`ngml- 1
`.
`By use of the 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 15
`wish to administer the intra-muscular injection as a divided
`dose, i.e. a 5 ml formulation is sequentially administered in
`two separate injections of 2.5 ml, this is a further feature of
`the invention
`Simply solubilising fulvestrant in an oil based liquid 20
`formulation is not predictive of a good release profile or lack
`of precipitation of drug after injection at the injection site.
`Table 3 shows the solubility of fulvestrant in a castor oil
`vehicle additionally containing alcohols ethanol and benzyl
`alcohol with or without benzyl benzoate. The results clearly 25
`show the positive effect of benzyl benzoate on fulvestrant
`solubility in castor oil, despite fulvestrant having a lower
`solubility in benzyl benzoate than in either alcohol or castor
`oil.
`
`10
`
`TABLE 4-continued
`
`Effect of formulation on precipitation of fulvestrant at the injection site
`
`Days
`
`Formulation a
`
`2
`
`4
`
`7
`
`10
`
`30
`
`51
`
`Formulation Fl
`castor oil based
`Formulation F2
`Miglyol 812-N based
`Formulation F3
`sesame seed oil/castor
`oil