`on
`co
`42-~
`co
`
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`
`U.S. PTO
`12/285887
`
`10I15l2008
`
`.._.——'—
`_—-——'
`fl—fl
`flan—'—
`5_—A_—-
`PTO/$3105 (08-08)
`._._—"""
`O—b
`Approved for use through 06/30/2010. OMB 0651-0032
`_._..—-
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`U.S. Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
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`0'1
`uired to resond to a collection of information unless it disla s a valid OMB control number.
`
`0
`O)
`
`
`
`
`
`
`— C
`
`ADDRESS TO:
`
`ommissioner for Patents
`PO. Box 1450
`Alexandria VA 22313-1450
`
`UTILITY
`
`
`
`i
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`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 12 minutes to
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`
`InnoPharma Exhibit 1042.0001
`
`
`
`I
`
`Z70635
`
`a
`
`_
`
`‘
`
`-1-
`
`FORMULATION
`
`The invention relates to a novel sustained release pharmaceutical formulation adapted
`
`for administration by injection containing the compound
`‘
`, 5 7a-[9-(4,4,5;5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17B-diol, more
`particularly to a formulation adapted for administration by injection containing the compound
`70t-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17|3-diol in
`solution in a ricinoleate vehicle which additionally comprises at least one alcohol and a non- ~
`
`10
`
`i
`‘ aqueous ester solvent which is miscible in the ricinoleate vehicle. ‘
`IOestrogen 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 surgical, radiotherapeutic; or medical means, and, in
`postmenopausal-womemby the use
`aromataserinhibitors.
`‘
`W
`7
`H
`i
`n
`An alternative approach to oestrogen withdrawal is to antagonise oestrogens with
`15 , antioestrogens. These are drugs that bind to and compete for oestrogen receptors (ER) present
`in the nuclei of oestrogen-responsive tissue. Conventional nonsteroidal antioestrogenspsuch
`
`as tamoxifen, compete efficiently 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‘).
`V
`-
`i
`The potential for nonsteroidal antioestrogens to display agonistic properties prompted 7
`the search for novel compounds that would bind ER with
`affinity without 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 eliciting complete ablation of the trophic effects cf oestrogens. Such r
`
`20
`
`'
`
`25 compounds are referred to as Estrogen Receptor—DomegulatOrs (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, 19900. Wakeling and Bowler 1987, 1988.
`
`I
`
`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 a1 1989).
`
`30 One of these, 7a-[9-(4,4,5,5,5-pentafluoroperityl sulphinyl)nonyl]oestra-l,3,5-(10)triene-
`
`3,17B-diol was selected for intensive study on the basis of its pure oestrogen antagonist
`
`activity and significantly increased antioestrogenic potency over other available
`
`InnoPharma Exhibit 1042.0002
`
`
`
`Z70635
`
`F
`\.._ I
`
`'
`
`m ‘
`
`antioestrogens. In vitro findings and early clinical experience with
`
`-2-
`
`7a-[9—(4,4,S,S ,5-pentafluoropentylsulphinyl)nonyl]oestra-l,3-5(lO)—triene-3,17B-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 gynaecological conditiOns.
`70L-[9-(4,4,S,5,S-Pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(l 0)-triene-3,1 7 B-diol,
`
`or ICI 182,780, has been allocated the international non-proprietary namefiilvestrant, 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
`an affinity similar to that of oestradiol and completely
`
`10
`
`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 uterotr0phic action of oestradiol in rats, mice and monkeys, and also blocks the
`
`7‘ uterotrophic activity of tamoirifen.
`
`' Because fulvestant has none of the oestrogen-like stimulatory activity that is
`
`characteristic of clinically available antioestrogenssuch as tamoxifen or. toremifene, it may
`
`offer improved therapeutic activity characterised by more rapid, complete, or longer-lasting
`
`tumour regression; a IOWer incidence or ratevof development of resistance to treatment; and a
`reduction of tumour invasiveness.
`V
`I
`r
`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
`
`15
`
`20
`
`also true in humans, these findings could be of extreme importance clinically. Reduced bone
`
`density limits the duration of oestrogen-ablative treatment for endOmetriosis. Fulvestrant does
`
`. not block hypothalamic ER. Oestrogen ablation also causes. or eitacerbates hot flushes and
`
`rother menopausal symptoms; fulvestrant will not cause such effects because it does not cross
`
`25
`
`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 Eirample 35
`of the compound 7a-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)n0nyl]oestra-
`.
`l,3,5(lO)-triene-3,l713-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\
`
`30
`
`pharmaceutical composition comprising a steroid derivative of the invention together with a
`
`InnoPharma Exhibit 1042.0003
`
`
`
`270635
`
`r
`
`i
`
`,
`
`ix’
`
`-3-
`
`pharmaceutically-acceptable diluent or carrier. It is stated therein that the composition can be
`in a form suitable for oral or parenteral administration.
`-
`i
`Fulvestrant shows, along with other steroidal based compounds, certain physical
`
`5
`
`prOperties which make formulation of these compounds difficult. Fulvestrant is a particularly
`lipOphilic molecule, even when compared with other steroidal compounds, and its aqueous
`solubility is extremely low at around 10 ngml‘l (this is an estimate from a water/solvent
`
`tnixturesolute since measurements this low could not be achieved in a water only solute).
`Currently there are a number of sustained release injectable steroidal formulations
`
`which have been commercialised. Commonly these formulations use oil as a solvent and
`10’ wherein additional excipients may be present. Below in 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 excipientssuch as benayl benzoate, benzyl alcohol—and ethanol have
`
`been used. Volumes of oil needed to solubilise the steroid active ingredient are low. Extended
`
`15
`
`release is achievable for periods fiom l to 8 Weeks.
`
`20
`
`-25
`
`InnoPharma Exhibit 1042.0004
`
`
`
`270635
`
`Table 1 - OIL BASED LONG—ACTING INTRAMUSCULAR INJECTIONS
`
`PRODUCT NAME
`
`STEROID
`
`99.3.5.
`
`TYPE
`
`COMP’..
`
`SOURCE '
`
`QLL
`
`52.1.31
`
`BzOfl
`
`EIQHDQSEDSNG
`
`SUSTANON 100
`
`PROLUTON
`DEPOT
`
`TOCOGESTAN
`
`iTROPHOBOLENE
`
`NORISTERAT
`
`BENZO-
`GYNOESTRYL
`PROGESTERONE
`~RETARD
`'
`GRAVIBINAN
`
`Testosterone proprionate
`Testosterone
`
`phenylproprionate
`Testosterone isocaproate ‘
`Testosterone deeanoatc
`
`Hydroxy progesterone
`hexanoate
`
`Hydroxy progesterone
`enantate
`
`Progesterone
`a-Tocopherol
`Estraprpnieate
`Nandrolone undecanoate
`
`Hydroxyprogesterone
`heptanoate
`Norethisterone
`oenanthoate
`
`Estradiol
`
`hexahydrobenzoate
`Hydroxy progesterone
`caproate
`
`Estradiol 17-B-valerate
`Hydroxyprogesterone
`' caproatc
`
`30mg
`
`Androgen
`
`Organon
`
`ABPI lData
`Sheet
`
`Comp. T999
`
`Araehis
`
`0.1ml
`
`lml
`
`3 weeks
`
`Progestogen
`
`Schering
`HC
`
`I Progestogen
`
`Theramax
`
`ABPI Data
`Sheet
`
`Comp. 1999
`Diet. Vidal
`1999
`"
`
`Castor
`
`Ethyl
`oleate
`
`up to
`46%
`
`*40%
`
`1 or
`2ml
`
`1 week
`
`2ml
`
`.
`
`< lweek
`
`Mixed
`
`Theramax
`
`Dict. Vidal
`1997
`'
`
`Olive
`
`45%
`
`lml
`
`15 to 30 '
`days
`
`Contraceptive
`
`Sehering ~
`HC
`
`ABPl Data
`Sheet
`
`Castor
`
`YES
`
`lml
`
`8 weeks
`
`5mg
`
`Estradiol
`
`Rdussel
`
`.250mgml'l
`
`Progestogen
`
`Pharlon,
`
`5mgml"
`250mgml"
`
`Mixed
`
`Sehering’ ‘
`HC
`
`Comp. 1999
`Diet. Vidal
`1998
`i
`Diet. Vidal
`1999 ,
`Diet. Vidal
`[99S
`
`. Araehis
`
`Castor
`
`‘ YES
`
`Castor
`
`YES
`
`lml
`
`1 week
`
`I or
`2ml
`l or
`2m]
`
`1 week
`
`1 ‘- 2
`weeks
`
`InnoPharma Exhibit 1042.0005
`
`
`
`270635
`
`PARABOLAN
`
`Trenbolone
`
`DELESTROGEN
`
`Estradiol
`valeratc
`
`76mg Androgeri
`
`20mgml"
`40mg1'nl'I
`
`Estradiolr
`
`Negina
`
`BMS
`
`DELALUTIN
`
`l7-Hydroxy
`progesterone
`
`250mgml"
`
`Progestrogen
`
`DMS
`
`Diet. Vidal
`1997 '
`
`'
`
`Arachis
`
`'
`
`75mg
`
`45mg
`
`l.5ml
`
`2weeks
`
`Castor
`
`78%
`58%
`
`‘
`
`20%
`40%
`
`2%
`2%
`
`Castor
`
`YES
`
`YES
`
`up to
`2%
`
`JTPhan'ln.
`Sci
`
`(1964):
`53(8) 891
`J.Pharrit.
`
`Sci.(l9o4)
`53(8) 891
`
`. EtOH = ethanol DiCt. Vidal = Dictionnaire Vidal
`3232 == benzylbenzoate BzOH = benzylalcohol
`5 ~ % are w/v and " approximate as measured directly from a Single sample
`
`InnoPharma Exhibit 1042.0006
`
`
`
`Z7Qs35
`
`~
`
`I
`
`i
`
`-6-
`
`described which comprises 50mg of fulvestIant,‘400mg of b‘enzyl 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 US 5,l83,814 willbe complicated by the high alcohol
`concentration. Therefore, there is a need to lower the aloohol concentration in fulvestxant
`
`formulations whilst-preventing precipitation of fillvestrant from the formulation.
`
`Table 2 shows the solubility of fulvestrant in a number of different solvents.
`
`Table 2 - SOLUBILITY OF FULVESTRANT
`
`7
`
`I
`
`SOLVENT
`
`Water ‘
`
`A‘mehié' oil '
`
`Sesameoi]
`Castor oil
`Miglyol 810
`
`Migly01812
`
`Ethyl oleate 4
`
`Benzyl benzoate
`
`Isopropyl myristate
`
`Span 85 (surfactant)
`Ethanol
`‘
`
`' Benzyl Alcohol
`
`10
`
`SOLUBILITY
`
`(mgml-f at 25°C)
`
`0.001
`
`0.45
`
`-
`
`0.58
`20
`3.06
`
`2.72
`
`1.25 A
`
`6. 1 5
`
`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 hydroxylgroups of ricinoleic acid, which is the major
`
`I' constituent of the fatty acids within the triglycerides present in'castor oil - see (Riffldn et.a1. J.
`
`15
`
`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
`
`InnoPharma Exhibit 1042.000?
`
`
`
`Z7os35
`
`:
`
`’ I
`
`-7-
`
`significant release rate. To achieve a therapeutically significant release rate the amount of '
`
`fulvestrant needed wouldrequire 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.
`
`_ 5
`
`Currently guidelines recommend that no more than 5mls of liquid is injected
`intramuscularly in a single injection. Phannacologically active doses required for a 1 month
`
`long acting depot formulation of fulvestrant is around 250mg. Therefore, when dissolved in
`
`just castor oil, fulvestrant would need to be administered in at least 10ml of castor oil.
`
`The addition of organic solvents in, which fulvestrant is freely soluble, and which are
`
`10 miScible with castor oil, may be used, such as an alcohol. With the addition of high
`
`concentrations of analcohol concentrations of >50mgml",of fulvestrant in a castor oil
`
`below.
`formulation is achievable, thereby giving an injection volumes of <5ml - see Table
`-We have surpriSingly found that the introduction of anon-aqueous ester solvent which is
`miscible in the castor oil and an alcohol surprisingly eases the solubilisation of fulvestrant into
`
`15
`
`'
`
`a concentration of at least 50 mgrnl'I - 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 fulvestrant in an alcohol. The solubility of fiilvestrant is also lower
`- in non-aqueous ester solvents than is the solubility offulvestrant in castor oil.
`Therefore, we present as a feature of the invention a pharmaceutical formulation 7
`20 comprising fulvestrant (preferany fulvestrant is present'at 3-1’0%w/v, 4-9%w/v, 4-8%w/v,
`I4-7%'w/v, 4-6%W/v and most preferably at about 5%w/v) in a ricinoleate vehicle, a
`r
`' phannaceutically acceptable non-aqueous ester solvent, and a pharmaceutically acceptable
`alcohol wherein the fonnulation 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 formulation comprising
`fulvestrant in which the formulation is adapted for intra-muscular injection into a human and
`
`25
`
`which is capable after injection of attaining a therapeutically significant blood plasma
`fulvestrant concentration for at least 2 weeks.
`i
`.
`
`Further features of the invention include a pharmaceutical formulation adapted for
`
`30 intra-muscular injection comprising fulvestrant, 30% or less weight of a pharmaceutically-
`
`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
`
`InnoPharma Exhibit 1042.0008
`
`
`
`270635
`
`-
`
`(M7P-‘r
`
`J
`
`-3-
`
`formulation and a sufficient amount ofa ricinoleate vehicle so as to prepare a formulation
`
`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; 35% (preferably 30% and ideally 25%) or less
`
`5
`
`weight of a phannaceutically-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 of formulation and a sufficient
`
`amount of a ricinoleate vehicle so as to prepare a formulation of at least 45mgml" of
`fiilvestrant.
`V
`i
`i
`
`10
`
`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
`formulationa‘ certain percentage ofthe-constitu-entby wei will be present, fer—example a.
`
`1% weight per volume formulation will contain within a 100ml volume of formulation 1 g of
`IS the constituent. By way of further illustration
`
`
`
`Preferred pharmaceutical formulations of the invention are as described above
`
`wherein:
`
`20
`
`l.
`The total volume of the formulation is 6m], or less, and the concentration of
`fulvestrant is at least 45mgrnl“ .
`'
`
`2.
`
`The total amount of fulvestrant in the formulation is 250mg, or more, and the total
`
`volume of the formulation is 6ml, or less.
`3.
`The total amount of fiilvestrant in the formulation is 250mg and the total volume of
`
`25
`
`the formulation is 5-5.25ml.
`
`InnoPharma Exhibit 1042.0009
`
`
`
`z70i535
`
`it
`
`‘
`
`-
`
`'1
`
`‘
`
`-9-
`
`It is appreciated that in the formulation an excess of formulation may be included to
`allow the attendant physician or care giver to be able to deliver the required dose. Therefore,
`when a 5ml dose is required it would be appreciated that an excess of up to 0.25ml, preferably
`
`up to 0.151111 will also be present in thefonnulation. Typically the formulation will be
`5 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 of the invention.
`
`I
`
`_ Preferred concentrations of a pharmaceutically-acceptable alcohol present in any of the
`- above'forrnulations are; at least 3%w/v, at-least 5%w/v, at least 7%w/v, at least 10% w/v, at i
`V
`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,
`10 preferably, at least 16% w/v. Preferred maximal concentrations of phannaceutically-
`aCceptable 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 al‘cOhol present in any of the
`aboveiformtilationsare’ selected 'fi‘om any
`or maximum-value described above and _
`preferably are; 3-35%w/v, 4-35%w/v, 5_-3S%w/v, $-32%w/v, 7-32%w/v, lO—30%w/v, 12-
`,15 28%w/v, 15-25%w/v, 17—23%w/v, 18-22%w/v and ideally 19—21%w/v. V
`I
`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—
`
`‘
`
`acceptable alcohols for parenteral administration are ethanol, benzyl alcohol or a mixture of
`both ethanol and benzyl alcohol, preferably the ethanol and benzyl alcohol are present in the l
`20 ' formulation in the same W/v amounts. Preferably the formulation alcohol contains 10% w/v
`. ethanol and 10% w/v benzyl alcohol.
`
`I The pharmaceutically-acceptable non-aqueous ester Solvent may consist of one or a
`mixture of two or more phannaceutically-acceptable non-aqueous ester solvents, preferably
`
`just one. A preferred phmmaceutically-acceptable non-aqueous ester solvent for parenteral
`
`25 administration is 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 50%
`
`30
`
`weight per volume of formulation.
`It will be understood by the skilled person that the pharmaceutically-acceptable
`alcohol will beof 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
`
`InnoPharma Exhibit 1042.0010
`
`
`
`270635
`
`.
`
`C
`
`-10-
`
`some water and possibly other organic solvents, for ex ample ethanol in the US Pharmacopeia
`contains nOt less than 94.9% by volume and not more than 96.0% by volume of ethanol vvhen
`
`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-acceptable 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 1 1% 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—acceptable non-aqueous ester solvent are; 60% w/v or
`less, 50%w/v or less, 45% w/v or less, 40% vv/v or less, 35% w/v or less, 30% w/v or less and
`
`10
`
`- 25% w/v or less. A preferred concentration is 15% w/v. Preferred ranges of pharmaceutically—
`
`acceptable nomaqueous ester solvent present in any of the above formulations are selected
`from any
`or maximum value described [above and preferably are; ‘5-60-%vvl/iv,x7-
`55%w/v, 8-50%w/v; 10-50%w/v, 10-45%{£r/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-
`"l 6%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—acceptab1e 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 phannacopoeias).
`
`. Preferred combinations of pharmaceutically-acceptable alcohol and pharmaceutically-
`
`acceptable non-aqueous ester solvent in the fonnulation are set out below:
`
`15
`
`20
`
`Pharmaceutically-acceptable
`
`Pharmaceutically—acceptable non-aqueous
`
`alcohol(%w/v)
`
`ester (%w/v)
`
`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
`
`InnoPharma Exhibit 1042.0011
`
`
`
`270635
`
`-11-'
`
`A 5-60, 7-55, 8-50, 10-50, 10-45, 10-40, 10-35, 10-
`
`
`ideally 14-16.
`
`30, 10-25, 12-25, 12-22, 12-20, 12-18, 13-17 and
`
`
`
` 3—35, 4435, 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 15%
`
`
`By the use of the' term ric‘iholeate vehicle‘we mean an oil which has‘as a proportion (at’
`least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% «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
`intra-muscular injection, satisfactory release of fulvestrant over an extended period of time.
`_ This finding is indeed surprising for the following reasons.
`Previously tested by the applicants have been intra-Irluscular injections of fulvestrant
`1.
`in the form of an aqueous suSpension. We have found eitensive local tissue irritation at the
`injection site as well as a poor release profile. It is believed that the tissue
`A
`
`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 fiilvestrant release
`
`rate was notsufficiently high to be clinically significant.
`
`2.
`
`Our findings fiom 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.
`
`10
`
`15
`
`20
`
`InnoPharma Exhibit 1042.0012
`
`
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`270635
`
`C
`
`-12-
`
`It is known that benzyl benzoate is metabolised by conjugation to glycine to fonn
`
`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 therapeutically significant levels of fulvestrant over an extended period can still
`achieved by the formulation of the invention.
`
`10
`
`15
`
`By use of the term “therapeutically significant levels” we mean that blood plasma
`concentrations of a: least 2.5 ngml'l,‘ideally at least 3 ngmr‘, at least 8.5 nng", and up to 12
`
`ngml'I of fulvestrant are achieved in the patient. Preferably blood plasma levels shouldlbe less
`than is figml-a.‘
`‘
`‘
`’
`’
`'
`‘
`'
`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- weeks and more preferably for the following periods (weeks)
`2.5-5, 2.5-4, 344, 3.5-4 and most preferably for at least abOut 4 weeks.
`V
`i
`It will be understood that the attendant physician may Wish to administer the
`
`20
`
`intramuscular injection as a divided dose, Le. a Sml formulation is sequentially administered
`
`in two separate injections of 2.51111, this is a further feature of the invention
`Simply solubilising fiilvestrant in an oil based liquid formulation is not predictive of a
`good release profile or lack ofprecipitation 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 show the positive effect ofbenzyl benzoate on fulvestrant solubility in castor oil,
`despite fulvestrant having a lower solubility in benzyl benzoate than in either. alcohol or castor
`
`oil.
`
`25
`
`30
`
`InnoPharma Exhibit 1042.0013
`
`
`
`270635
`
`Ethanol
`
`(96%)
`
`Benzyl
`
`Alcohol
`
`Benzyl
`
`Benzoaté
`
`Table 3 - EFFECT OF BENZYL BENZOATE ON FULVESTRANT SOLUBILITY IN CASTOR OIL AT 250C
`
`Table 3
`
`10
`
`% w/v
`
`10.
`
`'15
`
`15
`
`10
`
`10
`
`10
`
`10
`
`15
`
`15
`
`15
`
`.
`
`15
`
`15
`
`15'
`
`’m‘
`
`'
`
`\_
`
`Castor Oil
`
`to 100
`
`Fulvcstranl
`
`27
`
`to l 00
`
`36
`
`_to 100
`
`46
`
`to 100
`
`to 100
`
`to 100
`
`to 100
`
`to 100
`
`54
`
`45
`
`65
`
`76
`
`102
`
`Solubility
`
`[mgml'l 1
`
`InnoPharma Exhibit 1042.0014
`
`
`
`Z70635
`
`if; ‘
`
`V
`
`I
`
`g C,
`
`-14-
`
`The following Table 4 shows the solubility of fulvestrant in a range of oil based
`
`formulations which contain the same amounts of alcohol
`
`benzyl benzoate but in which the
`
`oil is changed. The data also shows solubility of fulvestrant afier removal of the alcohols.
`
`Table 4
`
`Solubility comparisons of fulvestrant in oil based formulations with and without
`alcohols
`‘
`4
`
`' F
`
`ulvestrant Solubility~ mg ml"l @ 25°C
`
`
`
`
`
` Formulation (a) Complete vehicle Vehicle minus alcohols
`
`caster oil based
`
`Miglyol 812-N based
`
`81.2
`
`86.8
`
`sesame seed/Castor on (1:1) based
`
`70.1
`
`_
`
`Sesame seed oilbased
`
`45.7
`
`12.6
`
`1.7
`
`4.4
`
`0.7
`
`IO
`
`15
`
`20
`
`< 0.2
`40.2
`V Arachis oil-based
`
`
`25
`
`(a) Complete Vehicle Formulations comprised ethanol [96%](10%), benzyl alcohol (10%) and benzyl benzoate
`(15%) made to volume with the stated oil. Excess fiilvestrant was added to each solvent mixture and solubility
`determined.
`
`Effect of formulation on precipitation of fulvestrant at the injection site
`
`30
`
`Formulation '
`
`Formulation Fl
`castor oil based
`
`35
`
`2
`
`0
`
`3
`
`0
`
`v
`
`Days
`
`4
`
`C
`
`'
`
`7
`
`0
`
`10'
`
`30 »
`
`5 1
`
`0
`
`0
`
`'
`
`0
`
`O
`
`+
`
`Formulation F2
`Miglyol 812-N based
`
`Fomafion F3
`sesame seed oil/castor
`oil based
`
`++ b
`
`+++
`
`+4-i-
`
`+++
`
`+4—l-
`
`++
`
`+ “
`
`++
`
`4+
`
`-H-+
`
`++
`
`' +
`'
`
`,40
`
`45
`
`0, + , ++, +++ = Degree of precipitation (None detected, Mild, Moderate, Severe)
`a Formulations comprised fillvestrant (5%), ethanol [96%] (10%), benzyl alcohol (10%) and benzyl benzoate
`(15%) made to volume with the stated oil.
`" Mainly large needle shaped crystals
`° Small needles and/or sheafs of crystals'
`
`InnoPharma Exhibit 1042.0015
`
`
`
`270635 -
`
`C;
`
`‘
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`_
`
`Precipitation of fulvestrant and the release profile was determined with the above
`formulations in an in vivo rabbit study.
`.
`
`’ Figure 1 shows the release profile in vivo of the four formulations from the second part
`
`V
`
`of Table 4 and shows the effect of the fixed oil component on fulvestrant-plasrna profile over
`
`five days following intramuscular administration in rabbits (data normalised to 50mg per 3kg;
`
`mean given; number of animals per timepoint = 8, plasma samples assayed for fulvestrant
`
`content using lc-ms/ms detection following solvent extraction). Ascan be seen the castor oil
`formulation showed a particularly even release profile ‘with no evidence of precipitation of
`fulvestrant at the injection site.
`
`.
`
`10
`
`Therefore we present‘as ‘a further feature of the invention an extended release
`
`pharmaceutical formulation adapted for intramuscular injection comprising fulvestrant; 35%
`(preferabl 30% or ideally 25%) or less wei
`t of a harrnaceutically-acceptable alcohol per
`3’
`P
`_
`volume of formulation, at least l% (preferably atleast 5% or ideally 10%) weight of a
`
`4
`
`15
`
`pharmaceutically-acceptable non-aqueous ester solvent miscible in a ricinoleate vehicle per
`volume of formulation and sufficient amount of a ricinoleate vehicle, taking into account the
`addition of any further optional pharmaceutically—acceptab1e excipients, so as to prepare a
`
`formulation of at least 45mgml“ of fulvestrant.
`
`A further feature of the invention is a pharmaceutical formulation adapted for
`intramuscular injection, as defined above, for use in medical therapy.
`V
`
`i
`
`20
`
`A further feature of the invention is a method of treating a benign or malignant
`
`_' diseases of the breast or reproductive tract, preferably treating breast cancer, by administration
`
`to a human inneed of such tI'eatrnent by intramuscular injection an extended release
`
`ricinoleate vehicle based pharmaceutical formulation comprising at least 45mgml" of‘
`
`fulvestrant; 35% (preferably 30% or ideally 25%) or less weight of a pharmaceutically-
`
`3 25
`
`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 in a
`
`ricinoleate vehicle per volume of formulation.
`
`I
`
`Preferably 5ml of the intramuscular injection is administered.
`
`A further feature of the invention is use of fulvestrant in the preparation of a
`pharmaceutical formulation as describe hereinabove, for the treatment of a ben