(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`
`
`(43) International Publication Date
`23 January 2003 (23.01.2003)
`
`PCT
`
`(10) International Publication Number
`W() 03/006064 A1
`
`(51) International Patent Classification7:
`47/44, 47/10, 31/565
`
`A61K 47/14,
`
`(74) Agents: GILES, Allen, Frank et al.; Astrazeneca, Global
`Intellectual Property, Mereside, Alderley Park, Maccles—
`field, Cheshire SK10 4TG (GB).
`
`(21) International Application Number:
`
`PCT/GB02/03092
`
`(22) International Filing Date:
`
`3 July 2002 (03.07.2002)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`
`English
`
`English
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, 1N, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, M2, NO, NZ, OM, PH, PL, PT, Ro, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
`VN, YU, ZA, ZM, ZW.
`
`01166193
`60/315,711
`
`7 July 2001 (07-07-2001)
`30 August 2001 (30.08.2001)
`
`GB
`US
`
`(71) Applicant 0’0r all designated States except MG, US): AS-
`TRAZENECA AB [SE/SE]; S—151 85 Sodertalje
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, SK,
`TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`
`(71) Applicant (for MG only): ASTRAZENECA UK LIM—
`ITED [GB/GB]; 15 Stanhope Gate, London WlY 6LN
`(GB).
`
`GW’ ML, MR, NE, SN, TD, TG)-
`
`Published:
`7 with international search report
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): CAHILL, Julie,
`Kay [GB/GB]; Alderley Park, Macclesfield, Cheshire
`SK10 4TG (GB). GELLERT, Paul, Richard [GB/GB];
`Alderley Park, Macclesfield, Cheshire SK10 4TG (GB).
`IRVING, Alan, Marshall
`[GB/GB]; Alderley Park,
`Macclesfield, Cheshire SK10 4TG (GB).
`
`7 before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations ” appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`03/006064A1
`
`(54) Title: PHARMACEUTICAL FORMULATION FOR THE INTRAMUSCULAR ADMINISTRATION OF FULVESTRANT
`
`(57) Abstract: The invention relates to a sustained release pharmaceutical formulation adapted for administration by injection con—
`O tajning the compound fulvestrant, 7 a—[9—(4,4,5,5,5—pentafluoropentylsulphinyl)nonyl]oestra—l,3,5(10)—triene—3,l7 B—diol, at con—
`a centration ofat least 100mg/ml in solution in a ricinoleate vehicle which additionally comprises at least one alcohol and a non—aque—
`ous ester solvent which is miscible in the ricinoleate vehicle.
`
`InnoPharma Exhibit 1037.0001
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`-1-
`
`PHARMACEUTICAL FORMULATION FOR THE INTRAMUSCULAR ADMINISTRATION OF FULVESTRANT
`
`The invention relates to a sustained release pharmaceutical formulation adapted for
`
`administration by injection containing the compound fulvestrant, 7oc-[9-(4,4,5,5,5-
`
`5 pentafluoropentylsulphinyl)n0nyl]oestra-1,3,5(10)-triene-3,17B-diol, at concentration of at
`
`least 100mg/ml 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.
`
`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
`
`10
`
`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
`
`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
`
`15 as tamoxifen, compete efficiently for ER binding but their effectiveness is often limited by the
`
`partial agonism they display, which results in an incomplete blockade of oestrogen-mediated
`
`activity (Furr and Jordan, Pharmacology & Therapeutics, 2;:127-206, 1984; May and
`
`Westley, J Biol Chem @15894-15899, 1987).
`
`The potential for nonsteroidal antioestrogens to display agonistic properties prompted
`
`20 the search for novel compounds that would bind ER with high affinity without activating any
`
`of the normal transcriptional hormone responses and consequent manifestations of oestrogens.
`
`Such molecules would be “pure” antioestrogens, clearly distinguished from tamoxifen—like
`
`ligands and capable of eliciting complete ablation of the trophic effects of oestrogens. Such
`
`compounds are referred to as Estrogen Receptor-Downregulators (E.R.D.). The rationale for
`
`25 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 al 1989).
`
`One of these, 70t-[9-(4,4,5,5,5—pentafluoropenty1 sulphinyl)nonyl]oestra-1,3,5-(10)triene-
`
`30 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
`
`antioestrogens. In vitro findings and early clinical experience with
`
`InnoPharma Exhibit 1037.0002
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`-2-
`
`70c-[9-(4,4,5,5,5-pentafluoropentylsulphiny1)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.
`
`70t-[9-(4,4,5,5,5-Pentafluoropentylsulphinyl)nonyl]oestra-1,3-S(10)-triene-3 ,1 7B-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
`
`10
`
`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 toremifene, it may
`
`15
`
`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
`
`2O
`
`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
`
`the blood-brain barrier.
`
`25
`
`European Patent Application No. 0 138 504 discloses that certain steroid derivatives
`
`are effective antioestrogenic agents. The disclosure includes information relating to the
`
`preparation of the steroid derivatives. In particular there is the disclosure within Example 35
`
`of the compound 70t-[9-(4,4,5,5,5-pentafluoropenty1sulphinyl)nonyl]oestra-
`
`1,3,5(10)-triene-3,17B-diol, which compound is specifically named in Claim 4. It is also
`
`30
`
`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 1037.0003
`
`

`

`10
`
`15
`
`20
`
`W0 03/006064
`
`PCT/GB02/03092
`
`-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 ngml‘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
`
`which have been commercialised. Commonly these formulations use oil as a solvent and
`
`wherein additional excipients may be present.
`
`In US 5,183,814 Example 3 an oil based injection formulation of fulvestrant is
`
`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.
`
`The Table below shows the solubility of fulvestrant in a number of different solvents.
`
`SOLVENT
`
`Water
`
`Arachis oil
`
`Sesame oil
`
`Castor oil
`
`Miglyol 810
`
`Miglyol 812
`
`Ethyl oleate
`
`Benzyl benzoate
`
`Isopropyl myristate
`
`Span 85 (surfactant)
`
`SOLUBILITY OF FULVESTRANT
`
`SOLUBILITY
`
`(mgml‘l at 25°C)
`
`0.001
`
`0.45
`
`0.58
`
`20
`
`3.06
`
`2.72
`
`1.25
`
`6.15
`
`0.80
`
`3.79
`
`
`
`InnoPharma Exhibit 1037.0004
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`Ethanol
`
`Benzyl Alcohol
`
`- 4 _
`
`>200
`
`>200
`
`As can be seen fulvestrant is significantly more soluble in castor oil than any of the
`
`other oils tested. The greater solvating ability of castor oil for steroidal compounds is known
`
`and is attributed to the high number of hydroxy groups 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).
`
`Our earlier application PCT/GB01/00049, WO 01/51056, describes certain fulvestrant
`
`formulations at a most preferred concentration of 50mg/ml. This application disclosed one
`
`formulation with a solubility up to 102 mg/ml — see the last formulation in Table 3 thereof
`
`10
`
`with 15 % weight of ethanol per volume of formulation, 15 % weight of benzyl alcohol per
`
`volume of formulation, 15 % weight of benzyl benzoate per volume of formulation in a
`
`ricinoleate vehicle. However there is a need for further formulations of fulvestrant that
`
`contain high concentrations of fulvestrant to facilitate administration thereof at higher doses
`
`or less frequent intervals.
`
`15
`
`According to another aspect of the invention there is provided a pharmaceutical
`
`formulation adapted for intramuscular injection comprising 100 mg/ml or more of fulvestrant,
`
`10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation
`
`vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per
`
`volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of
`
`20
`
`formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol
`
`per volume of formulation vehicle and provided that the following formulation is excluded:
`
`fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 %
`
`weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate
`
`per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per
`
`25
`
`volume of formulation vehicle.
`
`A preferred pharmaceutical formulation adapted for intramuscular injection is one
`
`comprising 105 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically
`
`acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a
`
`pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and
`
`30
`
`5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the
`
`formulation comprises at least 5 % weight of ethanol per volume of formulation vehicle.
`
`InnoPharma Exhibit 1037.0005
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`- 5 _
`
`A more preferred pharmaceutical formulation adapted for intramuscular injection is
`
`one comprising 110 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically
`
`acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a
`
`pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and
`
`5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the
`
`formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation
`
`vehicle.
`
`A more preferred pharmaceutical formulation adapted for intramuscular injection is
`
`one comprising 115 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically
`
`acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a
`
`pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and
`
`5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the
`
`formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation
`
`vehicle.
`
`A more preferred pharmaceutical formulation adapted for intramuscular injection is
`
`one comprising 120 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically
`
`acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a
`
`pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and
`
`5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the
`
`formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation
`
`vehicle.
`
`A more preferred pharmaceutical formulation adapted for intramuscular injection is
`
`one comprising 130 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically
`
`acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a
`
`pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and
`
`5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the
`
`formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation
`
`vehicle.
`
`A more preferred pharmaceutical formulation adapted for intramuscular injection is
`
`one comprising 140 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically
`
`acceptable alcohol per volume of formulation vehicle, 12.5 % or more weight of a
`
`pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and
`
`5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the
`
`10
`
`15
`
`20
`
`25
`
`30
`
`InnoPharma Exhibit 1037.0006
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`- 6 _
`
`formulation vehicle comprises at least 10 % weight of ethanol per volume of formulation
`
`vehicle.
`
`A more preferred pharmaceutical formulation adapted for intramuscular injection is
`
`one comprising 150 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically
`
`acceptable alcohol per volume of formulation vehicle, 17.5 % or more weight of a
`
`pharrnaceutically acceptable non—aqueous ester solvent per volume of formulation vehicle and
`
`5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the
`
`formulation vehicle comprises at least 10 % weight of ethanol per volume of formulation
`
`vehicle.
`
`10
`
`15
`
`Another aspect of the invention provides any of the formulations described herein
`
`stated as having any minimum ethanol content removed. For example, the formulation
`
`described in the paragraph immediately above becomes: a pharmaceutical formulation adapted
`
`for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 15 % or more
`
`weight of a pharrnaceutically acceptable alcohol per volume of formulation vehicle, 17.5 % or
`
`more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of
`
`formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of
`
`formulation vehicle.
`
`According to another aspect of the invention there is provided a pharmaceutical
`
`formulation having a solubility for fulvestrant of at least Y mg/ml adapted for intramuscular
`
`20
`
`injection comprising;
`
`100 mg/ml or more of fulvestrant;
`
`5% (w/v) or more castor oil per volume of formulation vehicle;
`
`and at least the following amounts (% weight/volume of formulation vehicle) of ethanol
`
`(ETOH), benzyl alcohol (BA), benzyl benzoate (BB) determined by the algorithm:
`
`25
`
`Y = -29.77 + 5.44 x ETOH + 2.38 x BA +1.57 x BB
`
`wherein x is at least 100, ETOH is at least 5, BA is at least 5 and BB is at least 5.
`
`A preferred pharmaceutical formulation is one wherein Y is selected from the group
`
`consisting of 105,110,115,120,125,130,135,140,145,150,155,160,170,180,190, and
`
`200.
`
`30
`
`A more preferred pharmaceutical formulation is one wherein Y is selected from the
`
`group consisting of 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, and 200.
`
`A more preferred pharmaceutical formulation is one wherein Y is selected from the
`
`group consisting of 150, 155, 160, 170, 180, 190 and 200.
`
`InnoPharma Exhibit 10370007
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`- 7 _
`
`A more preferred pharmaceutical formulation is one wherein Y is selected from 150,
`
`155, 160, 170, 180, 190 and 200 and the formulation comprises at least lSOmg/ml of
`
`fulvestrant.
`
`A more preferred pharmaceutical formulation is one wherein Y is 200 and the
`
`formulation comprises at least 200mg/ml of fulvestrant.
`
`According to another aspect of the present invention there is provided a pharmaceutical
`
`formulation having a solubility for fulvestrant of at least 100 mg/ml adapted for intramuscular
`
`injection comprising;
`
`100 mg/ml or more of fulvestrant;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`5% (w/v) or more castor oil per volume of formulation vehicle;
`
`and at least the following amounts (% weight/volume of formulation vehicle) of ethanol
`
`(EtOH), benzyl alcohol (BA), benzyl benzoate (BB) determined by the algorithm:
`
`100 = -29.77 + 5.44 x ETOH + 2.38 x BA +1.57 x BB; and
`
`provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 %
`
`weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per
`
`volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation
`
`vehicle and 30 % or more weight of castor oil per volume of formulation vehicle.
`
`According to another aspect of the invention there is provided a pharmaceutical
`
`formulation comprising fulvestrant at a concentration of at least 100 mg/ml in which the
`
`formulation is adapted for intra-muscular injection into a human and which is capable after
`
`injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a
`
`human for at least 2 months and provided that the following formulation is excluded:
`
`fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 %
`
`weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate
`
`per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per
`
`volume of formulation vehicle.
`
`According to another aspect of the invention there is provided a pharmaceutical
`
`formulation comprising fulvestrant in which the formulation is adapted for intra-muscular
`
`injection into a human and which is capable after injection of attaining a therapeutically
`
`significant blood plasma fulvestrant concentration in a human for at least 2 months.
`
`According to another aspect of the invention there is provided a pharmaceutical
`
`formulation comprising fulvestrant at a concentration of at least 100 mg/ml in which the
`
`formulation is adapted for intra-muscular injection into a human and which is capable after
`
`InnoPharma Exhibit 1037.0008
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`-8-
`
`injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a
`
`human for at least 2 months.
`
`According to another aspect of the invention there is provided a pharmaceutical
`
`formulation comprising fulvestrant at a concentration of at least 150 mg/ml in which the
`
`formulation is adapted for intra-muscular injection into a human and which is capable after
`
`injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a
`
`human for at least 2 months.
`
`According to another aspect of the invention there is provided a pharmaceutical
`
`formulation comprising fulvestrant at a concentration of at least 200 mg/ml in which the
`
`formulation is adapted for intra-muscular injection into a human and which is capable after
`
`injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a
`
`human for at least 2 months.
`
`According to another aspect of the invention there is provided a pharmaceutical
`
`formulation comprising fulvestrant at a concentration of at least 300 mg/ml in which the
`
`formulation is adapted for intra-muscular injection into a human and which is capable after
`
`injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a
`
`human for at least 2 months.
`
`According to one aspect of the invention there is provided any one of the following
`
`10
`
`15
`
`pharmaceutical formulations comprising about:
`
`20
`
`i)
`
`10% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`15% weight per volume of benzyl benzoate
`
`500-555mg of fulvestrant for each 5ml of finished formulation
`
`25
`
`30
`
`and the remaining amount as castor oil;
`
`ii)
`
`10% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`500-700mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`iii)
`
`10% weight per volume of ethanol
`
`
`
`InnoPharma Exhibit 1037.0009
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`20% weight per volume of benzyl alcohol
`
`50% weight per volume of benzyl benzoate
`
`500-750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as cast'or oil;
`
`iv)
`
`20% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`500-1175mg of fulvestrant for each 5ml of finished formulation
`
`10
`
`15
`
`and the remaining amount as castor oil;
`v)
`r
`
`15% weight per volume of ethanol
`
`10% weight per volume of benzyl alcohol
`
`50% weight per volume of benzyl benzoate
`
`500-810 mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`vi)
`
`15% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`20
`
`50% weight per volume of benzyl benzoate
`
`500 mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`vii)
`
`15% weight per volume of ethanol
`
`25
`
`20% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`500-630mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`viii)
`
`30
`
`10% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`50% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`InnoPharma Exhibit 1037.0010
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`-10-
`
`and the remaining amount as castor oil;
`
`ix)
`
`20% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`X)
`
`15% weight per volume of ethanol
`
`10
`
`10% weight per volume of benzyl alcohol
`
`50% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`xi)
`
`15
`
`9% weight per volume of ethanol
`
`19% weight per volume of benzyl alcohol
`
`47% weight per volume of benzyl benzoate
`
`700mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`20
`
`xii)
`
`14% weight per volume of ethanol
`
`19% weight per volume of benzyl alcohol
`
`48% weight per volume of benzyl benzoate
`
`700mg of fulvestrant for each 5ml of finished formulation
`
`25
`
`and the remaining amount as castor oil;
`
`xiii)
`
`15% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`45% weight per volume of benzyl benzoate
`
`30
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`xiv)
`
`9% weight per volume of ethanol
`
`InnoPharma Exhibit 1037.0011
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`-11-
`
`19% weight per volume of benzyl alcohol
`
`47% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`xv)
`
`19% weight per volume of ethanol
`
`19% weight per volume of benzyl alcohol
`
`28% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`10
`
`and the remaining amount as castor oil;
`
`xvi)
`
`14% weight per volume of ethanol
`
`9% weight per volume of benzyl alcohol
`
`47% weight per volume of benzyl benzoate
`
`15
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`xvii)
`
`14% weight per volume of ethanol
`
`19% weight per volume of benzyl alcohol
`
`20
`
`47% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`xviii)
`
`10% weight per volume of ethanol
`
`25
`
`20% weight per volume of benzyl alcohol
`
`45% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`xix)
`
`30
`
`15% weight per volume of ethanol
`
`10% weight per volume of benzyl alcohol
`
`45% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`
`
`InnoPharma Exhibit 1037.0012
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`-12..
`
`and the remaining amount as castor oil;
`
`xx)
`
`20% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`25% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`xxi)
`
`10% weight per volume of ethanol
`
`10
`
`30% weight per volume of benzyl alcohol
`
`25% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`xxii)
`
`15
`
`10% weight per volume of ethanol
`
`25% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`20
`
`xxiii)
`
`10% weight per volume of ethanol
`
`30% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`25
`
`and the remaining amount as castor oil;
`
`xxiv)
`
`15% weight per volume of ethanol
`
`25% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`30
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil;
`
`xxv)
`
`15% weight per volume of ethanol
`
`InnoPharma Exhibit 1037.0013
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`- 13 -
`
`25% weight per volume of benzyl alcohol
`
`25% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil; and
`
`xxvi)
`
`15% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil.
`
`The term “comprising about” in this context means that the numerical value assigned
`
`to each component of the formulation may be varied independently to accommodate
`
`manufacturing specifications encountered by a skilled person when making up the
`
`formulations. Typically this means plus or minus 5%, more preferably plus or minus 4%,
`
`more preferably plus or minus 3%, more preferably plus or minus 2%, more preferably plus or
`
`minus 1%. In a preferred embodiment, more variation in drug level is allowed compared with
`
`other components. For example:
`
`10
`
`15
`
` _
`
`Drug (+/- %)
`
`5
`
`
`
`
`
`
`
`
`
`
`
`
`20
`
`The individual formulations described herein may comprise further excipients
`
`commonly used in the formulation field including, for example, an antioxidant preservative, a
`
`colorant or a surfactant.
`
`According to another aspect of the invention there is provided any one of the following
`
`pharmaceutical formulations:
`
`25
`
`i)
`
`10% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`InnoPharma Exhibit 1037.0014
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`-14-
`
`15% weight per volume of benzyl benzoate
`
`500-555mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil
`
`ii)
`
`10% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`500-700mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil
`
`10
`
`iii)
`
`10% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`50% weight per volume of benzyl benzoate
`
`500-750mg of fulvestrant for each 5ml of finished formulation
`
`15
`
`and the remaining amount as castor oil
`
`iv)
`
`20% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`500-1175mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil
`
`V)
`
`15% weight per volume of ethanol
`
`10% weight per volume of benzyl alcohol
`
`5 0% weight per volume of benzyl benzoate
`
`500-810 mg of fulvestth for each 5ml of finished formulation
`
`and the remaining amount as castor oil
`
`vi)
`
`15% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`50% weight per volume of benzyl benzoate
`
`500 mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil
`
`20
`
`25
`
`30
`
`InnoPharma Exhibit 1037.0015
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`- 15 -
`
`vii)
`
`15% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`500-630mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil
`
`viii)
`
`10% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`50% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil
`
`ix)
`
`20% weight per volume of ethanol
`
`20% weight per volume of benzyl alcohol
`
`30% weight per volume of benzyl benzoate
`
`750mg of fulvestrant for each 5ml of finished formulation
`
`10
`
`15
`
`and the remaining amount as castor oil
`
`X)
`
`20
`
`15% weight per volume of ethanol
`
`10% weight per volume of benzyl alcohol
`
`50% weight per volume of benzyl benzoate
`
`750mg of fiilvestrant for each 5ml of finished formulation
`
`and the remaining amount as castor oil.
`
`25
`
`30
`
`A preferred pharmaceutical formulation described herein is one wherein the
`
`pharmaceutically-acceptable alcohol is a mixture of ethanol and benzyl alcohol.
`
`A preferred pharmaceutical formulation described herein is one wherein the
`
`pharmaceutically-acceptable non-aqueous ester solvent is selected from benzyl benzoate, ethyl
`
`oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof.
`
`A preferred pharmaceutical formulation described herein is one wherein the
`
`pharmaceutically-acceptable non-aqueous ester solvent is benzyl benzoate.
`
`A preferred pharmaceutical formulation described herein is one wherein the ricinoleate
`
`excipient is castor oil.
`
`InnoPharma Exhibit 10370016
`
`
`
`

`

`W0 03/006064
`
`PCT/GB02/03092
`
`-16-
`
`According to one aspect of the present invention there is provided a pharmaceutical
`
`formulation adapted for intramuscular injection comprising 100 mg/ml or more of fulvestrant,
`
`lO % or more weight of a