Européisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`lillililililliiiilliilliiillilliiiiilililliiiilliliiliilililiilliiiliilli
`
`@ Publication number:
`
`0 346 014 B1
`
`EUROPEAN PATENT SPECIFICATION
`
`9 6
`
`9
`
`Date oipubiication ofpaient specification: 03.68.94 @ int. Ci.5: A61K 31/565, //(A61 K31/565,
`31 :165
`@ Application number: 893055612
`I
`
`@ Date of filing: 02.06.89
`
`@ Therapeutic DTOGIUGI I0!‘ the treatment Of peri- 0|’ postmenopausal conditions.
`
`
`
`Priority: 06.06.88 GB 8813353
`
`Date of publication of application:
`13.12.89 Bulletin 39/50
`
`Publication of the grant of the patent:
`03.08.94 Bulletin 94/31
`
`@ Proprietor: ZENECA LIMITED
`Imperial Chemical House, 9 Milibank
`London SW1P 3JF(GB)
`
`E2)
`
`inventor: Dukes, Michael
`54 Styai Road
`WIIITISIOW Cheshire, SK9 4AQ(GB)
`
`Representative: Tait, Brian Steele et al
`ICI Group Patents Service Dept.
`PO Box 6
`Shire Park
`Bessemer Road
`
`weiwyn Garden City Herts AL71HD (GB)
`
`Designated Contracting States:
`AT BE CH DE ES FR GB GR IT LI LU NL SE
`
`References cited:
`EP-A- 0 124 369
`EP~A- 0 138 504
`
`CHEMICAL ABSTRACTS, vol. 109, no. 3, 18th
`July 1988, page 73, abstract no. ‘i7199p, Co-
`lumbus, Ohio, US; N. FROEHLANDEH et ai.:
`“Growth hormone and somatomedin C dur-
`
`ing post-menopausal replacement therapy
`with estrogen alone and in combination with
`an antiestrogen“, & MATURITAS 1988, 9(4),
`297-802
`
`EP0346014B1
`
`Note: Within nine months from the publication of the mention of the grant of the European patent, any person
`may give notice to the European Patent Office oi opposition to the European patent granted. Notice of opposition
`shall be filed in a written reasoned statement.
`it shall not be deemed to have been filed until the opposition fee
`has been paid (Art. 99(1) European patent convention).
`
`Rank Xerox (UK) Biisinens Services
`i3.i0/3.09l3.3.3i
`
`innoPharma Exhibit 10550001
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`

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`EP 0 346 014 B1
`
`Description
`
`This invention relates to a therapeutic product for use in a new method of medical treatment and, more
`particularly,
`it relates to a product comprising an oestrogen and a pure antioestrogen for use in a new
`method for the treatment or prophylaxis of perimenopausal or postmenopausal conditions, particularly
`perimenopausal or postmenopausal osteoporosis. The invention also relates to a pharmaceutical composi-
`tion comprising an oestrogen and a pure antioestrogen and to the use thereof in the manufacture of a new
`medicament for use in the treatment or prophylaxis of perimenopausal or postmenopausal conditions.
`When a female animal, particularly a human female, enters the perimenopausal stage the animal's
`ovaries begin to secrete less of the female sex hormones. particularly oestradiol. Symptoms in women at
`this stage include the following: vasomotor disturbances (hot flushes), urogenital atrophy (particularly
`affecting the vagina and distal urethra), psychosomatic complaints, changes in
`lipid metabolism and
`osteoporosis. The rate of decline of ovarian function and the severity of the above—mentioned symptoms are
`highly variable between individual women but
`in a substantial number of individuals the symptoms are
`sufficiently severe that treatment is required. Oestrogen replacement therapy has been used in women and
`it
`is generally recognised to be effective in combatting the typical perimenopausal and postmenopausal
`Symptoms (Qt???E11.,.M§E{lSZ§i...9.9H.[fl§.1v 19371 ..?..9...§r 914; £.\..Er1§[E9at!..£9i!.E!3§l...2i...9.i?.§tei.:...§n9..§m§29.l.-~ 1937- .12?
`1298 and 1347). However oestrogen replacement therapy can also cause uterine hyperplasia,
`irregular
`vaginal menstruation and, in a small proportion of women, endometrial cancer (American Journal of Obstet.
`and Gynecot, 1987,1533‘, 1313).
`To combat the continuous unopposed stimulation of oestrogen-responsive tissues an oestrogen and a
`progestogen are normally co-administered for part of each treatment period thereby causing regular vaginal
`menstruation. (American Journal of Obstet. and Gynecol., 1987, 156, 1304). However the continuation of
`menstrual periods is unattractive to many postmenopausal women and, in addition, progestogens can cause
`side effects, for example oedema, premenstrual irritability and breast tenderness.
`Alternative therapies are therefore required.
`It has recently been shown that compounds demonstrating a mixture of oestrogenic and antioestrogenic
`properties in warm-blooded animals, including humans, may be of use in the treatment of postmenopausal
`conditions (European Patent Specification No..0178862). Particular compounds stated to have such activity
`include clomiphene and tamoxifen. Comprehensive reviews of the clinical usage of these compounds are
`available, for example a review of clomiphene by Clark et al.
`in Pharmacology and Therapeutics, 1982,
`Volume 15, pages 467 to 519, and a review of tamoxifen by Furr et al. in Pharmacology and Therapeutics,
`1984, Volume 25, pages 127-205.
`It has also recently been shown that a treatment regime comprising the closing to postmenopausal
`women of the oestrogen ethinyloestradiol led to an increase in serum growth hormone (GH) levels whereas
`the periodic dosing of both ethinyloestradiol and the antioestrogen tamoxifen led to a reduction of GH levels
`to pre-treatment levels [N. Froehlander et al., Maturitas, 1988, 9(4), 297 (Chem. Abstracts, "109, 17199p)].
`It has also recently been shown that a treatment regime comprising the dosing of a small amount of an
`oestrogen, for example oestrone sulphate or natural conjugated oestrogens, followed by the dosing of an
`antioestrogen, for example tamoxifen or clomiphene led to the partial inhibition of the maximum oestrogen-
`induced stimulation of uterine endometrial tissue (A. Kauppila et al., Gynecol. obstet.
`lnvest., 1988, 25, 58
`and Arch. Gynecoi, 1983, 2:35, 49).
`It has now been found that administration of an oestrogen and a pure antioestrogen, whether
`simultaneously, sequentially or separately,
`results in the oestrogen being selectively effective in some
`oestrogen-responsive tissues,
`for example bone, and being selectively opposed in other oestrogen-
`responsive tissues, for example the endometrium of
`the uterus, and this is the basis of the present
`invention.
`
`A pure antioestrogen is a compound which possesses antioestrogenic activity and no oestrogenic
`activity. This may be demonstrated in rats by the effect of the compound in antagonising the increase in
`weight of the uterus of an immature female rat produced by administering oestradicl benzoate to said rat.
`Thus, when each of a pure antioestrogen and oestradiol benzoate are administered for 3 days to such a rat,
`a smaller increase in uterine weight is produced than the substantial increase which would be produced by
`the administration of oestradiol benzoate alone. Unlike the known antioestrogens tamoxifen and clomiphene,
`when a pure antioestrogen is administered alone to a rat no increase in uterine weight whatsoever is
`observed.
`
`an»-
`is disclosed in European Patent Specification No. 138504 that certain preferred steroidal
`It
`tioestrogens are pure antioestrogens.
`It
`is also disclosed in European Patent No. 124369 that certain
`preferred non-steroidal antioestrogens are pure antioestrogens.
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`EP 0 346 014 B1
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`According to the present invention there is provided a product comprising an oestrogen and a pure
`antioestrogen as a combined preparation for simultaneous, sequential or separate use in selective oestrogen
`therapy of perimenopausal or postmenopausal conditions, the pure antioestrogen being selected from
`E-n—butyI—fl-methyl-, E-1H,1H-heptailuorobutyl-E-methyt or fig-(3-methylpentamethylene)—11-(3,17;3—
`dihydroxyoestra-1,3,5(10)—trien-7a-yl)undecanamide;
`[§l—n—butyl—
`or
`[fl-1H,1H-heptatluorobutyl-3-Q-[4-(3,17;3—dihydroxyoestra—1 ,3,5(10)-trien—7a-yl)butyl]—
`phenylpropionamide;
`7a-(10-gchlorophenylthiodecyl)-, 7a-(10-p-chlorophenylsulphinyldecyl)-, Ta-[9-(4,4,5,5.5-pentat|uoropen-
`tylsulphinyl)nonyl]~, 7a-[10~(4,4,4-tritluorobutylsulphiny|)clecyl]- or 7a~[10~(_p~chlorobenzylsulphinyl)decyl]—
`oestra-1,3,5(10)-triene-3,1713-diol;
`7a-(9-n-heptylsulphinylnonyhoestra-1,3,5(10)-triene-3,173-diol; and
`a compound oi the formula:—
`
`NU-A-X-R‘
`
`-(CH2)5-(1,4-
`
`-(CH2)11' or
`
`wherein NU is 6-hydroxy-2-p—hydroxyphenylnaphth-1-yl and A is '(CH2)1o-,
`phenylene)—(CH2)g-;
`or NU is 1,2,3,4-tetrahydro—6—hydroxy-2-p—hydroxyphenylnaphth—1-yl (either 1RS,2FtS or 1FtS,2SR iso-
`mer), or 1,2,3, 4-tetrahydro—6-hydroxy-2-p-hydroxyphenyl-2—methylnaphth—1-yl
`(either
`the lRS,2RS or
`1FlS,2SFl isomer), and A is -(CH2)m-, -(CH2jl11-or—(CHg)4—(1,4-phenylene)—~(CH2)2—;
`or NU is (1RS,2RS)-5-hydroxy—2—p-hydroxypherlylindan-1-yl or (1RS,2FlS)-5~hydroxy—2—p-hydroxyphenyl-2-
`methylindan-1-yl and A is ~(CH2)1o-, -(CH2)n-or -(CH2)4-(1,4-phenylene)-(CH2)2—;
`and wherein XR‘ is -CONPJRQ wherein R2 is hydrogen or methyl and Ft‘
`is n-butyl, 1H,1H~heptailuorobutyl,
`n-pentyl or n-hexyl, or XI’-ti
`is
`-SR‘, SORl or -502R‘ wherein R‘
`is n-pentyl, n-hexyl, 4,4,5,5,5-pen-
`tailuoropentyl or IH, 1 H,2H.2H,3H,3H—heptafluorohexyl.
`the invention is
`In a particular product of
`the invention the oestrogen component of a product of
`oestradiol, ethinyloestradiol, oestriol, oestrone, natural conjugated oestrogens, piperazine oestrone sulphate,
`mestranol, chlorotrianisene, dienoestrol, stilboestrol or hexoestrol or a pharmaceutically-acceptable ester
`thereof.
`
`A pharmaceutically-acceptable ester of the oestrogen component of a product of the invention is, for
`example, an alkyl or aryl ester each of up to 12 carbon atoms.
`It will be appreciated that an ester of a
`steroidal oestrogen may be termed at the 3-position, the 17-position or at both of these positions. It will also
`be appreciated that an ester may be formed at one or both of the phenolic groups in some non-steroidal
`oestrogens, for example stilboestrol and hexoestrol. A suitable alkyl ester of up to 12 carbon atoms is, for
`example, an acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, cyclopentyl-
`propionate, nonanoate, decanoate, undecanoate or dodecanoate. A suitable aryl ester of up to 12 carbon
`atoms is, for example, a benzoate, toluate or naphthoate. A preferred pharmaceutically-acceptable ester of
`the oestrogen component of a product of the invention includes, for example, oestradiol benzoate, oestradiol
`cyclopentylpropionate, oestradiol clipropionate, oestradiol heptanoate, oestradiol undecanoate, oestradiol
`valerate and stilboestrol dipropionate.
`In a further particular product of the invention the pure antloestrogen is
`_l\_l-rt-butyi-, E-n-butyl-_l\j-methyl-, _|fl-n-pentyl, fl“-(1H,1H~heptatluorobuty|)-or E-(1H,1H-heptatluorobutyl)~_lfl-
`methyl-3-p-[5-(6-hydroxy—2-p-hydroxyphenylnaphth-1-yl)pentylhahenylpropionamide;
`Q-methylfl-(1 H,1 H-heptafluorobutyl)-p-[4-[(1R8,2RS)-6-hydroxy-2-p-hydroxphenyl-2—methyl-1 ,2,3,4-
`letrahydronaphth-1-yl]~butyl] phenylpropionamide;
`the
`(1FlS,2FtS)—1—[4-[p-(2-n-hexy|thioethy|)phenyl]butyl]—2-p-hydroxyphenyl-1,2,3,4—tetrahydronaphth-6—ol or
`corresponding 4,4,5,5,5—pentailuoropentylthio derivative, or the corresponding hexylsulplninyl, hexylsulphonyl
`or pentatluoropentylsulphinyl derivatives;
`2—E—hydroxyphenyl-1-[5-[Q-(2-n~hexy1thi0e’thyl)phenyl]pentyl]naphth-6-01 or the corresponding hexylsulphinyl
`derivative; or
`
`(1 RS, 2R8)-1-[4[p-(2-n-hexylthioethyl)phentyl]butyl]-2-E-hydroxyphenyl-2-methyl-1,2,3,4-tetrahycironaphth-W
`0] or the corresponding 4,4,5.5,5-pentatluoropentylthio derivative, or the corresponding hexylsulphinyl or
`pentatluoropentyleulphinyl derivative, or the corresponding (1FlS,2SR) isomers of both the hexylthio and
`hexylsulphinyl derivatives,
`A preferred product of the invention comprises an oestrogen and a pure antioestrogen for use as stated
`above wherein the oestrogen is oestracliol or ethinyloestradiol, or a pharmaceutically-acceptable ester
`thereof, and the pure antioestrogen is 7a—[9-(4,4,5,5,5—pentatIuoropentylsulphinyl)nonyl]oestra—1,3,5(10)-
`triene-3,17,6-diol or (1RS,2RS)-2-p-hydroxyphenyl-2-methyl-1-[9-(4,4,5,5,5-pentatluoropentylsulphinyl)nonyl]-
`
`|nnoPharma Exhibit 10550003
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`EP 0 346 014 B1
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`1 ,2,3,4-tetrahyclronaphth—6-oi.
`A particularly preferred product of the invention comprises an oestrogen and a pure antioestrogen for
`use as stated above wherein the oestrogen is oestradiol, oestradiol benzoate, oestradiol valerate or
`oestradiol undecanoate and the pure antioestrogen is 7a—[9—(4,4,5,5,5-pentafluoropenlylsulphinyl)nonyl]-
`oestra-1,3,5(10)-triene-3,17[3—diol.
`According to a further feature of the invention there is provided a process for the manufacture of a
`product comprising an oestrogen and a pure antioestrogen as a combined preparation for simultaneous,
`sequential or separate use in selective oestrogen therapy of perimenopausal or postmenopausal conditions.
`which process comprises bringing together said oestrogen and said pure antioesirogen.
`In a further feature oi the invention there is provided a process for the manufacture of a product
`comprising an oestrogen and a pure antioestrogen for simultaneous use in selective oestrogen therapy of
`perimenopausal or postmenopausal conditions, which process comprises bringing into admixture said
`oestrogen and said pure antioestrogen.
`A product of the invention may be administered to a warm-blooded animal, including a human, in the
`form of a pharmaceutical composition. Thus according to a further feature of the present invention there is
`provided a pharmaceutical composition which comprises the product of
`the invention together with a
`pharmaceutically-acceptable diluent or carrier.
`for selective oestrogen therapy of peri-
`As mentioned above a product of the invention is useful
`rnenopausal or postmenopausal conditions. It will be understood that there is no absolute requirement that
`the oestrogen and pure antioesirogen components of
`the product of
`the invention must be dosed
`simultaneously. Sequential or separate use of these components may also provide selective oestrogen
`therapy and such use is to be understood to fall within the definition of a product of the invention. Thus it
`will be appreciated that a pharmaceutical composition according to the present
`invention includes a
`composition comprising an oestrogen, a pure antioestrogen and a pharmaceutically-acceptable diluent or
`carrier. Such a composition conveniently provides the product of the invention for simultaneous use in
`selective oestrogen therapy of perimenopausal or postmenopausal conditions. A pharmaceutical composi-
`tion according to the present invention also includes separate compositions comprising a first composition
`comprising an oestrogen and a pharmaceutically—acceptable diluent or carrier, and a second composition
`comprising a pure antioestrogen and a pharmaceutically-acceptable diluent or carrier. Such a composition
`conveniently provides the product of the invention for sequential or separate use in selective oestrogen
`therapy of perimenopausal or postmenopausal conditions.
`The compositions of the invention may be in a term suitable for oral use (for example as tablets,
`capsules, aqueous or oily suspensions, emulsions or dispersible powders or granules), for topical use (for
`example as creams, ointments, gels, or aqueous or oily solutions or suspensions; for example for use within
`a transdermal patch), for parenteral administration (for example as a sterile aqueous or oily solution or
`suspension for intravenous, subcutaneous,
`intramuscular or intravascular dosing), or as a suppository for
`rectal dosing or as a pessary for vaginal dosing.
`The compositions of the invention may be obtained by conventional procedures using conventional
`pharmaceutical excipients, well known in the art.
`inert
`for example.
`Suitable pharmaceuticaiiy acceptable excipients tor a tablet formulation include,
`diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granuiating and
`disintegrating agents such as corn starch or alginic acid; binding agents such as gelatin or starch;
`lubricating agents such as magnesium stearate, stearlc acid or talc; preservative agents such as ethyl or
`propyl Q-hydroxybenzoate, and antioxidants, such as ascorbic acid. Tablet formulations may be unooated
`or coated 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.
`Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is
`mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft
`gelatin capsules in which the active ingredient
`is mixed with water or an oil such as peanut oil,
`liquid
`paraffin or olive oil.
`Aqueous suspensions generally contain the active ingredient in finely powdered form together with one
`or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl—
`methylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
`wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example
`polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for
`example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters
`derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation
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`EP 0 346 014 B1
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`products of ethylene oxide with partial esters derived from fatty acids and hexltol anhydrides, for example
`polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives
`(such as ethyl or propyl _p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents,
`tlavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
`Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as
`arachis oil, castor oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily
`suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.
`Sweetening agents, such as those set out above, and flavouring agents may be added to provide a
`palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as
`ascorbic acid.
`Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition oi
`water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent
`and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exempli-
`fied by those already mentioned above. Additional excipients, such as sweetening, tlavouring and colouring
`agents, may also be present.
`The pharmaceutical compositions of the invention may also be in the form of oil—in~water emulsions.
`The oily phase may be a vegetable oil, such as castor oil, soya bean oil or arachls oil, or a mineral oil, such
`as,
`for example,
`liquid paraiiin or a mixture oi any oi
`these. Suitable emulsifying agents may be, for
`example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides
`such as lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example
`sorbitan monooleate) and condensation products of
`the said partial esters with ethylene oxide such as
`polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, llavouring and preserva-
`tive agents.
`The pharmaceutical compositions may also be in the form of sterile injectable aqueous or oily
`suspensions, which may be formulated according to known procedures using one or more of
`the
`appropriate dispersing or wetting agents and suspending agents which have been mentioned above. A
`sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic
`parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol, in a vegetable oil (such
`as arachis oil, castcr oil or coconut oil) or in a mineral oil (such as liquid paraffin).
`Conveniently the subcutaneous or intramuscular injection oi an aqueous suspension or an oily solution
`or suspension of a pharmaceutical composition of the invention provides a depot of the active ingredients at
`the injection site irom which these ingredients may leach out over a period of time to provide the sustained
`release thereof.
`
`Suppository formulations may be prepared by mixing the active ingredient with a suitable non—irritating
`excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt
`in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene
`glycols.
`Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions,
`may generally be obtained by formulating an active ingredient with a conventional, topically acceptable,
`vehicle or diluent using conventional procedure well known in the art.
`According to a further feature of the invention there is provided a process for the manufacture of a
`pharmaceutical composition as defined above which comprises bringing into admixture a product as defined
`above together with a pharmaceutically-acceptable diluent or carrier.
`The invention also provides the use of a product as defined above for the manufacture of a combined
`preparation for use simultaneously, sequentially or separately in selective oestrogen therapy of peri-
`menopausal or postmenopausal conditions.
`the invention and the pharmaceutical
`the product of
`It will be appreciated that
`the definition of
`composition of
`the invention includes only those products or compositions which are useful
`in a new
`method for the treatment or prophylaxis of perimenopausal or postmenopausal condition. Pharmaceutical
`compositions comprising an oestrogen and a pure antloestrogen, together with a pharmaceutically-accept
`able diluent or carrier, are novel.
`In European Patent Sepciiications Nos. 138504 and 124369 it is disclosed
`that the antioestrogenic activity of the compounds disclosed therein may be demonstrated by the co-
`administration of a test compound and oestradiol benzoate to an immature female rat. Antioestrogenic
`activity is demonstrated by antagonism of the increase in weight of the uterus of the rat which is produced
`when oestradiol benzoate alone is administered to said rat.
`It is to be noted that, during those tests, the
`oestradiol benzoate was given by subcutaneous injection whereas the test compound was given separately
`either orally or subcutaneously.
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`the invention there is provided a pharmaceutical composition
`According to a further aspect of
`comprising an oestrogen and a pure antioestrogen together with a pharmaceutically~acceptable diluent or
`carrier.
`
`The pharmaceutical compositions of this feature of the invention may be obtained by conventional
`procedures using conventional pharmaceutical excipients well known in the art such as, for example, those
`disclosed above.
`
`the manufacture of a pharmaceutical
`the invention also provides a process for
`This aspect of
`composition as defined immediately above which comprises bringing into admixture an oestrogen and a
`pure antioestrogen together with a pharmaceuticaily—acceptable diluent or carrier.
`The invention also provides the use of a pharmaceutical composition as defined immediately above for
`the manufacture of a new medicament
`for use in selective oestrogen therapy of perimenopausal or
`postmenopausal conditions.
`As stated above a product of the invention is of use in selective oestrogen therapy of perimenopausal
`or postmenopausal conditions. Selective oestrogen therapy may be demonstrated using the standard
`procedure set out below:—
`a) an
`vivg assay measuring the antioestrogenic activity of a compound and any oestrogenic activity
`possessed by that compound. This may be demonstrated in rats by the effect of the compound in
`antagonising the increase in weight of the uterus of an immature female rat produced by administering
`oestradiol benzoate to said rat. Thus, when each of a pure antioestrogen and oestradiol benzoate are
`administered for 3 days to such a rat, a smaller increase in uterine weight
`is produced than the
`substantial increase which would be produced by the administration of oestradiol benzoate without the
`pure antioestrogen. Unlike the known antioestrogens tamoxifen and clomiphene, when a pure an-
`tioestrogen is administered alone to a rat no increase in uterine weight whatsoever is observed.
`The oestrogenic activity of a compound may be demonstrated in rats by the effect of the compound
`when it is administered alone to said rat on the uterine weight of the animal.
`b) An i_n @ assay in mature rats measuring the antioestrogenic activity of a compound by the effect of
`the compound when closed during a test period of 28 days in antagonising the protective effect on the
`animals‘ bone density of their endogenous oestrogens. The bone density of a group of ovariectomised
`rats in which endogenous oestrogen levels are much reduced serves as a control for the effect expected
`to be produced by a fully effective antioestrogen.
`The antioestrogenic activity of the compound in mature rats can also be measured in the same
`assay by measuring the effect of the compound in antagonising the effect of the animals’ endogenous
`oestrogens which serve to increase the weight of their uteri.
`A comparison of the potencies of the antioestrogenic effects of a compound as measured by its effects
`on the animals‘ bone density and uterine weights allows the selectivity of the antioestrogenic effects of the
`compound to be measured.
`Although the pharmacological properties of a product of the invention vary with the structures of the
`oestrogenic and antioestrogenic components and with the route of administration,
`in general a product of
`the invention comprises-
`(i) an oestrogen which possesses oestrogenic activity in the above test (a) at doses in the range, for
`example, 0.002-2.0 mg/kg orally or in the range, for example, 0.0001~0.1 mg/kg subcutaneously;
`(ii) a pure antioestrogen which possesses antioestrogenic activity in the above tests (a) and (b) at doses
`in the range, for example, in test (a): ED5o 0.05-5 mg/kg orally or ED5o 0.01-1.0 mg/kg subcutaneously;
`in test
`(b): antiuterotrophic effect:- ED5o < 20 mg/kg/day orally, < 2 mgllrg./day subcutaneously or
`intramuscularly and < 10 mg/kg/injection when closed as an intramuscular depot injection; reduction in
`bone density:- [3050 > 20 mg/kg/day orally, > 5 mg/kg/day subcutaneously or intramuscularly and > 10
`mg/kg/injection when dosed as an intramuscular depot injection.
`A product of the invention is thereby seen to be surprisingly selective as the activity of the pure
`antioestrogen component is expressed to a high degree within uterine tissue but to a lesser degree on
`bone.
`
`The size of the dose, for therapeutic or prophylactic purposes, of a product of the invention as declined
`above will naturally vary according to the nature and severity of the conditions presented,
`the age and
`menopausal state of the animal and the route of administration.
`In general the minimum quantity of the oestrogenic component of a product of the invention as defined
`above will be chosen so as to provide a beneficial effect with regard to the nature and severity of the
`conditions presented. The quantity of the pure antioestrogenic component is then chosen to antagonise to a
`substantial degree the effect of the oestrogenic component on the uterine tissue. Methods of evaluating the
`condition of uterine tissue are well known to the man skilled in the art, for example, by examination of a
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`lnnoPharma Exhibit 1055.0006
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`EP 0 346 014 B1
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`specimen of endometrial tissue taken by, for example, suction or, for example, by way of a biopsy.
`So far as the oestrogenic component of a product of the invention as defined above is concerned the
`size of the dose and routes of administration conventionally utilised in oestrogen replacement therapy may
`be used. Thus, for example, a tablet containing, for example, 0.5 to 2 mg of oestradiol, oestradiol benzoate,
`natural conjugated oestrogens or oestradiol valerate may be administered daily. Alternatively a tablet
`containing 10 to 100 ug of ethinyloestradiol may be administered daily. Alternatively the oestrogenic
`component may be administered by, for example, intramuscular injection utilising, for example,
`1
`to 10 mg
`of oestradiol benzoate dissolved in an oil such as ethyl oleate; for example. transdermal means utilising, for
`example, 10400 ug of oestradiol contained within a transdermal patch; or, for example, vaginal application
`utilising, for example, daily application of 0.5 to 2 mg of natural conjugated oestrogens contained within 0.5
`to 5 ml of a cream.
`
`So far as the antioestrogenic component of a product of the invention as defined above is concerned
`the size of the dose is chosen such that the effect of the oestrogenic component on uterine tissue is
`antagonised to a substantial degree whereas the beneficial effect of the oestrogenic component on bone is
`substantially unopposed. Thus, for example,
`the antioestrogenic component may be formulated in like
`manner to the oestrogenic component, for example as a tablet, an oily solution suitable for intramuscular
`injection, within a transdermal patch, or within a cream suitable for vaginal application.
`The daily administration of one or more tablets containing conveniently 50 mg to 5 g, and preferably 50 mg
`to 500 mg, of a pure antioestrogen may be used. Preferably the pure antioestrogen may be administered
`by the periodic intramuscular injection of,
`for example, an aqueous suspension or an oily solution or
`suspension containing 50 mg to 5 g of the pure antioestrogen. Preferably an oily solution, for example a
`solution containing arachis or castor oil, an alcohol such as benzyl alcohol and 50 mg to 500 mg of the pure
`antioestrogen is employed. Such an injection provides a depot of the pure antioestrogen which thereafter
`leeches out from the injection site to provide a selective antioestrogenic effect for a period of, for example,
`one to six weeks.
`
`As mentioned above a product of the invention is useful for selective oestrogen therapy of peri-
`menopausal or postmenopausal conditions. As previously mentioned perimenopausal and postmenopausal
`conditions include,
`for example, vasomotor disturbances (hot flushes), urogenital atrophy (particularly
`affecting the vagina and the distal urethra), psychosomatic complaints, changes in the lipid metabolism and
`oesteoporosis. The selective antioestrcgenic effect of the pure antioestrogenic component of a product of
`the invention, as demonstrated by a greater antioestrogenic effect on the uterus of a rat than on the bone of
`the rat, allows the beneficial effect of the oestrogenic component of the product of the invention to be
`selectively applied to the bone and prevents the detrimental effect of an unopposed oestrogenic effect on
`the uterus. The utero—selective effect of the pure antioestrogenic component of a product of the invention
`will allow the beneficial effect of the oestrogenic component of a product of the invention to be applied to
`other oestrogen-responsive tissues,
`for example those causing vasomotor disturbances, pyschosomatic
`complaints and changes in lipid metabolism.
`The invention will now be illustrated in the following non—limiting Examples.
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`Example 1
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`Assay in Mature Rats of the Selective Antioestrogenic Activity of at Pure Antioestrogen
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`The pure antioestrogen used was (1 RS,2RS)-2-p-hydroxyphenyl-2-methyl-1-[9—(4,4,5,5.5—pentafluoropen-
`lylsulphinyl)nonyl]—1,2,3,4-tetrahydronaphth-6—ol.
`The compound was given subcutaneously as a solution in arachis oil at doses of 2 mg/kg/day and 10
`mg/kg/day to two groups of 5 mature rats for a total of 28 days. Further groups of 5 mature rats served as
`an untreated control group. A further group of 5 mature rats was ovariectomised to serve as another control
`group. At the end of the treatment period the weights of the uteri of the test and control groups of rats were
`determined.
`In addition the femurs were dissected, weighed and their volumes were determined using
`Archimedes Principle. The femurs were then burned and t