`
`flu
`
`ATTORNEY DOCKET NO.: 056291-5004-O117497u.s.PTO10/872784
`
`PATENT
`
`llllllllll
`
`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:
`
`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 l)
`
`3.
`
`Oath or Declaration
`
`E 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 and is hereby
`incorporated by reference therein.
`»
`
`1~wA/2211553 . 1
`
`|nnoPharma 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
`
`[Z
`
`A Preliminaiy 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/International priority is claimed under 35 USC 119(e)/120/365(c) based on the
`following provisional, nonprovisional and/or PCT international app1ications(s):
`
`
`Filing Datemi
`09/756,291
`1
`9. 2001 —*
`Janua
`
`
`
`.—
`
`
`
`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.
`
`IX]
`
`Priority of the following foreign application(s) is/are claimed: i
`
`
`
`
`Certified copy(ies):
`
`0000313.7
`0O08837.7
`l:] is/are attached.
`C] will follow.
`was/were filed in prior U.S. Application No. 09/756,291
`filed January 9, 2001.
`
`January 10, 2000
`April 12,2000
`
`
`
`
`
`5.
`
`6.
`
`7.
`
`Assignment
`
`[Z
`
`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
`
`|nnoPharma Exhibit 1046.0002
`
`
`
`PATENT
`ATTORNEY DOCKET NO. 056291-5004-O1
`Continuation of Application No.: 09/756,291
`Page 3
`
`8.
`
`Fee Calculation (37 C.F.R. § 1.16)
`
`;Z-__ 2;
`1% 2
`F:ct:
`L._._..——_
`.——_*:“
`.._.._.1:1:
`
`0 1
`
`70339
`
`Filed Afler
`Preliminary
`Amendment
`
`Basic Fee
`
`Utility $770.00
`
`D Assignment Recording Fee TOTAL FEE =
`
`Independent Claims
`
`(37 C.F.R.§1.16(b))
`
`I] First presentation of Multiple Dependent Claim(s)
`
`L__
`
`Power of Attorney
`
`IE
`
`El
`
`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
`
`|nnoPharma Exhibit 10460003
`
`
`
`PATENT
`ATTORNEY DOCKET NO. 056291-5004-O1
`
`Continuation of Application No.: 09/756,291
`Page 4
`
`10.
`
`Fee Payment
`
`[X]
`
`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, D.C. 20004
`Tel. No.: 202-739~3000
`
`DJB:mk
`
`1-WA/2211568 . 1
`
`|nnoPharma Exhibit 1046.0004
`
`
`
`-1-
`
`FORMULATION
`
`The invention relates to a novel sustained release pharmaceutical formulation adapted
`
`for administration by injection containing the compound
`5 70c-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(1O)-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 ,1”/B-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, cornpeteefficiently 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).
`9
`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 9
`
`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
`A
`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 70¢ 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 su1phinyl)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
`
`|nnoPharma Exhibit 1046.0005
`
`
`
`Z"/0635
`
`“
`
`'
`
`)
`
`'
`
`i
`
`-2-
`
`)
`
`antioestrogens. In vitro findings and early clinical experience with
`
`7ot—[9-(4,4,5,5,5-pentafluoropentylsulphir1yl)nonyl]oestra-1,3-5(l0)-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.
`
`70¢-[9-(4,4,5,5 ,5-Pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(10)—triene-3,l7[3-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 fiilvestrant 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 findingsficould 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 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
`
`|nnoPharma Exhibit 1046.0006
`
`
`
`zi0635 '-
`
`“
`
`'
`
`)
`
`I
`
`'
`
`-3-‘
`
`kl
`
`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 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
`
`b 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
`
`|nnoPharma Exhibit 1046.000?
`
`
`
`Z70635
`
`Table 1 - OIL BASED LONG-ACTING INTRAMUSCULAR INJECTIONS
`
`PRODUCT NAME
`
`STEROID
`
`;
`
`_l_)_Q_SE
`
`mg;
`
`C MP’.
`
`SOURCE _ Q11,
`
`_ BzBz
`
`BzOH
`
`EtQ_lj
`
`I_)_O_S_l_5_ DOSING
`
`'
`
`SUSTANON 100
`
`PROLUTON
`DEPOT
`
`TOCOGESTAN
`
`TROPHOBOLENE
`
`NORISTERAT
`
`-
`
`Testosterone proprionate
`Testosterone
`phenylproprionate
`Testosterone isocaproate V
`Testosterone decanoate
`Hydroxy progesterone
`hexanoate
`
`Hydroxy progesterone
`enantate
`Progesterone
`oi-Tocopherol
`Estrapronicate
`Nandrolone undecanoate
`Hydroxyprogesterone
`heptanoate
`Norethisterone
`oenanthoate
`
`Estradiol
`BENZO-
`hexahydrobenzoate
`GYNOESTRYL
`PROGESTERONE Hydroxy progesterone
`-RETARD
`caproate
`GRAVIBINAN
`Estradiol 17-[3—valerate
`Hydroxyprogesterone
`caproate
`
`30mg Androgen
`60mg '
`'
`
`Organon
`
`Arachis
`
`0.1rnl
`
`1ml
`
`3 weeks
`
`ABPI Data
`Sheet
`Comp. 1999
`»
`
`60mg
`100mg
`250mgm]"
`
`Progestogen
`
`.
`
`Schering ‘ ABPI Data
`HC
`Sheet
`
`Castor
`.
`
`up to
`46%
`
`1 or
`2ml
`
`1 week
`
`V"
`
`_
`
`200mg
`
`Progestogen
`
`Comp.1999
`Theramax Diet. Vidal
`1999
`
`Ethyl
`oleate
`
`*40%
`
`Zml
`
`< lweek
`
`50mg
`250mg
`1.3mg Mixed
`50mg
`80mg
`
`Theramax
`
`Dict. Vidal
`1997
`
`Olive
`
`45%
`
`*
`
`_1ml
`
`15 to 30
`days
`
`'
`
`200mg Contraceptive
`
`Schering - ABPI Data
`HC
`Sheet
`
`Castor
`
`YES
`
`5mg Estradiol
`
`Roussel
`
`I
`250mgml"
`
`Progcstogen
`
`Pharlon
`
`Smgml" Mixed
`250mgml”'
`
`Schering
`HC
`
`Comp.1999
`Dict. Vidal
`199 8
`Dict. Vidal
`1999
`Diet. Vidal
`1995
`
`Arachis
`
`C
`
`Castor
`
`.
`YES
`
`Castor
`
`YES
`
`lrnl
`
`8 weeks
`
`1m]
`
`1 or
`2m]
`1 or
`2m]
`
`1 week
`'
`1 week
`
`1 - 2
`weeks
`
`\__
`
`|nnoPharma Exhibit 1046.0008
`
`
`
`Z70635
`
`PARABOLAN
`
`Trenbolone
`
`76mg Androgen
`
`Negma
`
`DELESTROGEN
`
`Estradiol
`valerate
`
`.
`20mgml"
`40mgml"
`
`Estradiol
`
`BMS
`
`DELALUTIN
`
`17-Hydroxy
`progesterone
`
`.
`
`250mgm]"
`
`Progestrogen
`
`DMS
`
`Diet. Vidal
`1997
`J.Pharm.
`Sci
`(1964)
`53(8) 891
`J.Phann.
`Sci.(1964)
`53(8) 891
`
`Arachis
`
`* 75mg
`
`45mg
`
`1.5m1
`
`Zweeks
`
`Castor
`
`78%
`58%
`
`20%
`40%
`
`2%
`2%
`
`Castor
`
`YES
`
`YES
`
`up to
`2%
`
`p
`
`.
`
`-
`
`*-
`
`EtOH = ethanol Dict. Vidal = Dictionnaire Vidal
`BzBz = benzylbenzoatc BZOH = benzylalcohol
`5 % are w/v and “‘ approximate as measured directly from a single sample
`
`|nnoPharma Exhibit 1046.0009
`
`
`
`ziosss '-
`
`"
`
`'
`
`.1
`
`'
`
`A
`
`i
`
`l
`
`-5-
`
`described which comprises 50mg of fulvestrant,‘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 fulvestrant fiom the formulation.
`
`Table 2 shows the solubility of fiilvestrant in a number of different solvents.
`
`Table 2 - SOLUBILITY OF FULV}iZSTRANT
`
`SOLlJB1LITY
`
`(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
`
`I
`
`'
`
`p
`
`'
`
`0
`
`‘
`
`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 atuibuted 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.
`
`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
`
`|nnoPharma Exhibit 1046.001O
`
`
`
`ziosss '-
`
`"
`
`'
`
`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 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. 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" 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 mgml‘l - see Table 3 below. The finding is surprising since the
`
`solubility of fulvestrant in non-aqueous ester solvents - see Table 2'above - is significantly
`lower than the solubilityiof fulvestrant 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 fulvestrant (preferably fulvestrant is present at 3-1 O%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-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
`
`|nnoPharma Exhibit 1046.0011
`
`
`
`Z70635 ’-
`
`"
`
`’
`
`3
`
`i
`
`A
`
`t
`
`-3-
`
`: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
`
`fillvestrant concentration for at least 2 weeks.
`
`Further features of the invention include a phazmaceutical fonnulation 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 fonnulation, 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.
`‘
`
`T
`
`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 at 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 6rnl, or less, and the concentration of
`
`fulvestrant is at least 45mgml" .
`
`2.
`
`The total amount of fiilvestrant in the formulation is 250mg, or more, and the total
`
`volume of the formulation is 6ml, or less.
`
`3.
`
`The total amount of fillvestrant in the formulation is 250mg and the total volume of
`
`25
`
`the formulation is 5-5.25ml.
`
`|nnoPharma Exhibit 1046.0012
`
`
`
`z'io63s ‘
`
`-
`
`"
`
`‘
`
`5
`
`‘
`
`i
`
`‘J
`
`-9-
`
`It is appreciated that in the formulation an excess of formulation may be included to
`
`allow the attendant physician or care giver to be able to deliver the required close. Therefore,
`when a 5ml dose is required it would be appreciated that an excess of up to 0.25ml, 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
`
`aboveformulations 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 pharmaceutically-
`
`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-I:’:2%w/v, 7-32%w/v, l0—30%w/v, 12-
`
`15 28%w/v, 15-25%w/v, 17-23%w/V, 18-22%w/v and ideally 19-2l%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 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
`
`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 pharrnaceutically-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
`
`|nnoPharma Exhibit 10460013
`
`
`
`270635 ’-
`
`--
`
`'
`
`1
`
`i
`
`i
`
`-10-
`
`1
`
`some water and possibly other organic solvents, for exarnple ethanol in the US Pharmacopeia
`
`contains not less than 94.9% by volume and not more than 96.0% by volume of ethanol when
`
`meas_ured 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
`
`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
`Japanese pharrnacopoeias).
`
`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
`
`ailcohol("/ow/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
`
`|nnoPharma Exhibit 1046.0014
`
`
`
`2.70635 '-
`
`"
`
`’
`
`l
`
`5;"
`
`-11 -
`
`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.
`
`preferably each at about 10%
`
`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%
`
`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) 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 thepabove 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-muscular injections of fulvestrant
`
`in the form of an aqueous suspension. We have found eiitensive local tissue irritation at the
`
`injection site as well as a poor release profile. It is believed that the tissue
`
`irritation/inflarnrnation was due to the presence of fulvesuant 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.
`
`|nnoPharma Exhibit 1046.0015
`
`
`
`Z’./D635 *
`
`"
`
`i
`
`V)
`
`i
`
`l
`
`-12-
`
`l
`
`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
`
`V
`
`We have found that despite the rapid elimination of the additional solubilising
`
`excipients, i.e. the alcohol and pharmaceutically-acceptable non-aqueous ester solvent, from
`
`the formulation vehicle and the site of injection 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
`
`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 ngmfl, at least 8.5 ngml'l, and up to 12
`
`ngml’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.>Preferab1y extended release of
`
`fulvestrant is for at least 2- 5 weeks and more preferably for the following periods (weeks)
`2.5-S, 2.5-4, 3-4, 3.5-V4 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 Sml 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
`
`|nnoPharma Exhibit 1046.0016
`
`
`
`Z70635
`
`Ethanol
`
`(96%)
`
`Benzyl
`
`Alcohol
`
`Benzyl
`
`Benzoaté
`
`Castor Oil
`
`to 100
`
`Fulvestrant
`
`27
`
`Solubility
`
`lmgml" ]
`
`Table 3 - EFFECT OF BENZYL BENZOATE ON FULVESTRANT SOLUBILITY IN CASTOR OIL AT 25°C
`
`Table 3
`
`—«
`
`15
`
`15
`
`15
`
`15
`
`15
`
`to 100
`
`to 100
`
`to 100
`
`46
`
`54
`
`45
`
`to 11)O
`
`65
`
`to 100
`
`to 100
`
`76
`
`102
`
`15
`
`to100
`
`36
`
`K
`
`|nnoPharma Exhibit 1046.001?
`
`
`
`z"/6635 "
`
`"
`
`’ 3
`
`'
`
`A
`
`-14-
`
`I)
`
`The following Table 4 shows the solubility of fulvestrant in a range of oil based
`
`formulations which contain the saine 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
`
`A
`
`81.2
`
`-
`
`' 12.6
`
`.195 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
`
`'
`
`1.7
`
`4.4
`
`0.7
`
`< 0.2
`
`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
`determined.
`
`Effect of formulation on precipitation of fulvestrant at the injection site
`
`30
`
`Formulation 3
`
`Formulation F1
`35 Castor oil based
`
`Formulation F2
`Miglyol 812-N based
`
`40 Formuiation F3
`sesame seed oil/castor
`oil based
`
`Days
`
`2
`
`0
`
`3
`
`0
`
`-
`
`-
`
`4
`
`0
`
`‘
`
`7
`
`0
`
`10
`
`0
`
`30
`
`0
`
`+-F "
`
`+-l—l-
`
`+-l—l-
`
`-l—l—l-
`
`-l—H-
`
`++
`
`+ °
`
`4—a-
`
`++
`
`+—l—l-
`
`4+
`
`+
`
`.
`
`51
`
`0
`
`0
`
`+
`
`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
`
`|nnoPharma Exhibit 1046.0018
`
`
`
`z'f0635 '
`
`-15-
`
`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; nurnber of animals per timepoint = 8, plasma sarnples 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 of a ricinoleate vehicle, taking into account the
`addition of any further optional pharmaceutically-acceptable excipients, so as to prepare a
`
`formulation of at least 45mgml“ of fulvestrant.
`
`I
`
`A fiirther feature of the invention is a pharmaceutical formulationadapted for
`
`intramuscular injection,