WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`‘M
`WO 97/21440
`
`(11) International Publication Number:
`
`(51) International Patent Classification 6 =
`
`A61K 31/565, 9/08, 47/44
`
`A]
`
`_
`_
`_
`(43) International Publication Date:
`
`19 June 1997 (19.06.97)
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`HU, IL. IS. JP, KE. KG, KP. KR, KZ, LC. LK. LR. LS,
`LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL,
`PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, T1“, UA,
`UG, US, UZ, VN, ARIPO patent (KE, LS, MW, SD, SZ,
`UG), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TI,
`TM), European patent (AT, BE, CH, DE, DK, ES, Fl, FR,
`GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (HF,
`135. CF. CG, CI. CM. GA. GN, ML. MR. NE. SN, TD. TG).
`
`Published
`
`With international search report.
`
`(21) International Application Number:
`
`PCT/GB96/03022
`
`(22) International Filing Date:
`
`9 December 1996 (09.l2.96)
`
`(30) Priority Data:
`9525l94.8
`
`12 December I995 (l2.l2.95)
`
`GB
`
`(71) Applicant (for all designated States except US): ZENECA
`LIMITED [GB/GB];
`I5 Stanhope Gate, London WIY 6LN
`(GB).
`
`(72) Inventors; and
`FERDINANDO,
`(for US only):
`(75) Inventors/Applicants
`Josephine,
`loan, Christine [GB/GB]; Frankland Road,
`Blagrove, Swindon, Wiltshire SN5 8YS (GB). HUTCHIN-
`SON, Keith, Graeme [GB/GB]; Frankland Road, Blagrove,
`Swindon, Wiltshire SN5 8YS (GB). PARKER, Roya
`[GB/GB]; Frankland Road, Blagrove, Swindon, Wiltshire
`SN5 SYS (GB).
`
`(74) Agent: TAIT, Brian, Steele; ZCl’lCC2l Pharmaceuticals, Intellec-
`tual Property Dept., Mereside, Alderley Park, Macclesfield,
`Cheshire SKID 4TG (GB).
`
`(54) Title: A SOLUTION FOR ORAL ADMINISTRATION CONTAINING ICI 182,780
`
`(57) Abstract
`
`The invention concerns a pharmaceutical composition in the form of a solution formulation adapted for oral administration which
`comprises ICI 182,780, a pharmaceutical]y-acceptable oil, a pharmaceutically—acceptab|e lipophilic surfactant, a pharmaceutically-acceptable
`hydropliilic surfactant, and a pharmaceutically-acceptable water-miscible solvent, and the use of the composition on oral administration to
`a warm-blooded animal to produce an antioestrogenie effect.
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 1
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`

`
`FOR THE PURPOSES ()F INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AM
`AT
`AU
`BB
`
`BF
`HG
`BJ
`BR
`BY
`CA
`CF
`CG
`CI]
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`EE
`
`Fl
`FR
`GA
`
`Annenia
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cdte d‘lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Estonia
`Spain
`Finland
`France
`Gabon
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`ltaly
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 2
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`

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`W0 97/21440
`
`PCT/C B96/03022
`
`-1-
`
`A SOLUTION FOR ORAL ADMINISTRATION CONTAINING ICI 182,780
`
`The invention relates to a novel pharmaceutical composition, particularly to a
`
`pharmaceutical composition adapted for oral administration containing the compound
`
`7a-[9-(4.-1.5.5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(lO)—triene-3,l 7D—diol. and
`
`more particularly to a solution formulation containing the compound
`
`7ot-[9-(4,4,5,5.5-pentafluoropentylsulphinyl)nonyl]oestra- l ,3,5( l 0)-triene—3 , l 7B-diol. The
`
`invention also relates to the use of the pharmaceutical composition of the invention for oral
`
`administration to a warm blooded animal to produce an antioestrogenic effect and to a
`
`method of producing an antioestrogenic effect by the oral administration of an effective
`
`amount of the pharmaceutical composition of the invention.
`
`It is disclosed in European Patent Application No. 0 138 504 that certain steroid
`
`derivatives are effective antioestrogenic agents. The disclosure includes information
`
`relating to the preparation of the steroid derivatives of that invention.
`
`In particular there is
`
`the disclosure within Example 35 of the compound
`
`7ot-[9—(4,-4,5.5,5—pentafluoropentylsulphinyl)nonyl}oestra- 1,3 ,5(l 0)—triene-3,1 7B-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 pharmaceutically-
`
`acceptable diluent or carrier.
`
`It is stated therein that the composition can be in a form
`
`suitable for oral or parenteral administration. For oral administration it is stated that a
`
`tablet or capsule containing the steroid derivative of the invention is particularly
`
`convenient.
`
`It is further stated therein that the tablet formulation can contain diluents, for
`
`example mannitol or maize starch, disintegrating agents, for example alginic acid, binding
`
`agents, for example methyl-cellulose, and lubricating agents, for example magnesium
`
`stearate. No pharmaceutically~acceptable diluent or carrier for a capsule formulation is
`
`specifically disclosed therein.
`
`Subsequently the compound
`
`7oz-[9-(4.4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)—triene-3,17B-diol has
`
`been identified by the code number ICI 182.780 and that number shall be utilised for the
`
`compound hereinafter.
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 3
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`

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`WO 97/21440
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`PCT/G B96/03022
`
`-2-
`
`It is further disclosed in Cancer Eesearch, 1991, 5_I, 3867-3873 and
`
`J, Endocrinology, 1992, Lfi. 239-247 that the antioestrogenie effect of ICI 182,780 in
`
`immature rats, mature rats or monkeys can be assessed by the administration of a
`
`suspension of the compound in arachis oil. This formulation was dosed either orally or by
`
`5
`
`subcutaneous injection. The studies in rats demonstrated that the potency of the compound
`
`when closed in arachis oil suspension was at least ten fold poorer when administration was
`
`by the oral route than when administration was by the subcutaneous route suggesting that
`
`the oral bioavailability of the compound from that formulation was low. A prolonged
`
`antioestrogenic effect was demonstrated when a dispersion of the compound in arachis oil
`
`10 was administered subcutaneously.
`
`It is further disclosed in, for example, , 1993, 3;,
`
`247-251 that ICI 182,780 may be formulated for administration by intramuscular injection
`
`in a castor oil-based depot formulation. That formulation when given to laboratory animals
`
`at a dose of 4 milligrams per kilogram was found to inhibit the effects of endogenous
`
`15 oestrogen for three to four weeks.
`
`Furthermore it is disclosed in , 1992, 1_3§, 239-247,
`
`J, Endocrinology, 1993, 118, 203-209 and , 1994, _5_4, 408 that
`
`ICI 182,780 may be provided for administration by daily intramuscular injection in a
`
`‘short-acting’ liquid formulation comprising ICI 182,780 in a propylene glycol-based
`
`20 solution.
`
`It is an object of the present invention to provide a solution formulation
`
`containing the hydrophobic drug ICI 182,780 which does not exhibit, or which exhibits to
`
`a lesser degree, the problem of low oral bioavailability.
`
`Many pharmaceutical compositions have been disclosed which are stated to be
`
`25 ‘suitable for the dosing of hydrophobic drugs. Many of these formulations contain an oil
`
`such as arachis oil in which the hydrophobic drug is dissolved or dispersed. However the
`
`lack of miscibility of the oil with the aqueous environment of the gastrointestinal tract can
`
`lead to variable rates of absorption of the drug. To try to overcome the problem. it is
`
`common practice for a surfactant to be added to the pharmaceutical composition.
`
`30 particularly a hydrophilic surfactant such as a surfactant with a hydrophilic—lipophi1ic
`
`balance (HLB) of greater than about 8 and less than about 30. Such a surfactant may
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 4
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`

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`wo 97/21440
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`PCT/GB96/03022
`
`-3-
`
`produce an emulsion which, if the particle size is small, may lead to more complete
`
`absorption of the hydrophobic drug. However the use of hydrophilic surfactants may give
`
`a formulation of poor homogeneity as the surfactant may not be sufficiently miscible with
`
`the oil in which the hydrophobic drug is dissolved or dispersed.
`
`In a further refinement of
`
`such hydrophilic surfactant formulations, it is known that a lipophilic surfactant may be
`
`added to try to obtain the desired balance of hydrophilic and hydrophobic components to
`
`provide a stable emulsion when the formulation is added to an aqueous environment. The
`
`problem with this approach is that for each hydrophobic drug more than routine skill and
`
`knowledge is required to identify the exquisite balance of lipophilic and hydrophobic
`
`components which will provide a pharmaceutical composition of that hydrophobic drug
`
`which can be dosed orally to provide a reasonable oral bioavailability.
`
`The many and various pharmaceutical compositions of the hydrophobic drug
`
`cyclosporin illustrate the complexities in this field of pharmaceutical research.
`
`Thus. for example, it is disclosed in UK Patent Application No. 2 222 770 that
`
`cyclosporin may be formulated in a mixture of an oil such as a medium chain fatty acid
`
`triglyceride, a hydrophilic phase such as a mono- or di-alkyl ether of a polyoxyalkanediol,
`
`and a surfactant such as a hydrophilic or lipophilic surfactant or mixtures thereof.
`
`Further it is disclosed in UK Patent Application No. 2 257 359 that cyclosporin
`
`may be formulated in a mixture of an oil such as a mixture of mono-, di- and tri-glycerides.
`
`a hydrophilic surfactant such as a surfactant having a HLB of at least 10, and the
`
`10
`
`15
`
`20
`
`hydrophilic solvent 1,2-propylene glycol.
`
`In addition it is disclosed in UK Patent Application No. 2 228 198 that
`
`cyclosporin may be formulated in a mixture of an oil such as a fatty acid triglyceride, a
`
`lipophilic surfactant such as a glycerol fatty acid partial ester, and a hydrophilic surfactant
`
`having a HLB of at least 10.
`
`It has also been disclosed in PCT Patent Application WO 95/24893 that a
`
`hydrophobic drug may, for example, be formulated in a mixture of an oil such as a
`
`complete or partial ester ofa medium chain or long chain fatty acid with a low molecular
`
`weight mono-, di- or polyhydric alcohol (for example a vegetable oil), a lipophilic
`
`30
`
`surfactant such as a fatty acid or a mono- or di-glyceride of a fatty acid, and a hydrophilic
`
`surfactant having a HLB of greater than 10.
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 5
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`

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`wo 97/21440
`
`PCT/G B96/03022
`
`-4-
`
`While this prior art shows some promising results, it should be recognised that
`
`ICI 182,780 is not a cyclic peptide like cyclosporin. ICI 182.780 is also a compound of
`
`higher molecular weight (M01. Wt. = 603) and lipophilicity (estimated log P = 8 approx.)
`
`than the many drugs listed in PCT Patent Application WO 95/24893. Accordingly a
`
`pharmaceutical composition of ICI 182,780 is not disclosed in this prior art, nor can such a
`
`formulation be directly or unambiguously identified from consideration of this prior art.
`
`We have investigated the factors which influence the solubilisation of
`
`ICI 182,780 and the maintenance of the compound in an absorbable form when it is dosed
`
`orally. We have developed solvents and mixtures of solvents which effectively solubilise
`
`the compound and we have also identified those oils and surfactants which facilitate the
`
`presentation of the compound in a suitable emulsion form to allow the enhanced absorption
`
`of the compound. We have discovered that surprisingly the selection and combination of
`
`particular classes of ingredients from within the formulations of known hydrophobic drugs
`
`provides the desired increase in oral bioavailability.
`
`According to the invention there is provided a pharmaceutical composition in the
`
`form of a solution formulation adapted for oral administration which comprises:-
`
`(i)
`
`lCl 182,780;
`
`(ii)
`
`a pharmaceutically-acceptable oil;
`
`(iii)
`
`a pharmaceutically-acceptable lipophilic surfactant;
`
`(iv)
`
`a pharmaceutically-acceptable hydrophilic surfactant; and
`
`(v)
`
`a pharmaceutically-acceptable water-miscible solvent.
`
`Suitable pharmaceutically-acceptable oils include, for example, medium or long
`
`chain (C6 to C22, preferably C12 to C20, more preferably C6 to C12) fatty acids and
`
`mono-, di- or tri-glycerides of such fatty acids and mixtures of said fatty acids and mono-,
`
`di- and tri-glycerides. Preferably the pharmaceutically—acceptable oil is a triglyceride of a
`
`C6 to C12 fatty acid or a diglyceride of a C14 to C20 fatty acid. Examples of preferred
`
`pharmaceutically-acceptable oils include vegetable oils such as soyabcan oil, olive oil,
`
`arachis oil and coconut oil, fractionated vegetable oils such as fractionated coconut oil, and
`
`animal oils such as fish liver oil. Ofthese oils, fractionated coconut oil is more preferred.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 6
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`

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`W0 97/21440
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`PCT/G B96/03022
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`-5-
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`Suitable fractionated coconut oils include, for example, those made available
`
`commercially under the trade name “Miglyol” from Huls (UK) Ltd., Milton Keynes. UK
`
`such as:—
`
`Miglyol 810 which comprises a mixture of caprylic and capric acid triglycerides
`
`having an approximate fatty acid composition of C6 : 2%; C8 : 68%; C10 : 28% and C12 :
`
`2%;
`
`Miglyol 812 which comprises a mixture of caprylic and capric acid triglycerides
`
`having an approximate fatty acid composition of C6 2 3%; C8 : 56%; C10 : 36% and C12 :
`
`5%; and
`
`Miglyol 818 which comprises a mixture of caprylic, capric and linoleic acid
`
`triglycerides having an approximate fatty acid composition of C6 : 3%: C8 2 53%: C10 :
`
`33%; C12 1 4% and C18 : 5%.
`
`Of these fractionated coconut oils, Miglyol 812 is preferred.
`
`Suitable pharmaceutically-acceptable lipophilic surfactants include. for example,
`
`surfactants with a hydrophilic-lipophilic balance (I-ILB) of less than about 10, for example
`
`fatty acids such as capric, caprylic, oleic and linoleic acid, and mono- or di-glycerides (or
`
`mixtures of mono- and di-glycerides) of fatty acids such as capric, caprylic and oleic acid.
`
`for example the lipophilic surfactants made available under the trade name “Imwitor” from
`
`Huls (UK) Ltd. such as Imwitor 988, Imwitor 742 and Imwitor 308 and those made
`
`available under the trade name “Capmul” from Karlshamns, Karlshamn, Sweden such as
`
`Capmul MCM.
`
`Of these lipophilic surfactants, mixtures of the mono- and/or di-glycerides of
`
`capric and caprylic acids such as Imwitor 988 and Imwitor 742. especially Imwitor 988, are
`
`preferred.
`
`Suitable pharmaceutically-acceptable hydrophilic surfactants include, for
`
`example, surfactants with a HLB of greater than about 10, for example the condensation
`
`products of an alkylene oxide such as ethylene oxide with Castor oil or with hydrogenated
`
`castor oil. for example the hydrophilic surfactants made available under the trade name
`
`10
`
`15
`
`20
`
`25
`
`“Cremophor” from BASF, Cheadle Hulme, Cheshire, England such as Cremophor R1140,
`
`30
`
`those niade available under the trade name “Etocas” from Croda Chemicals. North
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 7
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`W0 97/21440
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`PCT/G B96/03022
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`-6-
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`Humberside, England such as Etocas 40, and those made available under the trade name
`
`“Nikkol” from Nikko Chemicals Co. Ltd., Tokyo, Japan such as Nikkol HCO-60.
`
`Of these hydrophilic surfactants, Cremophor RH4O is preferred.
`
`Suitable pharmaceutically-acceptable water-miscible solvents include, for
`
`example, a (l-4C)alc0hol such as ethanol and propanol, a poly-alcohol, for example, a
`
`monomeric poly-alcohol such as a (1-4C)all(ylenepolyol, for example glycerol
`
`(propane-1,2,3-triol), or a (l-l2C)glycol, for example ethylene glycol (ethane-1.2-diol),
`
`propylene glycol (propane-l,2~diol), diethylene glycol (3-oxapentane—l ,5-diol), triethylene
`
`glycol (3,6—dioxaoctane-1,8-diol) and tetraethylene glycol
`
`(3,6,9-trioxaundccane-1,1 l-diol). Alternatively a suitable pharmaceutically—acceptable
`
`water-miscible solvent is, for example, a polymeric poly-alcohol such as polyethylene
`
`glycol (PEG), for example a PEG having an average molecular weight in the range 150 to
`
`800 such as PEG 200, PEG 300, PEG 400 and PEG 600. Alternatively a suitable
`
`pharmaceutically-acceptable water-miscible solvent is, for example, an ether derivative of a
`
`pharmaceutically—acceptable poly-alcohol as defined hereinbefore, for example a
`
`mono-(l-4C)alkyl ether derivative such as a mono-methyl ether derivative or, for example
`
`a mono-cyclic ether derivative such as a furfurylmethyl, tetrahydrofurfurylmethyl or
`
`tetrahydropyranylmethyl ether derivative. Examples of such suitable etherified
`
`poly-alcohols include glycerol mono-methyl ether, ethylene glycol mono-methyl ether,
`
`propylene glycol mono-methyl ether, ethylene glycol mono-tetrahydrofuriurylmethyl ether,
`
`diethylene glycol mono-methyl ether, diethylene glycol mono-ethyl ether (ethyl digol),
`
`diethylene glycol mono-tetrahydrofurfurylmethyl ether (glycofurol), diethylene glycol
`
`mono-tetrahydropyranylmethyl ether, triethylene glycol mono-methyl ether, triethylene
`
`glycol mono-ethyl ether, triethylene glycol mono-tetrahydrofurfurylmethyl ether,
`
`tetraethylene glycol mono-methyl ether and tetraethylene glycol
`
`10
`
`15
`
`20
`
`25
`
`mono-tetrahydrofurfury[methyl ether. A suitable pharmaceutically—acceptable water-
`
`miscible solvent includes a mixture of two or more of the above-mentioned suitable water-
`
`miscible solvents. Preferred pharmaceutically-acceptable water-miscible solvents include
`
`propylene glycol and ethyl digol. Preferably ethanol or propylene glycol. or a mixture of
`
`30 ethanol and propylene glycol is used.
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 8
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`W0 97/21440
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`PCT/GB96/03022
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`-7-
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`In a further advantage of the invention, it has been determined that, surprisingly,
`
`the combination of the above—mentioned ingredients of the pharmaceutical composition of
`
`the invention in the correct ratios improves the desired increase in oral bioavailability. In
`
`the table below, the advantageous relative ratios (as percentages of the weight of the
`
`formulation) are disclosed:-
`
`Co
`
`ne
`
`ICI 182,780
`
`oil
`
`generally
`
`Preferred
`
`More Erefierred
`
`Further Prefierred
`
`1-20%
`
`1-20%
`
`2-18%
`
`2—l8%
`
`5-15%
`
`5—15%
`
`8-12%
`
`5-15%
`
`20-30%
`
`35-50%
`
`8-16%
`
`hydrophilic surfactant
`
`5-45%
`
`10-40%
`
`20-30%
`
`lipophilic surfactant
`
`15-70%
`
`25-60%
`
`water-miscible solvent
`
`130%
`
`2-28%
`
`35-50%
`
`5-25%
`
`The solution formulation of the invention may be presented in a form suitable for
`
`oral administration, for example a unit dosage form may be metered onto a spoon of
`
`suitable size and administered by mouth. Altematively the solution formulation may be
`
`encapsulated by methods well known to those skilled in the arts of pharmaceutical science,
`
`for example by encapsulation within a shell comprising a gelatin or starch capsule such as
`
`a hard gelatin or starch capsule or a soft gelatin capsule [which may be formed from
`
`gelatin. an appropriate plasticiser (such as glycerin and sorbitol) and water].
`
`The compositions of the invention may be obtained using conventional
`
`pharmaceutically—acceptable diluents well known in the art such as colouring, sweetening,
`
`flavouring and/or preservative agents.
`
`In the case of a soft gelatin capsule said diluents
`
`may be present in the liquid solution formulation encapsulated within the gelatin capsule or
`
`alternatively they may be present within the gelatin shell of the capsule. Capsule forms of
`
`the invention may be coated or uncoated either to modify their disintegration and the
`
`subsequent absorption of the active ingredient within the gastrointestinal tract. or to
`
`improve their stability and/or appearance, in either case using conventional coating agents
`
`and procedures well known in the art.
`
`The amount ofactive ingredient i.e. lCl 182,780, which is employed in a single
`
`dosage unit will necessarily vary depending on the host treated and the particular dosage
`
`10
`
`15
`
`20
`
`25
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`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 9
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`W0 97/21440
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`PCT/G B96/03022
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`-3-
`
`form employed. For example a solution formulation which is administered on a spoon will
`
`generally have a volume in the range, for example, 0.5 ml to 10 ml and will contain the
`
`active ingredient at a concentration in the range, for example, 5 mg/ml to 150 mg/ml,
`
`preferably in the range, for example, 20 mg/ml to 100 mg/ml. Alternatively a soft gelatin
`
`capsule having an internal volume of, for example, 0.5 ml, 1 ml, 2 ml, 3 ml or 5 ml may be
`
`employed and will contain the active ingredient at a concentration in the range, for
`
`example, 5 mg/ml to 150 mg/ml, preferably in the range, for example, 15 mg/ml to 120
`
`mg/ml, more preferably 100 mg/ml.
`
`The size of the dose of ICI 182,780 will naturally vary according to the nature and
`
`severity of the disease state being treated, and the age of the animal or patient being
`
`treated. In general ICI 182,780 will be administered so that a daily dose in the range, for
`
`example. 0.1 to 10 mg/kg body weight is received given, if required, in divided doses.
`
`Preferably a daily dose in the range, for example, 0.1 to 2 mg/kg body weight will be
`
`administered.
`
`As stated previously it was disclosed in .1. Endocrinology, 1992, _l_3j, 239-247 and
`
`1993, 138, 203-209 that ICI 182,780 may be formulated for administration by
`
`intramuscular injection as a solution formulation comprising ICI 182,780 in a propylene
`
`glycol—based solution. There was no disclosure therein of the dosing of that solution
`
`formulation by the oral route. The only specific disclosures of the administration of
`
`ICI 182,780 by the oral route were made in the first of the above-mentioned papers in
`
`J, Endognnology and in gfiancer Researoh, 1991, fl, 3867-3873 wherein the formulation
`
`comprised a suspension of the compound in arachis oil.
`
`Thus according to this aspect of the invention there is provided the use of a
`
`10
`
`15
`
`20
`
`solution formulation comprising:-
`
`25
`
`(i)
`
`ICI 182,780;
`
`(ii)
`
`a pharmaceutically-acceptable oil;
`
`(iii)
`
`a pharmaceutically-acceptable lipophilic surfactant;
`
`(iv)
`
`a pharmaceutically—acceptable hydrophilic surfactant; and
`
`(v)
`
`a pharmaceutically—acceptable water-miscible solvent;
`
`30 in the manufacture of a medicament for oral administration to a warm-blooded animal to
`
`produce an antioestrogenic effect.
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 10
`
`

`
`wo 97/21440
`
`PCT/G B96/03022
`
`-9-
`
`This aspect of the invention also includes a method of producing an
`
`antioestrogenic effect by the oral administration to a warm—blooded animal in need of such
`
`an effect of an effective amount of a solution formulation comprising:-
`
`(i)
`
`ICI 182,780;
`
`5
`
`(ii)
`
`a pharmaceutically-acceptable oil;
`
`(iii)
`
`a pharmaceutical1y-acceptable lipophilic surfactant;
`
`(iv)
`
`a pharmaceutically-acceptable hydrophilic surfactant; and
`
`(v)
`
`a pharmaceutically—acceptable water—miscible solvent.
`
`10
`
`In these aspects of the invention the weight ratios of the ingredients of the solution
`
`formulation are as defined hereinbefore. In addition the single dosage unit of the liquid
`
`solution formulation and the daily dosage rate are as defined hereinbefore.
`
`The invention will now be illustrated in the following Examples which involve
`
`tests of the aqueous dispersion profiles and oral bioavailabilities of ICI 182,780 contained
`
`15 within various pharmaceutical formulations.
`
`In general the test procedures used were those
`
`described be1ow:-
`
`T st 0
`
`ueous Di
`
`ersion Profiles
`
`The aqueous dispersion profiles of the solution formulations of the invention were
`
`20 assessed using the following conventional procedure which was conducted at ambient
`
`temperature. An aliquot (0.2 ml of the formulations containing 2 g ofICI 182,780 per
`
`100 ml and 0.04 ml ofthe formulation containing 10 g ofICI 182,780 per 100 ml) of each
`
`test formulation was added to an aqueous sodium chloride solution (0.154 M, 10 ml) in a
`
`vial. The vial was sealed with a cap and the contents were mixed by the repeated inversion
`
`25 of the vial. The dispersion of the formulation and/or the precipitation of the active
`
`ingredient of the formulation was assessed visually.
`
`Test of Oral Bigavailahilig
`
`The oral bioavailability ofICI 182,780 in the dog from various formulations of
`
`30 the compound was determined using the following method. Each test formulation was
`
`dosed to a group of five male beagle dogs, each weighing approximately 18 kg. Unless
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 11
`
`

`
`WO 97/21440
`
`PCT/G B96/03022
`
`-10-
`
`otherwise stated the studies were carried out with the animals in a ‘fasted’ state, that is the
`
`animals were not fed later than 18 hours prior to the dosing of a test formulation and they
`
`were not fed until 5 or 6 hours after dosing. The formulation of Example 1 was dosed
`
`orally by gavage. Each of the other formulations was contained in a hard gelatin capsule
`
`(size 00) and closed orally.
`
`In each case, water (approximately 150 ml) was dosed
`
`immediately thereafter by way of gavage. Blood samples were taken from an external
`
`jugular vein at various times up to 8 hours after dosing. The level of ICI 182,780 in each
`
`blood sample was determined using a conventional radioimmunoassay using an analogous
`
`procedure to that described in Cancer Research, 1994, 531, 408 {antibodies were obtained
`
`on administration to a group of sheep of a conjugate obtained by a mixed anhydride based
`
`coupling of l7[3—(3-carboxypropionyloxy)—70¢-[9-(4,4,5,5,5—pentafluoropentylthio)nonyl]-
`
`5
`
`10
`
`oestra-1,3,5(l0)-triene-3 -01 [obtained from
`
`7ot-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]oestra-1,3,5(l0)—triene-3 ,17B-diol
`
`(Example 35 of European Patent Application No. 0 138 504) and succinic acid] and
`
`15
`
`thyro globulin} .
`
`Using this methodology, the oral bioavailability of ICI 182,780 obtainable from
`
`each test formulation was assessed using the conventional parameters of maximum drug
`
`concentration [ Cp (max) ], the area under the graph of drug concentration versus time
`
`[ AUC (0-8h) ] and a percentage figure for the oral bioavailablity based on a comparison of
`
`20
`
`the AUC results obtained for the test formulation and for a formulation which was dosed
`
`intramuscularly (IM) comprising:—
`
`1M Formulation
`
`%
`
`i ht in r m
`
`rml
`
`ICI 182,780
`
`Ethanol
`
`Water (Ph. Eur.)
`
`poloxamer 407
`
`2.0
`
`10.0
`
`8.0
`
`1.0
`
`propylene glycol (Ph. Eur.)
`
`to 100%
`
`The following calculation was carried out to determine the oral bioavai1ability:-
`
`25
`
`% Oral Bioavailability = AUC {oral} x Dose (IM) X 100
`
`AUC (IM) x Dose (oral)
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 12
`
`

`
`WO 97721440
`
`PCT/GB96/03022
`
`-11-
`
`i
`
`a
`
`e 1
`
`The solution formulation comprised the ingredients shown below. Addition of the
`
`formulation to aqueous sodium chloride resulted in the formation of a precipitate which
`
`was noted to aggregate over a period of about 10 minutes.
`
`mgredjem
`
`% weight
`
`Ehamacokinetic Parameter
`
`(g per 100 ml)
`
`ICI 182,780
`
`ethanol
`
`water
`
`2.0
`
`10.0
`
`8.0
`
`Dose
`
`Cp (max)
`
`50 mg
`
`13.3 i 2.7 ng mlil
`
`AUC (0 to 8 hours)
`
`34.9 i 6.3 ng h ml"
`
`propylene glycol
`
`to 100%
`
`Bioavailability
`
`1.1 %
`
`ar
`
`'ve Exa
`
`Ie 2
`
`The solution formulation comprised the ingredients shown below. Addition of the
`
`formulation to aqueous sodium chloride resulted in the formation of a crude emulsion.
`
`10
`
`re ' nt
`
`“/9 weight
`
`P
`
`c k’
`
`tic Para
`
`(g per 100 ml)
`
`[C1 182,780
`
`ethanol
`
`lmwitor 988
`
`10.0
`
`13.5
`
`76.5
`
`Dose
`
`Cp (max)
`
`50 mg
`
`14 i 2 ng ml"
`
`AUC (0 to 8 hours)
`
`28 : 5 ng h mi"
`
`Bioavailability
`
`0.8 %
`
`o
`
`ara ive E
`
`le
`
`The solution formulation comprised the ingredients shown below. Addition of the
`
`formulation to aqueous sodium chloride resulted in the formation of a hazy, opalescent
`
`15
`
`mixture, the turbidity of which increased gradually.
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 13
`
`

`
`wo 97/21440
`
`PCT/GB96/03022
`
`_ 12 -
`
`L[1g1’_%l_i§I1l
`
`“/9 weight
`
`Ehannacokinetic Parameter
`
`(g per 100 ml)
`
`ICI 182,780
`
`propylene glycol
`
`Imwitor 988
`
`10.0
`
`10.0
`
`80.0
`
`Dose
`
`Cp (max)
`
`50 mg
`
`20 i 4 ng ml"
`
`AUC (0 to 8 hours)
`
`51 i 10 ng h ml’!
`
`Bioavailability
`
`1.5 "/0
`
`Example 1
`
`The solution formulation comprised the ingredients shown below. Addition of the
`
`formulation to aqueous sodium chloride resulted in the formation of a hazy, opalescent
`
`mixture. the turbidity of which increased gradually over a period of 8 hours. The
`
`formulation gave the pharmacokinetic parameters shown below when dosed orally to dogs.
`
`Ingredient
`
`“[2 weight
`
`rmac kinetic Parameter
`
`(g per 100 ml)
`
`10.0
`
`40.0
`
`26.8
`
`13.2
`
`10.0
`
`Dose
`
`50 mg
`
`Cp (max)
`
`83 i 19 ng ml’!
`
`AUC (O to 8 hours)
`
`194 i 34 ng h ml"
`
`Bioavailability
`
`5.5 %
`
`ICI 182,780
`
`Imwitor 988
`
`Cremophor RH40
`
`Miglyol 812
`
`ethanol
`
`am
`
`2
`
`The solution formulation comprised the ingredients shown below. Addition of the
`
`formulation to aqueous sodium chloride resulted in the formation of a hazy, opalescent
`
`mixture, the turbidity of which increased gradually over a period of 8 hours. The
`
`formulation gave the pharmacokinetic parameters shown below when dosed orally to dogs.
`
`10
`
`15
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 14
`
`

`
`WO 97/21440
`
`PCT/GB96/03022
`
`Ingredient
`
`°/9 weight
`
`i etic P
`
`er
`
`- 13 -
`
`(g per 100 ml)
`
`10.0
`
`45.9
`
`22.95
`
`7.65
`
`13.5
`
`Dose
`
`50 mg
`
`Cp (max)
`
`78 i 17 ng ml"
`
`AUC (O to 8 hours)
`
`193 i 35 rig h ml]
`
`Bioavailability
`
`5.4 %
`
`IC1 182,780
`
`Imwitor 988
`
`Cremophor RH4O
`
`Miglyol 812
`
`propylene glycol
`
`Example 3
`
`The solution formulation comprised the ingredients shown below. Addition of
`
`the formulation to aqueous sodium chloride resulted in the formation of a hazy, opalescent
`
`mixture, the turbidity of which increased gradually over a period of 8 hours. The
`
`formulation gave the pharmacokinetic parameters shown below when dosed orally to dogs.
`
`red"
`
`% weight
`
`Pharmacokinetic Parameter
`
`(g per 100 ml)
`
`10.0
`
`40.0
`
`26.8
`
`13.2
`
`10.0
`
`Dose
`
`50 mg
`
`Cp (max)
`
`80 i 14 ng ml"
`
`AUC (0 to 3 hours)
`
`195 : 26 ng 11 mi"
`
`Bioavailability
`
`5.6 %
`
`ICI 182,780
`
`Imwitor 742
`
`Cremophor RI-I40
`
`Miglyol 312
`
`ethanol
`
`Example 4
`
`The solution formulation comprised the ingredients shown below. Addition of the
`
`formulation to aqueous sodium chloride resulted in the formation of a hazy, opalescent
`
`mixture, the turbidity of which increased gradually over a period of 8 hours. The
`
`formulation gave the pharmacokinetic parameters shown below when dosed orally to dogs.
`
`10
`
`15
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 15
`
`

`
`WO 97/21440
`
`PCT/G B96/03022
`
`lnzfliciignl
`
`"/9 weight
`
`ac
`
`inetic
`
`1'21
`
`ICI‘
`
`-14-
`
`ICI 182.780
`
`Imwitor 988
`
`Cremophor RH40
`
`Miglyol 812
`
`ethanol
`
`propylene glycol
`
`(g per 100 ml)
`
`10.0
`
`37.4
`
`22.95
`
`7.65
`
`7.0
`
`15.0
`
`Dose
`
`50 mg
`
`Cp (max)
`
`83 i 11 ng ml‘
`
`AUC (O to 8 hours)
`
`194 : 24 ng h ml"
`
`Bioavailability
`
`5.6 %
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 16
`
`

`
`wo 97/21440
`
`PCT/G B96/03022
`
`C_LAI.M_S
`
`- 15 -
`
`l.
`
`A pharmaceutical composition in the form ofa solution formulation adapted
`
`for oral administration which comprises:-
`
`(i)
`
`ICI 182,780;
`
`(ii)
`
`a pharmaceutically—acceptable oil;
`
`(iii)
`
`a pharmaceutically-acceptable lipophilic surfactant;
`
`(iv)
`
`a pharmaceutically-acceptable hydrophilic surfactant; and
`
`(V)
`
`a pharmaceutically-acceptable water—miscible solvent.
`
`10
`
`2.
`
`A pharmaceutical composition as claimed in claim 1 wherein the
`
`pharmaceutically-acceptable oil is a triglyceride ofa C6 to C12 fatty acid or a diglyceride
`
`ofa C14 to C20 fatty acid.
`
`15
`
`3.
`
`A pharmaceutical composition as claimed in claim 1 wherein the
`
`pharmaceutically-acceptable oil is fractionated coconut oil.
`
`4.
`
`A pharmaceutical composition as claimed in claim 1 wherein the
`
`pharmaceutically-acceptable lipophilic surfactant is a mixture of mono- and di-glycerides
`
`20
`
`of capric and caprylic acids.
`
`5.
`
`A pharmaceutical composition as claimed in claim 1 wherein the
`
`pharmaceutically-acceptable hydrophilic surfactant is the condensation product of ethylene
`
`oxide with castor oil or with hydrogenated castor oil.
`
`6.
`
`A pharmaceutical composition as claimed in claim 1 wherein the
`
`pharmaceutically-acceptable water-miscible solvent is ethanol, propylene glycol,
`
`diethylene glycol mono-ethyl ether or diethylene glycol mono—tctrahydrofurfurylmethyl
`
`ether, or a mixture thereof.
`
`25
`
`30
`
`MYLAN PHARMS. INC. EXHIBIT 1031 PAGE 17
`
`

`
`WO 97/21440
`
`PCT/G B96/03022
`
`-16..
`
`7.
`
`A pharmaceutical composition as claimed in claim 1 wher