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`PATENT Na, :3
`ATTORNEY DOCKET NO.: 056291-5004-01
`EC’
`F C
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`Commissioner for Patents
`U.S. Patent and Trademark Office
`
`220 20th Street S
`
`Customer Window, Mail Stop Patent Application
`Crystal Plaza Two, Lobby, Room 1B03
`Arlington, VA 22202
`
`Date:
`
`June 22, 2004
`
`09/756,291
`Prior Application No.
`Prior Application Filing Date:
`January 9, 2001
`
`1617
`Prior Group Art Unit:
`Prior Examiner: Hui, San Ming R.
`
`CONTINUATION PATENT APPLICATION TRANSMITTAL UNDER 37 C.F.R.
`
`§ 1.53(b)
`
`This is a request for filing a patent application under 37 C.F.R. § 1.53(b).
`
`1.
`
`This application is a Continuation patent application under 37 C.F.R. § 1.53(b), of
`copending prior application No. 09/756,291, filed January 9, 2001, of:
`
`Inventors:
`For:
`
`John R. EVANS and Rosalind U. GRUNDY
`FORMULATION
`
`2.
`
`The papers enclosed are as follows:
`
`Application of 24 pages including:
`
`19 Page(s) of specification
`
`3 Page(s) of claims
`1 Page of abstract
`1 Pages of Drawings
`
`(23 numbered claims)
`
`(Figure 1)
`
`3.
`
`Oath or Declaration
`
`[Z
`
`A copy of an oath or declaration (1 page) tiled in prior parent application No.
`09/756,291 is enclosed under 37 C.F.R. § 1.63(d). The entire disclosure of the
`prior application, from which a copy of the oath or declaration is supplied is
`considered as part of the disclosure of the accompanying application and is hereby
`incorporated by reference therein.
`»
`
`1-WA/2211568 . 1
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 1
`
`
`
`PATENT
`ATTORNEY DOCKET NO. 056291-5004-01
`
`Continuation of Application No.: 09/756,291
`Page 2
`
`4.
`
`Relate Back - 35 U.S.C. § 120
`
`IE
`
`A Preliminary Amendment is being filed concurrently herewith amending the
`specification by inserting before the first line the sentence:
`
`This is a Continuation of copending Application No. 09/756,291, filed_Janua1y 9,
`2001.
`
`Each listed U.S. Patent and/or application is entirely incorporated herein by
`reference in its entirety.
`
`Domestic/Intemational priority is claimed under 35 USC l19(e)/120/365(c) based on the
`following provisional, nonprovisional and/or PCT international applications(s):
`
`
`
`
`
`
`
`
`
`
`
`
`
`Filing Date
`0
`Janu
`9, 2001 —‘
`09/756,291
`(1
`— 4 —
`
`Priority - foreign applications under 35 U.S.C. § 119(a)-(d) or § 365(b) or PCT
`international applications under 35 U.S.C. § 365(a) designating at least one country other
`than the U.S.
`
`IE
`
`Priority of the following foreign application(s) is/are claimed: 3
`
`
`
`o0oo313.7
`
`0008837.7
`
`Great Britain
`
`January 10, 2000
`April 12, 2000
`
`
`
`
`Certified copy(ies):
`
`I:I is/are attached.
`B will follow.
`IX] was/were filed in prior U.S. Application No. 09/756,291
`filed January 9, 2001.
`
`5.
`
`6.
`
`7.
`
`Assignment
`
`E]
`
`E]
`
`Prior application No. 09/756,291 is assigned of record to ASTRAZENECA AB
`on March 27, 2001, at Reel/Frame 011635/0063.
`
`An Assignment of the invention and Form 1595, Recordation Form Cover Sheet,
`is enclosed.
`
`1-WA/2211568 . 1
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 2
`
`
`
`8.
`
`Fee Calculation (37 C.F.R. § 1.16)
`
`CLAIMS R FEE CALCULATION ’
`
`PATENT
`ATTORNEY DOCKET NO. 056291-5004-01
`
`Continuation of Application No.: 09/756,291
`Page 3
`
`Utility $770.00
`
`Total Fees
`
`
`L___fi____.
`
`Independent Claims
`(37 C.F.R.§ 1 . 1 6(b))
`
`2
`
`|:] First presentation of Multiple Dependent Claim(s)
`
`|:] Assignment Recording Fee
`TOTAL FEE =
`
`3
`
`1 l
`
`9.
`
`Power of Attorney
`
`IX
`
`IX]
`
`The power of attorney in the prior application is to at least one of the registered
`practitioners of Morgan, Lewis & Bockius LLP included in the Customer Number
`provided below to prosecute this application and to transact all business in the
`Patent and Trademark Office connected therewith, and all correspondence shall be
`addressed to that Customer Number.
`
`Please address all correspondence to Morgan, Lewis & Bockius LLP at Customer
`Number: 09629
`
`PETITION FOR EXTENSION OF TIME. If any extension of time is
`necessary for the filing of this application, including any extension in the prior
`application, application No. 09/756,291, filed January 9, 2001, for the purpose of
`maintaining copendency between the prior application and the present application,
`and such extension has not otherwise been requested, such an extension is hereby
`requested, and the Commissioner is authorized to charge necessary fees for such
`an extension to Deposit Account No. 50-0310.
`
`1-WA/2211568 . 1
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 3
`
`
`
`PATENT
`ATTORNEY DOCKET NO. 056291-5004-01
`
`Continuation of Application No.: 09/756,291
`Page 4
`
`10.
`
`Fee Payment
`
`K4
`
`No Fee is being paid at this time.
`
`
`
`.
`
`0.: (202) 739-5320
`Te
`Fax No.: (202)739-3001
`
`Date:
`
`June 22, 2004
`
`Morgan Lewis & Bockius LLP
`Customer No. 09629
`
`1111 Pennsylvania Avenue, N.W.
`Washington, DC. 20004
`Te1.No.: 202-739-3000
`
`DJB:mk
`
`1—WA/2211568 . 1
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 4
`
`
`
`\
`Z:;0635
`
`"
`
`'
`
`)
`
`.
`
`1
`
`-1-
`
`FORMULATION
`
`l
`
`The invention relates to a novel sustained release pharmaceutical formulation adapted
`
`for administration by injection containing the compound
`5 7oL-[9—(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(1O)—triene-3,17[3-diol, more
`
`particularly to a formulation adapted for administration by injection containing the compound
`
`7oz-[9-(4,4,5,5 ,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-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. A
`
`10
`
`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 surgical, radiotherapeutic, or medical means, and, in
`
`postmenopausal women, by the use of aromatase inhibitors.
`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 antioestrogens, such
`
`20
`
`as tamoxifen, competeefficiently for ER binding but their effectiveness is often limited by the
`partial agonism they display, which results in aniincomplete blockade of oestrogen-‘mediated
`activity (Furr and Jordan 1984, May and Westley 1987).
`I
`The potential for nonsteroidal antioestro gens to display agonistic properties prompted
`the search for novel compounds that would bind ER with high affinity without activating any I
`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
`25 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,
`
`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, 70:-[9-(4,4,5,5,5-pentafluoropentyl sulphinyl)nonyl]oestra—1,3,5—(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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 5
`
`
`
`z'}'063s
`
`-2-
`
`antioestrogens. In vitro findings and early clinical experience with
`
`7ot—[9-(4,4,5,5 ,5-pentafluoropenty1su1phiny1)nony1]oestra-1,3—5(10)-triene-3,17[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.
`
`7oL—[9—(4,4,5,5,5-Pentafluoropentylsulphinyl)nonyl]oestra—1,3-5(10)-triene-3 ,17B-diol,
`or ICI 182,780, has been allocated the international non—proprietary name fulvestrant, which is
`
`used hereinafter. When referring to fulvestrant we include pharmaceutically-acceptable salts
`
`thereof and any possible solvates of either thereof.
`
`Fulvestrant binds to ER with‘ an 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
`
`uterotrophic activity of tamoxifen.
`
`Because fulvestrant has none of the oestrogen-like stimulatory activity that is
`
`characteristic of clinically available antioestrogens such as tamoxifen or torernifene, it may
`
`offer improved therapeutic activity characterised by more rapid, complete, or longer-lasting
`
`tumour regression; a lower incidence 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 toincreased 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 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
`
`l0
`
`15
`
`20
`
`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 Example 35
`
`of the compound 70:-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-
`
`30
`
`1,3,5(10)-triene-3,17B-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 6
`
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`zio635 '-
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`pharmaceutically-acceptable diluent or carrier. It is stated therein that the composition can be
`
`in a fonn suitable for oral or parenteral administration.
`Fulvestrant shows, along with other steroidal based compounds, certain physical
`
`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 number of sustained release inj ectable steroidal formulations
`
`10
`
`which have been commercialised. Commonly these formulations use oil as a solvent and
`wherein additional excipients may be present. Below in Table 1 are described a few
`commercialised sustained release 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 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.
`
`15
`
`20
`
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`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 7
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 9
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`Z70635 ‘«
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`
`described which comprises 50mg of fi1lvestrant,_400mg 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 US 5,183,814 will be complicated by the high alcohol
`
`concentration. Therefore, there is a need to lower the alcohol concentration in fulvestrant
`
`formulations whilst preventing precipitation of fiilvestrant fi'om the formulation.
`
`Table 2 shows the solubility of fulvestrant in a number of different solvents.
`
`Table 2 - SOLUBILITY OF FULVE-ZSTRANT
`
`SOLITBILITY
`
`(mgml" at 25°C)
`
`0.001
`
`0.45
`
`0.58
`
`20
`
`3.06
`
`2.72
`
`1.25
`
`6.15
`
`0.80
`3 .79
`
`>200
`
`>200
`
`8
`
`\
`
`SOLVENT
`
`Water
`
`Arachis oil
`
`Sesame oil
`
`Castor oil
`
`Miglyol 810
`
`Miglyol 812
`
`Ethyl oleate
`
`Benzyl benzoate
`
`Isopropyl myristate
`Span 85 (surfactant)
`
`Ethanol
`
`Benzyl Alcohol
`
`10
`
`15
`
`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
`
`constituent of the fatty acids within the triglycerides present in castor oil - see (Riffldn 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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 10
`
`
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`
`significant release rate. To achieve a therapeutically significant release rate the amount of '
`
`fiilvestrant 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 Smls of liquid is injected
`
`intramuscularly in a single injection. Phaimacologically active doses required for a 1 month
`
`long acting depot formulation of fulvestrant is around 250mg. Therefore, when dissolved in
`
`just castor oil, fiilvestrant 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
`
`miscible with castor oil, may be used, such as an alcohol. With the addition of high
`
`concentrations of an alcohol concentrations of >50mgml" of fiilvestrant in a castor oil
`
`formulation is achievable, thereby giving an injection volumes of <5ml — 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 fiilvestrant into
`
`a concentration of at least 50 mgml'1 - see Table 3 below. The finding is surprising since the
`
`solubility of fiilvestrant in non-aqueous ester solvents - see Table 2'above - is significantly
`
`lower than the solubilitylof fulvestrant in an alcohol. The solubility of fulvestrant is also lower
`
`~ in non-aqueous ester solvents than is the solubility of fiilvestrant in castor oil.
`
`Therefore, we present as a feature of the invention a pharmaceutical formulation
`
`comprising fiilvestrant (preferably fiilvestrant 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
`3
`
`pharmaceutically 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 fiilvestrant concentration for at least 2 weeks.
`
`Another feature of the invention is a pharmaceutical fonnulation comprising
`
`fiilvestrant .in which the formulation is adapted for intra-muscular injection into a human and
`which is capable afler injection of attaining a therapeutically significant blood plasma
`fulvestrant concentration for at least 2 weeks.
`
`Further features of the invention include a pharmaceutical fonnulation adapted for
`
`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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 11
`
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`formulation and a sufficient amount of a ricinoleatel 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
`
`S
`
`intra—muscular injection comprising fulvestrant; 35% (preferably 30% and ideally 25%) or less
`
`weight of a pharmaceutically-acceptable alcohol per volume of formulation, at least 1%
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`(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 a.nd a sufficient
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`amount of a ricinoleate vehicle so as to prepare a formulation of at least 45mgml" of
`fulvestrant.
`i
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`0
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`It
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`10
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`For the avoidance of any doubt when using the term % weight per volume of
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`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_
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`1% weight per volume formulation will contain within a 100ml volume of formulation 1g of
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`15
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`the constituent. By way of further illustration
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`
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`Preferred pharmaceutical formulations of the invention are as described above
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`wherein:
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`20
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`1.
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`The total volume of the formulation is 6ml, or less, and the concentration of
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`fulvestrant is at least 4Smgrn1" .
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`2.
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`The total amount of fulvestrant in the formulation is 250mg, or more, and the total
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`volume of the formulation is 6ml, or less.
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`3.
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`The total amount of fulvestrant in the formulation is 250mg and the total volume of
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`25
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`the formulation is 5-5.25ml.
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 12
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`z7'o63s '
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`It is appreciated that in the formulation an excess of formulation may be included to
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`allow the attendant physician or care giver to be able to deliver the required close. Therefore,
`when a Sml dose is required it would be appreciated that an excess of up to 0.25ml, preferably
`
`up to 0.l5ml 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 of the invention.
`
`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
`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,
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`10
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`15
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`preferably, at least 16% w/v. Preferred maximal concentrations of pharmaceutically-
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`acceptable alcohol present in the formulation are ;28% w/v or less, 22% w/v or less and 20%
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`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
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`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-
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`28%w/v, 15-25%w/v, 17-23%w/v, 18-22%w/v and ideally 19-21%w/v.
`The pharmaceutically-acceptable alcoholmay consist of one alcohol or a mixture of
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`two or more alcohols, preferably a mixture of two alcohols. Preferred pharmaceutically-
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`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
`formulation in the same w/v amounts. Preferably the formulation alcohol contains 10% w/v
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`20
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`I ethanol and 10% w/v benzyl alcohol.
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`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
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`administration is selected from benzyl benzoate, ethyl oleate, isopropyl myristate,isopropyl
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`palmitate or a mixture of any thereof.
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`The ricinoleate vehicle should preferably be present in the formulation in a proportion
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`of at least 30% weight per volume of the forrnulation, ideally at least 40% or at least 50%
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`weight per volume of formulation.
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`It will be understood by the skilled person that the pharmaceutically-acceptable
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`alcohol will be of a quality such that it will meet pharmacopoeial standards (such as are
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`described in the US, British, European and Japanese pharmacopoeias) and as such will contain
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`25
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`30
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 13
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`Z70635 ’-
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`some water and possibly other organic solvents, for example ethanol in the US Pharmacopeia
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`contains not less than 94.9% by volume and not more than 96.0% by volume of ethanol when
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`meas_ured at 15.5 6°C. Dehydrated alcohol in the US Pharmacopeia contains not less than
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`99.5% ethanol by volume when measured at 15.56°C.
`Preferred concentrations of the pharmaceutically-acceptable non-aqueous ester solvent
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`present in any of the above forrnulations are; at least 5% w/v, at least 8% w/v, at least 10%
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`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,
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`at least 17% w/v, at least 18% w/v, at least 19% w/v and at least 20% w/v. Preferred maximal
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`concentrations of the pharmaceutically-acceptable non-aqueous ester solvent are; 60% w/v or
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`10
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`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 and
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`25% w/v or less. A preferred concentration is 15% w/v. Preferred ranges of pharmaceutically-
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`acceptable non-aqueous ester solvent present in any of the above formulations are selected
`fiom any minimum or maximum value described above and preferably are; 5—60%w/V, 7-
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`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-
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`15
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`l6%w/v. Preferably the ester solvent is benzyl benzoate, most preferably at about 15%w/v.
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`It will be understood by the skilled person that the pharmaceutically-acceptable non-
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`aqueous ester solvent will be of a quality that it will meet pharmacopoeial standards (such as
`described in the US, British, European
`Japanese pharmacopoeias).
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`20
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`Preferred combinations of pharmaceutically-acceptable alcohol and pharmaceutically-
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`acceptable non-aqueous ester solvent in the formulation are set out below:
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`Pharmaceutically-acceptable
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`Pharmaceutically-acceptable non-aqueous
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`aAlcohol(%w/v)
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`ester (%w/v)
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`ideally 14-16.
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`5-60, 7-55, 8-50, 10-50, 10-45, 10-40, 10-35, 10-
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`30, 10-25, 12-25, 12-22, 12-20, 12-18,13-17 and
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 14
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`Z20635 V
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`5-60,. 7-55, 8-50, 10-50, 10-45, 10-40, 10-35, 10-
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`30,10-25, 12-25,12-22, 12-20, 12-18, 13-17 and
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`ideally 14-16.
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`preferably each at about 10%
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`3-35, 4-35, 5-35, 5-32, 7-32, 10-30, 12-
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`" 28, 15-25, 17-23, 13-22 and ideally 19-
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`3-35, 4-35, 5-35, 5_-32, 7-32, 10-30, 12-
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`28, 15-25, 17-23, 18-22 and ideally 19-
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`21.
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`ethanol and benzyl alcohol, most
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`benzyl benzoate, most preferably at about 15%
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`By the use of the term ricinoleate vehicle we mean an oil which hasas a proportion (at
`least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or'95% w/v) ofits composition as
`triglycerides ofricinoleic acid. The ricinoleate vehicle may be a synthetic oil or conveniently
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`is castor oil, ideally of pharmacopoeial standards, as described above.
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`We have surprisingly found that thegabove formulations of the invention provide, afier
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`intra-muscular injection, satisfactory release of fulvestrant over an extended period of time.
`This finding is indeed surprising for the following reasons.
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`10
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`1.
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`Previously tested by the applicants have been ir1tra—muscular injections of fulvestrant
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`in the form of an aqueous suspension. We have found eirtensive local tissue irritation at the
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`injection site as well as a poor release profile. It is believed that the tissue
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`irritation/inflammation was due to the presence of fulvestrant in the form of solid particles.
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`The release profile appeared to be determined by the extent of inflammation/irritation present
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`at the injection site and this was variable and difficult to control. Also the fulvestrant release
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`rate was not sufficiently high to be clinically significant.
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`2.
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`Our findings from studies using 14C labelled benzyl alcohol show that it dissipates
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`rapidly from the injection site and is removed from the body within 24 hours of
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`administration.
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`It would be expected that ethanol will dissipate at least as quickly, if not more rapidly,
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`15
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`20
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`from the injection site.
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 15
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`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
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`Pharmacopoeia 32"d edition page 1103, and, therefore, it is unlikely that benzyl benzoate,
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`when used, is present at the injection site during the whole of the extended release period.
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`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
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`the formulation vehicle and the site of injection after injection of the formulation, extended
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`release at therapeutically significant levels of fulvestrant over an extended period can still
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`achieved by the formulation of the invention.
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`By use of the term “therapeutically significant levels” we mean that blood plasma
`concentrations of at_ least 2.5 ngml”, ideally at least 3 ngml“, at least 8.5 ngml", and up to 12
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`ngml’1 of fulvestrant are achieved in the patient. Preferably blood plasma levels shouldbe less
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`than 15 ngml".
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`By use of the term “extended release” we mean at least two weeks, at least three
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`weeks, and, preferably at least four weeks of continuous release of fulvestrant is achieved. In a
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`preferred feature extended release is achieved for 36 days._Preferably extended release of
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`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 5ml formulation is sequentially administered
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`in two separate injections of 2.5ml, this is a further feature of the invention
`Simply solubilising fiilvestrant in an oil based liquid formulation is not predictive of a
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`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
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`containing alcohols ethanol and benzyl alcohol with or without benzyl benzoate.’The results
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`clearly show the positive effect of benzyl benzoate on fulvestrant solubility in castor oil,
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`despite fulvestrant having a lower solubility in benzyl benzoate than in either alcohol or castor
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`oil.
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`l0
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`15
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`20
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`25
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`30
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 16
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 17
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`The following Table 4 shows the solubility of fiilvestrant in a range of oil based
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`formulations which contain the same amounts of alcohol and benzyl benzoate but in which the
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`oil is changed. The data also shows solubility of fulvestrant after removal of the alcohols.
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`Table 4
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`5 Solubility comparisons of fulvestrant in oil based formulations with and without
`alcohols
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`
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`Fulvestrant Solubility mg ml'1 @ 25°C
`Formulation (3)
`Complete vehicle
`Vehicle minus alcohols
`
`
`10
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`Castor oil based
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`_
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`81.2
`
`e
`
`‘ 12.6
`
`is Miglyol 812-N based
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`Sesame seed/Castor oil (1:1) based
`
`86.8
`
`70.1
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`1.7
`
`4.4
`
`"
`
`0.7
`45.7
`Sesame seed oil based
`< 0.2
`40.2
`20 7 Arachis oil-based
`
`
`25
`
`(a) Complete Vehicle Formulations comprised ethanol [96%](l0%), benzyl alcohol (10%) and benzyl benzoate
`(15%) made to volume with the stated oil. Excess fulvestrant was" added to each solvent mixture and solubility
`detem-lined.
`
`Effect of formulation on precipitation of fulvestrant at the injection site
`
`‘
`Days
`
`30
`
`51
`30
`10
`7
`'
`4
`3
`2
`Formulation ”
`
`
`Formulation Fl
`castor oil based
`
`35
`
`0
`
`0
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`O
`
`0
`
`0
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`0
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`-
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`1:ormu1a¢ion 1:2
`Miglyol 812-N based
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`+-I4 "
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`+++
`
`+++
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`+++
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`++
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`1
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`0
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`0
`
`4o Fonnulation 1:3
`sesame seed oil/castor
`oil based
`
`
`+ °
`
`++
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`-l—|-
`
`+++
`
`++
`
`+
`
`+
`
`45
`
`0, + , ++, +—H- = Degree of precipitation (None detected, Mild, Moderate, Severe)
`a 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
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 18
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`Z'l0635
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`-15-
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`Precipitation of fulvestrant and the release profile was determined with the above
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`formulations in an in vivo rabbit study.
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`Figure 1 shows the release profile in vivo of the four formulations from the second part
`
`of Table 4 and shows the effect of the fixed oil component on fulvestrant-plasma profile over
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`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). As can be seen the castor oil
`
`formulation showed a particularly even release profile with no evidence of precipitation of
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`fulvestrant at the injection site.
`
`10
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`15
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`Therefore we present as 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 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 and sufficient amount of a ricinoleate vehicle, taking into account the
`
`addition of any further optional pharmaceutically-acceptable excipients, so as to prepare a
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`_formulation of at least 45mgml" of fiilvestrant.
`
`I
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`A further feature of the invention is a pharmaceutical formulationadapted for
`intramuscular injection, as defined above, for use in medical therapy.
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`20
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`_
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`A further feature of the invention is a‘ method of treating a benign or malignant
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`diseases of the breast or reproductive tract, preferably treating breast cancer, by administration
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`to a hmnan in need of such treatment by intramuscular injection an extended release
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`ricinoleate ve