Old’8019391
`
`..
`E
`935 g
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`3‘01 %
`PATENT 0'?) g
`ATTORNEY DOCKET NO.: 056291-5004-01 §3 EN‘— E
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Commissioner for Patents
`US. 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.
`
`§ 1.530»)
`
`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:
`
`John R. EVANS and Rosalind U. GRUNDY
`
`For:
`
`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
`
`X A copy of an oath or declaration (1 page) filed 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 andIS hereby
`incorporated by reference therein.
`
`1~WA/2211553 . 1
`
`InnoPharma Exhibit 1046.0001
`
`

`

`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_January 9,
`2001.
`
`Each listed US. Patent and/or application is entirely incorporated herein by
`reference in its entirety.
`
`Domestic/International priority is claimed under 35 USC 119(e)/120/365(c) based on the
`following provisional, nonprovisional and/or PCT international applications(s):
`
`5.
`
`6.
`
`
`
`1
`09/756,291
`Janua
`9,2001
`__!
`
`""""""""""-""""" Filing Date -5-Anlcaion No. “FilmDate "7
`
`
`
`
`
`Priority - foreign applications under 35 USC. § 119(a)-(d) or § 365(b) or PCT
`international applications under 35 USC. § 365(a) designating at least one country other
`than the US.
`
`IX]
`
`Priority of the following foreign application(s) is/are claimed:
`
`
`
`
`Certified copy(ies):
`
`00003137
`
`00088377
`
`January 10, 2000
`
`April 12,2000
`
`[:1 is/are attached.
`[:1 will follow.
`was/were filed in prior US. Application No. 09/756,291
`filed January 9, 2001.
`
`
`
`
`
`7.
`
`Assignment
`
`[Z
`
`[:I
`
`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.
`
`l-WA/2211568 .l
`
`InnoPharma Exhibit 1046.0002
`
`

`

`PATENT
`ATTORNEY DOCKET NO. 056291-5004-01
`Continuation of Application No.2 09/756,29l
`Page 3
`
`.
`Fee Calculatlon (37 CPR. § 1.16)
`
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`;——=—~=:
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`
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`
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`6 8.
`
`0 1
`
`70339
`
` l
`Basic Fee
`Utility $770.00
`
`x $18.00 each-
`
`x $86 each—
`
`Total Fees
`
`0.00
`
`0.00
`
`$
`
`$
`s
`
`_
`
`0 00
`__ i.*__4
`
`0 00 S
`
`Filed Afler
`Preliminary
`Amendment
`
`ma] C'alms
`(37 CPR. §l.16(c))
`
`Independent Clalms
`(37 C.F.R.§l.16(b))
`
`.
`
`,
`
`: B First presentation of Multiple Dependent Claim(s)
`
`i‘ D Assignment Recording Fee
`TOTAL FEE =
`L.___k—“u
`
`l l
`
`9.
`
`Power of Attorney
`
`E]
`
`IE
`
`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.
`
`l-WA/2211568.1
`
`InnoPharma Exhibit 1046.0003
`
`

`

`PATENT
`ATTORNEY DOCKET NO. 056291—5004-01
`
`Continuation of Application No.: 09/756,291
`Page 4
`
`10.
`
`Fee Payment
`
`[Z]
`
`No Fee is being paid at this time.
`
` itte ,
`
`By:
`
`June 22, 2004
`Date:
`Morgan Lewis & Bockius LLP
`Customer No. 09629
`
`1111 Pennsylvania Avenue, NW.
`Washington, DC. 20004
`Tel. No.: 202-739~3000
`
`Dlemk
`
`B ckiu LLP
`
`.
`
`0.: (202) 739-5320
`Fax No.: (202) 739-3001
`
`1-WA/2211568 . 1
`
`InnoPharma Exhibit 1046.0004
`
`

`

`-1-
`
`FORMULATION
`
`The invention relates to a novel sustained release phannaceutical formulation adapted
`
`for administration by injection containing the compound
`5 70c-[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
`
`70L—[9-(4,4,5,S ,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. -
`
`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 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
`
`as tamoxifen, competeefficiently 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).
`i
`The potential for nonsteroidal antioestrogens to display agonistic properties prompted
`the search for novel compounds that would bind ER with high affinity without activating any i
`
`20
`
`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
`i
`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 a1 1989,
`
`Wakeling 1990a, 1990b, 1990c. Wakeling and Bowler 1987, 1988.
`
`Steroidal analogues of oestradiol, with an alkylsulphinyl side chain in the 70c position,
`
`provided the first examples of compounds devoid of oestrogenic activity (Bowler et a1 1989).
`
`30 One of these, 70t-[9-(4,4,5,5,5-pentafluoropentyl 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 1046.0005
`
`

`

`zi0635
`
`“
`
`'
`
`)
`
`)
`
`-2-
`
`antioestrogens. In vitro findings and early clinical experience with
`
`70t‘[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(10)-triene—3,17B-diol have
`
`promoted interest in the development of the drug as a therapeutic agent for oestrogen-
`
`dependent indications such as breast cancer and certain benign gynaecological conditions.
`
`7(1-[9-(4,4,5,5 ,5-Pentafluoropentylsulphjny1)nonyl]oestra-l ,3-5(lO)-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 .7_
`
`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 firlvestrant has none of the oestrogen-like stimulatory activity that is
`
`characteristic of clinically available antioestrogens such as tamoxifen or toremifene, it may
`
`offer improved therapeutic activity characterised by more rapid, complete, or longer-lasting
`
`tumour regression; a loWer 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 to'increased gonadotrophin secretion. If
`also true in humans, these findingshcould 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
`
`10
`
`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 7a—[9—(4,4,5,5,5-pentafluoropentylsulphinyl)nony1]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
`
`InnoPharma Exhibit 1046.0006
`
`

`

`Z70635 "
`
`“
`
`i
`
`l
`
`.)
`
`_3_'
`
`pharmaceutically-acceptable diluent or carrier. It is stated therein that the composition can be
`
`in a form suitable for oral or parenteral administration.
`Fulvestrant shows, along with other steroidal based compounds, certain physical
`
`properties which make 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 ngrnl’l (this is an estimate from a water/solvent
`
`mixture solute since measurements this low could not be achieved in a water only solute).
`
`Currently there are a number of sustained release inj ectable steroidal formulations
`
`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
`
`.25
`
`InnoPharma Exhibit 1046.0007
`
`

`

`Z70635
`
`PRODUCT NAME
`
`STEROID
`
`;
`
`DOSE
`
`ME
`
`C MP’.
`
`SOURCE . OIL
`
`
`. Bsz
`BzOH
`
`§_tO_Ij
`
`
`I_)_O_S_E_ DOSING
`
`'
`
`Table 1 - OIL BASED LONG-ACTING INTRAMUSCULAR INJECTIONS
`
`SUSTANON 100
`
`PROLUTON
`DEPOT
`
`TOCOGESTAN
`
`TROPHOBOLENE
`
`NORISTERAT
`
`.
`
`Testosterone proprionate
`Testosterone
`phenylproprionate
`Testosterone isocaproate ,
`Testosterone decanoate
`Hydroxy progesterone
`hexanoate
`
`Hydroxy progesterone
`enantate
`Progesterone
`a-Tocopherol
`Estrapronicate
`Nandrolone undecanoate
`Hydroxyprogesterone
`heptanoate
`Norethisterone
`oenanthoate
`
`Estradiol
`BENZO-
`hexahydrobenzoate
`GYNOESTRYL
`PROGESTERONE Hydroxy progesterone
`-RETARD
`caproate
`GRAVIBINAN
`Estradiol 17-[3ovalerate
`Hydroxyprogesterone
`caproate
`
`30mg Androgen
`60mg '
`'
`
`Organon
`
`Arachis
`
`0.1m!
`
`1ml
`
`3 weeks
`
`ABPI Data
`Sheet
`Comp. 1999
`,
`
`60mg
`100mg
`250mgml'I
`
`Progestogen
`
`,
`
`Schering ‘ ABPI Data
`HC
`Sheet
`
`Castor
`.
`
`up to
`46%
`
`1 or
`2ml
`
`1 week
`
`w.
`
`‘
`
`200mg
`
`Progestogen
`
`Comp.1999
`Theramax Diet. Vidal
`1999
`
`Ethyl
`oleate
`
`I“40%
`
`Zml
`
`< lweek
`
`50mg
`250mg
`1.3mg Mixed
`50mg
`80mg
`
`Theramax
`
`Dict. Vidal
`1997
`
`Olive
`
`45%
`
`'
`
`_1m]
`
`15 to 30
`days
`
`‘
`
`200mg Contraceptive
`
`Schering - ABPI Data
`HC
`Sheet
`
`Castor
`
`YES
`
`5mg Estradiol
`
`Roussel
`
`.
`250mgml'l
`
`Progestogen
`
`Pharlon
`
`5mgml'l Mixed
`250mgmr‘
`
`Schering
`HC
`
`Comp.1999
`Dict. Vidal
`199 8
`Diet. Vidal
`1999
`Diet. Vidal
`1995
`
`Arachis
`
`i
`
`Castor
`
`.
`YES
`
`Castor
`
`YES
`
`lrnl
`
`8 weeks
`
`1m]
`
`1 or
`2m]
`1 or
`2m]
`
`1 week
`'
`1 week
`
`1 - 2
`weeks
`
`H.
`
`InnoPharma Exhibit 1046.0008
`
`

`

`Z70635
`
`PARABOLAN
`
`Trenbolone
`
`76mg Androgen
`
`Negma
`
`DELESTROGEN
`
`Estradiol
`valerate
`
`.
`20mgml"
`40mgml‘|
`
`Estradiol
`
`BMS
`
`DELALUTIN
`
`l7-Hydroxy
`progesterone
`
`.
`
`250mgml'l
`
`Progestmgen
`
`DMS
`
`Diet. Vidal
`1997
`J.Pharm.
`Sci
`(1964)
`53(8) 891
`J.Phann.
`Sci.(1964)
`53(8) 891
`
`Arachis
`
`* 75mg
`
`45mg
`
`1.5ml
`
`Zweeks
`
`Castor
`
`78%
`58%
`
`20%
`40%
`
`2%
`2%
`
`Castor
`
`YES
`
`YES
`
`up to
`2%
`
`g
`
`.
`
`-
`
`v
`
`EtOH = ethanol Dict. Vidal = Dictionnaire Vidal
`Bsz = benzylbenzoate BzOH = benzylalcohol
`5 % are w/v and “' approximate as measured directly from a single sample
`
`InnoPharma Exhibit 1046.0009
`
`

`

`2&0635 5
`
`"
`
`'
`
`r
`
`'
`
`l
`
`l
`
`-6-
`
`described which comprises 50mg of fulvestrant,400mg of benzyl alcohol and sufficient castor
`
`oil to bring the solution to a volume of 1 m1. 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 fulvestrant from the formulation.
`
`Table 2 shows the solubility of fiilvestrant in a number of different solvents.
`
`Table 2 - SOLUBILITY OF FULVESTRANT
`
`SOLUBILITY
`
`(mgrnl‘ at 25°C)
`
`0.001
`
`0.45
`
`0.58
`
`20
`
`3.06
`
`2.72
`
`1.25
`
`6.15
`
`0.80
`3.79
`
`>200
`
`>200
`
`I
`
`'
`
`p
`
`'
`
`i
`
`‘
`
`SOLVENT
`
`Water
`
`Arachis oil
`
`Sesame oi]
`
`Castor oil
`
`Miglyol 810
`
`Miglyol 812
`
`Ethyl oleate
`
`Benzyl benzoate
`
`Isopropyl myristate
`Span 85 (surfactant)
`
`Ethanol
`
`Benzyl Alcohol
`
`As can be seen fiilvestrant 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
`
`I constituent of the fatty acids within the triglycerides present in castor oil - see (Riffldn et.a1. 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
`
`InnoPharma Exhibit 1046.0010
`
`

`

`23.0635 '-
`
`"
`
`'
`
`3,
`
`-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 m1. 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
`
`intramuscularly 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
`
`miscible with castor oil, may be used, such as an alcohol. With the addition of high
`
`concentrations of an alcohol concentrations of >50mgml‘l of fulvestrant 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 fulvestrant into
`
`a concentration of at least 50 mgrnl'1 - see Table 3 below. The finding is surprising since the
`
`solubility of fulvestrant in nomaqueous ester solvents - see Table 2'above - is significantly
`lower than the solubilityiof fiilvestrant in an alcohol. The solubility of fulvestrant is also lower
`
`A in non-aqueous ester solvents than is the solubility of fulvestrant in castor oil.
`
`Therefore, we present as a feature of the invention a pharmaceutical formulation
`
`comprising fiilvestrant (preferably fulvestrant is present at 3-10%w/v, 4-9%w/v, 4—8%w/v,
`
`4-7%w/v, 4-6%w/v and most preferably at about 5%w/v) in a ricinoleate vehicle, a
`
`pharmaceutically acceptable non-aqueous ester solvent, and a 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
`
`which is capable afier 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-niuscular injection cemprising 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
`
`InnoPharma Exhibit 1046.0011
`
`

`

`270635 ’-
`
`"
`
`‘
`
`g
`
`'
`
`-3-
`
`y)
`
`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
`
`fiilvestrant 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 pharrnaceutically—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
`fulvestrant.
`‘
`
`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
`
`formulation a certain percentage of the constituent by weight will be present, for example a_
`
`1% weight per volume formulation will contain within a 100ml volume of formulation lg of
`
`15
`
`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 45mgml" .
`
`2.
`
`The total amount of fillvestrant in the formulation is 250mg, or more, and the total
`
`volume of the formulation is 6ml, or less.
`
`3.
`
`The total amount of fulvestrant in the formulation is 250mg and the total volume of
`
`25
`
`the formulation is 5-5.25ml.
`
`InnoPharma Exhibit 1046.0012
`
`

`

`zi0635 '
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`~
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`"
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`5
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`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 0.25m1, preferably
`
`up to 0.15ml will also be present in the formulation. 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.
`
`Preferred concentrations of a pharmaceutically-acceptable alcohol present in any of the
`
`above'formulations are; at least 3%w7v, 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,
`
`10 preferably, at least 16% w/v. Preferred maximal concentrations of pharrnaceutically-
`
`acceptable alcohol present in the formulation are ;2 8% w/v or less, 22% w/v or less and 20%
`
`w/v or less.. Preferred ranges of pharmaceutically-acceptable alcohol present in any of the
`above formulations are selected from any minimum or maximum value described above and
`
`preferably are; 3—3 5%w/v, 4-35%w/v, 5-35%w/v, 5-32%w/v, 7-32%w/v, 10—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.
`The pharmaceutically-acceptable alcoholmay 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
`20 formulation in the same w/v amounts. Preferably the formulation alcohol contains 10% w/v
`‘ ethanol and 10% w/v benzyl alcohol.
`
`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 pharmaceutically-acceptable non-aqueous ester solvent for parenteral
`
`25 administration is selected fi'orn 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%
`
`weight per volume of formulation.
`
`30
`
`It will be understood by the skilled person that the phannaceutically-acceptable
`
`alcohol will be of a quality such that it will meet pharmacopoeial standards (such as are
`
`described in the US, British, European and Japanese pharmacopoeias) and as such will contain
`
`InnoPharma Exhibit 1046.0013
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`

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`270635 ’-
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`some water and possibly other organic solvents, for example ethanol in the US Pharmacopeia
`
`contains not less than 94.9% by volume and not more than 96.0% by volume of ethanol when
`
`measured at 15.56°C. Dehydrated alcohol in the US Pharrnacopeia contains not less than
`
`99.5% ethanol by volume when measured at 15.56°C.
`Preferred concentrations of the pharrnaceutically-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
`
`10
`
`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
`
`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
`fiom any minimum or maximum value described above and preferably are; 5-60%w/v,‘ 7-
`
`55%w/v, 8-50%w/v, 10-50%w/v, 10-45%vv/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-
`
`15
`
`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).
`
`20
`
`Preferred combinations of pharmaceutically-acceptable alcohol and pharmaceutically—
`
`acceptable non-aqueous ester solvent in the formulation are set out below:
`
`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
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`InnoPharma Exhibit 1046.0014
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`

`

`220635 '-
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`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.
`
`preferably each at about 10%
`
`ethanol and benzyl alcohol, most
`
`benzyl benzoate, most preferably at about 15%
`
`By the use of the term ricinoleate vehicle we mean an oil which has'as a proportion (at
`least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or‘95% w/v) of its composition as
`triglycerides of ricinoleic acid. The ricinoleate vehicle may be a synthetic oil or conveniently
`
`is castor oil, ideally of 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.
`
`10
`
`1.
`
`Previously tested by the applicants have been intra—mtiscular injections of fulvestrant
`
`in the form of an aqueous suspension. We have found entensive local tissue irritation at the
`
`injection site as well as a poor release profile. It is believed that the tissue
`
`irritation/inflammation was due to the presence of fulvestJant in the form of solid particles.
`
`The release profile appeared to be determined by the extent of inflammation/irritation present
`
`at the injection site and this was variable and difficult to control. Also the fulvestrant release
`
`rate was not sufficiently high to be clinically significant.
`
`2.
`
`Our findings from studies using 14C labelled benzyl alcohol show that it dissipates
`
`rapidly from the injection site and is removed from the body Within 24 hours of
`
`administration.
`
`It would be expected that ethanol will dissipate at least as quickly, if not more rapidly,
`
`15
`
`20
`
`from the injection site.
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`InnoPharma Exhibit 1046.0015
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`zi063s ‘-
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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
`
`Pharmacopoeia 32nd edition page 1 103, and, therefore, it is unlikely that benzyl benzoate,
`
`when used, is present at the injection site during the whole of the extended release period.
`
`5
`
`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 fonnulation vehicle and the site of injection afier 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
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`By use of the term “therapeutically significant levels” we mean that blood plasma
`
`concentrations of at least 2.5 ngml'l, ideally at least 3 ngml‘l, at least 8.5 ngml'l, and up to 12
`
`rigml‘1 of fulvestrant are achieved in the patient. Preferably blood plasma levels shouldbe less
`
`than 15 ngml“.
`
`By use of the term “extended release” we mean at least two weeks, at least three
`
`15 weeks, and, preferably at least four weeks of continuous release of fulvestrant is achieved. In a
`
`preferred feature extended release is achieved for 36 days.»Preferably extended release of
`
`fulvestrant is for at least 2- 5 weeks and more preferably for the following periods (weeks)
`2.5-5, 25-4, 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
`
`20
`
`in two separate injections of 2.5ml, 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
`
`25 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.
`
`30
`
`InnoPharma Exhibit 1046.0016
`
`

`

`Z70635
`
`Ethanol
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`(96%)
`
`Benzyl
`
`Alcohol
`
`Benzyl
`
`Benzoaté
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`Castor Oil
`
`to 100
`
`Fulvestrant
`
`27
`
`'
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`Solubility
`
`[mgml'l ]
`
`Table 3 - EFFECT OF BENZYL BENZOATE ON FULVESTRANT SOLUBILITY IN CASTOR OIL AT 250C
`
`Table 3
`
`10
`
`0/0 W/V
`
`10
`
`15
`
`10
`
`10
`
`10
`
`10
`
`15
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`15
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`'
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`15
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`'—/
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`15
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`15
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`15
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`to 100
`
`to 100
`
`to 100
`
`46
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`54
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`45
`
`to 100
`
`65
`
`to 100
`
`to 100
`
`76
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`'
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`102
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`15
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`tolOO
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`36
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`k
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`InnoPharma Exhibit 1046.0017
`
`

`

`Z70635 "
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`-14-
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`The following Table 4 shows the solubility of fulvestrant in a range of oil based
`
`fonnulations which contain the same amounts of alcohol and benzyl benzoate but in which the
`
`oil is changed. The data also shows solubility of fulvestrant after removal of the alcohols.
`
`Table 4
`
`5 Solubility comparisons of fulvestrant in oil based formulations with and without
`alcohols
`
`
`
`
`Fulvestrant Solubility mg ml'1 @ 25°C
`Complete vehicle
`Vehicle minus alcohols
`
`10
`
`Formulation (a)
`
`Castor oil based
`
`.
`
`81.2
`
`-
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`' 12.6
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`is Miglyol 812-N based
`
`Sesame seed/Castor oil (1:1) based
`
`Sesame seed oil based
`
`20
`
`' Arachis oil-based
`
`86.8
`
`70.1
`
`45.7
`
`40.2
`
`V
`
`1.7
`
`4.4
`
`0.7
`
`< 0.2
`
`
`
`25
`
`(a) Complete Vehicle Formulations comprised ethanol [96%](10%), benzyl alcohol (10%) and benzyl benzoate
`(15%) made to volume with the stated oil. Excess fulvestrant was added to each solvent mixture and solubility
`determined.
`
`Effect of formulation on precipitation of fulvestrant at the injection site
`
`30
`
`Formulation ”
`
`Formulation F1
`35 castor oil based
`
`Formulation F2
`Miglyol 812-N based
`
`4o Formulation F3
`sesame seed oil/caster
`oil based
`
`Days
`
`2
`
`0
`
`3
`
`0
`
`.
`
`.
`
`4
`
`0
`
`‘
`
`7
`
`0
`
`10
`
`0
`
`30
`
`0
`
`++ b
`
`-l—l-l-
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`-l—H-
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`4—H-
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`-l—l-l-
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`-1—|-
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`+ °
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`4—:-
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`-l-l-
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`4—a—r
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`4+
`
`+
`
`‘
`
`51
`
`0
`
`0
`
`+
`
`45
`
`0, + , H, 4-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.
`b Mainly large needle shaped crystals
`° Small needles and/or sheafs of crystals
`
`InnoPharma Exhibit 1046.0018
`
`

`

`zr0635 '-
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`"
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`'
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`3
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`I
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`-15-
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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
`
`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). As can be seen the castor oil
`
`formulation showed a particularly even release profile with no evidence of precipitation of
`
`fulvestrant at the injection site.
`
`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 or a ricinoleate vehicle, taking into account the