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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 1
`
`

`
`Z70635
`
`-1-
`
`FORMULATION
`
`The _invention relates to a novel sustained release pharmaceutical formulation adapted
`
`for administration by injection containing the compound
`‘7oc—[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(l0)-triene-3,1713-diol, more
`particularly to a formulation adapted for administration by injection containing the compound
`7oc-[9-(4,4,5 ,5,5-pentafluoropentylsulphinyl)nonyl]oestra- 1,3,5( l 0)-triene-3, 17B,-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 ricinoleate vehicle. »
`
`10
`
`Oestrogen deprivation is fimdamental 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’women,_by the use
`aromataseinhibitorsi
`V
`9
`i
`9
`V
`if
`1
`I
`A
`9
`it
`
`An alternative approach to oestrogen withdrawal is to antagonise oestrogens with
`_ antioestrogens. These are drugs that bind to and compete for oestrogen receptors (BR) present
`
`15.
`
`in the nuclei of oestrogen-responsive tissue. Conventional nonsteroidal antioestrogens,'such
`
`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).
`
`20
`
`I
`
`25
`
`The potential for nonsteroidal antioestrogens to display agonistic properties prompted 9
`
`the search for novel compounds that would bind ER with high 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 of oestrogens. Such _
`
`compounds are referred to as Estrogen Receptor—Downregulators (E.R.D.). The rationale for
`
`the ‘design and testing of novel, pure’ antioestrogens has been described in: Bowler et al'1989,
`
`V
`Wakeling 1990a, 1990b, 1990c. Wakeling and Bowler 1987, 1988.
`Steroidal analogues of oestradiol, with an alkylsulphinyl side chain in the 70L position,
`
`provided the first examples of compounds devoid of oestrogenic activity (Bowler et al 1989).
`
`30
`
`One of these, 7oL-[9-(4,4,5,5,5-pentafluoroperityl sulphinyl)nonyl]o'estra-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 antioestrogenic potency over other available
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 2
`
`

`
`Z70635
`
`;-v<-
`\._r'
`
`.
`
`[,5
`(N .’
`
`-2-
`
`antioestrogens. In vitro findings and early clinical experience with
`
`70.-[9—(4,4,5 ,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(10)—triene-3,l7[3-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-(4,4,5,5,.5—Pentafluoropentylsu1phinyl)nonyl]oestra-1,3-5(l0)-triene-3,17[3-diol,
`or ICI 182,780, has been allocated the international noun-proprietary namefulvestrant, 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 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 blocks the
`activity of tamoxifen.‘
`
`i
`
`' Because fulvestrant has none of the oestrogen-like stimulatory activity that is
`E
`characteristic of clinicallylavailable antioestrogensusuch as tamoxifen or torernifene, it may
`offer improved therapeutic activity characterised by more rapid, complete, or longer-lasting
`tumour regression; a lower incidence or rateof development ofresistance to treatment; and a
`reduction oftumour invasiveness.
`I
`I
`V
`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 findin_gs__.could be of extreme importance clinically. iReduced bone
`
`10
`
`15
`
`20
`
`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.
`
`25
`
`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 particularthere is the disclosure within Example 35
`of the compound 70:-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-
`.
`
`30
`
`1,3,5(10)-triene-3,l7[3-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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 3
`
`

`
`z7o63s
`
`b
`
`i
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`I
`
`A
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`Y(“,'
`
`-3-
`
`pharmaceutically-acceptable diluent or carrier. It is stated therein that the composition can be
`in a form suitable for oral or parenteral administration.
`A
`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" (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 numberof sustained release injectable steroidal formulations
`which have been commercialised. Commonly these formulations use oil as a solvent a.nd
`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 excipientswsuch as benzyl 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 from 1 to 8 weeks.
`
`20
`
`-25
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 4
`
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 6
`
`

`
`z7o_635
`
`C T
`
`8
`
`-5-
`
`Cl
`
`described which comprises 50mg of fu1vestrant,.400mg of benzyl alcohol and sufficient castor
`
`0 oil to bring the solution to a volume of _1 ml. Manufacture at a commercial scale of a
`formulation as described in US 5,183,814 willbe complicated by the high alcohol
`concentration. Therefore, there is a need to lower the alcohol concentration in fulvestrant
`formulations whilst preventing precipitation of fulvestrant from the formulation.
`
`Table 2 shows the solubility of fulvestrant in a number of different solvents.
`
`Table 2 - SOLUBILITY OF FULVESTRANT
`
`SOLVENT
`
`Water '
`
`A}aéhfs' oil ’
`
`Sesameoil
`
`Castor oil
`
`Miglyol 810
`
`Miglyo1812
`
`Ethyl oleate _
`
`Benzyl benzoate
`
`Isopropyl myristate
`
`Span as (surfactant)
`Ethanol
`A
`
`' Benzyl Alcohol
`
`10
`
`SOLUBILITY
`
`(mgml" at 25°C)
`0.001 .
`
`0.45
`
`'
`
`0.58
`
`20
`
`3.06
`
`V2.72
`
`1.25 b
`
`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 hydroxygroups of ricinoleic acid, which is the major
`
`H’ constituent of the fatty acids within the triglycerides present in-castor oil - see (Riffkin et.al. J.
`
`15
`
`Pharm. Sci., (1964), 53, 89l).
`
`However, even when using the best oil based solvent, castor oil, we have found that it
`
`is not possible to dissolve fulvestrant invan oil based solvent alone so as to achieve a
`
`enough concentration to dose a patient in a low volume injection and achieve a therapeutically
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 7
`
`

`
`Z70635
`
`C
`
`I
`
`J
`
`.
`
`-7-
`
`significant release rate. To achieve a therapeutically significant release rate the amount of ‘
`
`fulvestrant needed would require the formulation volume to be large, at least 10 ml. This
`requires the doctor to inject an excessively large volume of formulation to administer a‘ dose
`
`significantly high enough for human therapy.
`
`Currently guidelines recommend that no more than 5mls_ of liquid is injected
`intraniuscularly in a single injection. Pharmacologically 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 ai non-aqueous ester solvent which is
`miscible in the castor oil and an alcohol surprisingly eases the solubilisation of fulvestrant into
`a concentration of at least 50 mgml’l - see Table 3 below. The finding is surprising since the
`
`15
`
`-
`
`solubility of fulvestrant in non-aqueous ester solvents - see Table 2 above - is significantly
`lower than the solubilitynof fulvestrant in an alcohol. The solubility of fiilvestrant is also lower
`— 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 g
`20 comprising fulvestrant (preferably fulvestrant is present at 3-l0%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 pharmaceutically 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 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
`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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 8
`
`

`
`270635
`
`5
`
`(MiMa,-
`
`-3-
`
`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 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 pharmaceutically-acceptable alcohol per volume of formulation, at least 1% i
`
`(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 45mgrn1" of
`fulvestrant.
`I
`I
`5
`
`ii
`
`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
`formulation '5‘ certain puercentageuoif the "co.nsti’tu'eri't_ by Weight‘ will be present, ‘for_exa_mple a_
`
`1% weight per volume formulation will contain within a 100ml volume of formulation lg of
`the constituent. By way of further illustration
`
`15
`
`
`
`Preferred pharmaceutical formulations of the invention are as described above
`
`wherein:
`
`20
`
`1.
`
`The total volume of the formulation is 6m1, 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 5-5.25m].
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 9
`
`

`
`Z70635
`
`C;
`
`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 Sml dose is required it would be appreciated that an excess of up to 0.25ml, preferably
`
`up to O.15rnl will also be present in theformulation. 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 of the invention.
`
`1 Preferred concentrations of a pharmaceutically-acceptable alcohol present in any of the
`' aboveformulations are; at least 3%w/v, at-least 5%w/v, at least 7%w/v, at least 10% w/v, at I
`_
`‘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 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 in any of the
`above-forrnulationsare’ selected from any minimum or maximum. value described above and 1
`preferably are; 3-35%w/v, 4-35%w/v, 5_—35%w/v, 5-i32%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 ~19-2l%w/v.”
`I
`The pharmaceutically-acceptable alcoholmay consist of one alcohol or a mixture of
`two or more alcohols, preferably a mixture of two alcohols. Preferred pharmaceutically-
`
`I
`
`N
`
`10
`
`15
`
`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 I
`formulation in the same w/v amounts. Preferably the formulation alcohol contains 10% w/v
`1 ethanol and 10% w/v benzyl alcohol.
`
`20,
`
`' The pharmaceutically-acceptable non-aqueous ester solvent 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
`
`25
`
`administration is selected from benzyl benzoate, ethyl oleate, isopropyl myristate,isopropyl
`
`palrnitate 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%
`
`weight per volume of formulation.
`It will be understood by the skilled person that the pharmaceutically-acceptable
`
`30
`
`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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 10
`
`

`
`ii z7os35
`
`1
`
`.
`
`.
`
`-10-
`
`_,
`
`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 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 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-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
`
`4 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 any
`or maximum value described above and preferably are; -5-60%vv/iv, 7-
`55%w/v_, 8-50%w/v, 10-50%w/v, 10-45%vi//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, 12-1 8%W/V, 13-17%w/pv 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 pharmaceutically-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 pharmacopoeias).
`
`. Preferred combinations of pharmaceutically-acceptable alcohol and pharmaceutically-
`
`acceptable non-aqueous ester solvent in the formulation are set out below:
`
`15
`
`20
`
`Pharmaceutically-acceptable
`
`Pbarmaceutically-acceptable non-aqueous
`
`a'lcohol(%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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 11
`
`

`
`Z70635
`
`-11-A
`
`' 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.
`
` 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.
`
`
`
` ethanol and benzyl alcohol, most benzyl benzoate, most preferably at about 15%
`preferably each at about 10%
`
`
`
`
`
`By the use of the term ric’i‘r‘1ol'eat'e 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 pharmacopoeial standards, as described above.
`We have surprisingly found that the above formulations of the invention provide, afier
`intra-muscular injection, satisfactory release of fulvestrant over an extended period of time.
`_ This finding‘ is indeed surprising for the following reasons.
`I
`Previously tested by theiapplicarits have been intra-muscular injections of fulvestrant
`1.
`in the form of an aqueous suspension. -We have found eictensive 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 inflarnmation/irritation present
`
`at the injection site and this was variable and difficult to control. Also the fulvestrant release
`
`10
`
`15
`
`rate was notsufficiently high to be clinically significant.
`2.
`Our findings fi‘om 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.
`A
`It would be expected that ethanol will dissipate at least as quickly, if not more rapidly,
`
`20
`
`from the injection site.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 12
`
`

`
`_z7o635
`
`‘
`
`-12-
`
`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 32”’ 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, fiorri
`
`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 fonnulation 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 ngrnl'1, at least 8.5 ngml", and up to 12
`
`ngrnl'l of fulvestrant are achieved in the patient. Preferably blood plasma levels shouldbe less
`than l5 n'gml"‘..
`_
`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, 3-4, 3.5-.4 and most preferably for at least about 4 weeks.
`I
`i
`It will be understood that the attendant physician may wish to administer the
`intramuscular injection as a divided dose, i.-e. a 5ml formulation is sequentially administered
`
`in two separate injections of 2.5m1, this is a further feature of the invention
`Simply solubilising fulvestrant in an oil based liquid 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 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
`
`15
`
`20
`
`25
`
`30
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 13
`
`

`
`n223.
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`£85
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 14
`
`

`
`' Z70635
`
`L.
`
`‘
`
`-14-
`
`The following Table 4 shows the solubility of fiilvestrant 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
`
`5' Solubility comparisons. of fulvestrant in oil based formulations with and without
`alcohols
`‘
`4
`'
`
`
`10
`
`_
`
`V
`
`Formulation (3)
`'
`Complete vehicle
`Vehicle minus alcohols
`
`Fulvestrant Solubility. mg ml" @ 25°C
`
`Castor oil based
`
`15 Miglyol 812-N based
`
`81.2
`
`86.8
`
`Sesame seed/‘Castor oil (1:1) based
`
`12.5
`
`1.7
`
`4.4
`
`20
`
`I Sesame seed oilbased
`'
`, 40.2
`' Arachis oil-based
`
`
`.
`
`5
`
`45.7
`
`0.7
`
`< 0.2
`
`(a) ‘Complete Vehicle Formulations cornpxised ethanol [96%](10%), benzyl alcohol ( 10%) and benzyl benzoate
`(15%) made to volume with the statedoil. Excess fulvestrant was added to each solvent mixture’ and solubility
`determined.
`
`25
`
`Effect of formulation on precipitation of fulvestrant at the injection site
`
`30
`
`Formulation “
`
`Formulation Fl
`castor oil based
`
`35
`
`Formulation F2
`Miglyol 812-N based
`
`.40 Formulation F3
`sesame seed oil/castor
`oil based
`
`2
`
`0
`
`3
`
`0
`
`.
`
`4
`
`0
`
`Days
`
`10'
`
`30 A
`
`5 1
`
`0
`
`+—+— "
`
`+++
`
`+++
`
`+++
`
`+++
`
`++
`
`+ °
`
`4+
`
`++
`
`4-H»
`
`++
`
`+
`
`4
`
`0
`
`0
`
`+
`
`45
`
`0, + , ++, +‘H- = Degree of precipitation (None detected, Mild, Moderate, Severe)
`3 Formulations comprised fulvestrant (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’
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 15
`
`

`
`Z70635 -
`
`C;
`
`t
`
`-
`
`
`
`.
`J
`
`-15-
`
`L,
`
`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 viva of the four formulations from the second part
`
`V
`
`of Table 4 and shows the effect of the fixed oil component on fulvestrant-plasma 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 ofprecipitation of
`
`.
`
`fulvestrant at the injection site.
`
`10
`
`Therefore we presentas ‘a further feature of the invention an extended release
`
`pharmaceutical formulation adapted for intramuscular injection comprising fulvestrant; 35%
`.(preferably 30% or ideally 25%) or less weight of a pharmaceutically-acceptable alcohol per
`volume of formulation, at least l% (preferably atleast 5% or ideally 10%) weight of a
`
`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-acceptable excipients, so as to prepare a
`
`_formu_lation of at least 45mgrnl" of fiilvestrant.
`
`A further feature of the invention is a pharmaceutical formulation adapted for
`intramuscular injection, as defined above, for use in medical therapy.
`I
`
`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 in need of such treatment 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-
`
`‘.
`
`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.
`
`Preferably 5ml of the intramuscular injection is administered.
`
`30
`
`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 benign or
`malignant disease of the breast or reproductive tract, preferably treating breast cancer.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 16
`
`

`
`Z70635
`
`C,
`
`-15-
`
`Additional excipients commonly used in the fonnulation field including, for exam