PATENT SPECIFICATION
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`(11)
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`1 569 286
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`(22) Filed 27 Oct. I 976
`(21) Application No. 44625176
`(31) Convention Application No. 2548413 (32) Filed 27 Oct. 1975 in
`(33) Fed. Rep of Germany (DE)
`(44) Complete Specification Published 11 Jun. 1980
`(51) INT. CL. 3
`A61K 31156
`(52) Index at Acceptance
`A5B 823 835 L
`
`(54) OILY DEPOT SOLUTIONS OF
`GESTAGENS FOR INTRAMUSCULAR INJECTION
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`(71) We, SCHERING AKTIENGESELLSCHAFT. a Body Corporate organised
`according to the laws of Germany, of Berlin and Bergkamen. Germany. do hereby declare
`the invention, for which we pray that a patent may be granted to us. and the method by
`which it is to be performed, to be particularly described in and by the following statement:-
`The present invention is concerned with oily unsaturated depot solutions of gestagens. as
`hereinafter defined, for intramuscular injection and with their ·manufacture and use.
`Depot preparations capable of being used for injection have already been known. As
`compared with preparations capable of being used for oral administration. they have the
`advantage that a single injection is sufficient for one or more months. whereas. for
`10 example, tablets must be taken daily. A depot effect is often brought about by adding the
`active substance to a carrier substance that slowlv releases the active substance. An
`additional depot effect can be achieved by using a derivative of the active substance that
`decomposes to the active substance only in the body.
`Depot preparations of gestagenic substances are used. for example. as contraceptive
`15 agents. Thus, for example, an oily solution of 17a-ethynyl-l\l-nor-testosterone oenanthate
`(norethisterone oenanthate) has been a clinically approved depot contraceptive for some
`years. At a dosage of 200 mg in 1 ml of castor oiUbenzyl benzoate (6:4) the action lasts for
`12 weeks. However. it has been found that the number of pregnancies is somewhat greater
`than in the case of taking oral tablets daily. and that undesired pregnancies occur especially
`20 shortly before the end of .the injection-period. Moreover. it has been desired to obtain an
`action lasting for 13 weeks (3 months) because then the application-period can be .calculated
`more easily in relation to the menstrual cycle.
`It has now been found that a lengthening of the depot effect occurs when the volume of
`the injection solution is increased. while retaining the quantity of gestagen to be
`administered. .
`Female beagle hounds weighing about 13 kg were each injected simultaneously in the
`ri~ht and left M. glutaeus with 200 mg of 14.15-JH-marked norethisterone oenanthate and
`4- 4C-marked norethisterone oenanthate. respectivelv. in 1.8 ml and in 0.6 ml of castor
`oillbenzyl benzoate (6:4}. During 13 weeks the ·~c- and "1H-activity in the blood. plasma,
`urine and faeces was measured. The separation of the marked substances in proportion to
`the release from the depot showed up to 7 weeks after application no systematic difference
`between the selected volumes of application. There was found only a very small percentage
`reduction in the release during the initially high rates of release fr<W.the larger volumes.
`From the 8th week onwards the quantities of the marking applied with the larger volumes
`predominated. In the 13th week after application the release from the injection-volumes
`was increased in favour of the 1.8 ml solution by three and a half times. that is to say. in the
`13th week there was observed. as compared with the smaller volumes. a rate of release
`about 3.5 times higher.
`1f.
`The measured quantities for the 13th week are given in the accqr.upal\ying drawing.
`It could not have been foreseen that. by increasing the volume of the ?Oiution while using
`the same quantity of gestagen. after intramuscular injection a retarded release of gestagen
`and therewith a lengthening of the duration of action would occur.
`. Owing to the lengthening of the period of action by increasing the injection-volume, a
`quantity of 200 mg of norethisterone oenanthate is sufficient for a reliable protection
`against conception for 3 months in women of child-bearing_ age:· For a shorter or longer
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`l 569 286
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`period than 3 months smaller or larger quanmu.:s. rcspectivelv. of the \!esta11:en are
`required. Generally. 50 to 500 mg. and preferahly 200 to ~Oif m1!. of n;Jrethlsterone
`oenanthate. or corresponding q uantitics of another appropriate depot 'i!cst<tl!:en. are used i'n
`l to 6 mi. an~ preferahl~ 2 to ~ f!ll. of oily solution. Lengthening or'the period of action
`occurs even wnh a smallmcrease 10 the volume: however. an advanta!!eous increase in the
`volume of solvent is one and a half to three times (that is the concentration of active
`substance is 1/3 to 213 of that normally employed). A greater increase in the volume of
`solvent is basically possible within the scope of the present invention. but it is not
`recommended because such large volumes applkd intramuscularly lead to troublt!.
`The present invention accordingly provides an oily solution of a gestal!en. as hereinafter
`defined. the solution being suitable for usc as a depot preparation- bv intrumuscular
`injection and containing the gestagcn in a maximum com:entration as hercinafer defined.
`The gestagen is understood herein to exclude any one of the following compounds.
`namely progesterone. 17a-hydroxy-progcstaone and esters of 17a-hydroxy-pmgestcrone.
`The maximum concentrntion of the !!esta!!en in the oilv solution is understood herein to
`be a concentration havinl! n uestiH!enic activitv. as measured bv its effect on the cervical
`mucus of a human female. cl)rresponding to the gestag~::nic activity of substantially 133.33
`mg per ml of norcthisterone oenanthate in the same solvent.
`The gestagen is advantageously present in a wncentration thm is l/3 to 2/3 of the
`concentration of the gestagen normally used in nn oily solution suitable for use as a depot
`preparation by intrnmuscular injection. In other words. a "preferred range of concentm·
`tion·· for the gestagen in the oily solution is a concentration having u gestagenic activity. as
`measured by its gestal!enic effect on the cervical mu~·us of u human fl:mak. corresponding ·
`to the gestagenic activity of substantially 66.67 to 133.J3 mg per ml of noreth1sterone
`oenanthate in the same solvent.
`.
`There are a number of properties of the cervical mucus of a human female afft:cted bv the
`administration of a gestagen which are well known to the gynaecologist. so that one or more
`such parameters cnn be used to correlate the gestagenic effect.
`Gestagens are also known as gestogens. progcstins. progestogcms and progestational
`substances.
`The present invention also provides a process for the manufacture of an oily solution of.·
`the present invention. wherein the gestagen is dissolved in an amount of the solvent
`sufficient to form a substantiallv saturated solution of the uesta11:en. the rcsultinu solution is
`diluted with a further amount "of the solvent and the resulting diluted solution is filtered
`under sterile conditions. and. if desired. the resultin!! solution is introduced into i1t least one
`ampoule under aseptic conditions and sterilized. The ampoule may have a capacity of I. 2. 3
`or 4 mi.
`As gestagens there come into consideration one or more of these compounds that
`themselves. owing to their chemical structure. already display a protracted action when
`injected intramuscularly and for which. owing to their spectrum of action. a long lasting
`treatment is indicated. Such compounds nre. for example. lipophilic steroid hormones and
`in this case especially steroid alcohols in the form l)f their esters. Oily solutions of these
`steroids having a gestagenic activity may he used. for example. for the control of fertility in
`human beings and animals or the treatment of mcnopuusul complaints in women.
`As gestagenic steroid hormones (gestagens) there muy he mentioned. for example. esters
`of 19-nor-17-hydroxy-progesterone. and also esters of 17-hydroxy-progesterone deriva(cid:173)
`tives. for example 17-esters of 6a-mcthyl-17-hydroxy-pmg~::sterone. 6-methyl-6-dchydro-
`17-hydroxy-progesterone. 6-chloro- or 6-tluoro-6-dehydro-17-hydroxy-progestemne. 6-
`chloro- or 6-fluoro-6-dehydro-16a-mcthyl-17-hydroxy·progesterone. 6.16a-dimethyl-6·
`dehydro-17-hydroxy-progesterone. I a.la-methylenc-6-chloro- or -6-tluoro-6-dehydro-17-
`hydroxy-progesterone or also esters of 17a-ethynyl-19-nor-testosterone. 17a-ethynyl-1H·
`methyl-19-nor-testosterone. 17a-ethynyl-6 ~-oestrcne-3.1711-diol or 17a-ethynyl-6 "'(cid:173)
`oestren-17~-ol. The gestagenic steroid hormone is advantageously-c.;la-ethynyl-19-nor(cid:173)
`testosterone oenanthate.
`The esters are derived from acids. for example carboxylic acids. capable of forming
`physiologically tolerable esters. Preferred are the esters of organic carboxylic acids
`containing at least 4 carbon atoms. The acids may helong: to the aliphatic. ,s.ycloaliphatic.
`aromatic. aromatic-aliphatic or heterocyclic series. These <~cids may also l'ie unsaturuted
`and/or di- or poly-basic and/or substituted in the usual manner. As examp~s of substituents
`there may be mentioned alkyl. hydroxyl. alkoxy. oxo or amino groups or halogen atoms.
`There may be mentioned. for example. the following esters: hutyrutes. valerates.
`caproates. oenanthates. pelargonates. undecanoatcs. hcnzoatt:s. ~-cyclopentylpropionates
`and phenylacetates.
`A 3-keto group present in the steroid hormone niay be functionallv converted and
`present. for example. as an enol-ester or enol-ether group. ·ln the case· of an enol-ester
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`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 2
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`group there also com~ into consideration the ester groups already mentioned above. but
`also acetates and proptonates. In the case of an enol-ether group. the ether residue may be,
`preferably, a lower alkyl group. for example a methyl or ethyl group. Also suitable are
`cycloalkyl groups, for example a cyclopentyl or cyclohexyl group.
`The effective dose of the gestagen in the oily solutions of the present invention depends
`on the purpose of the treatment, on the nature of the active substance and the desired
`duration of the action. It is, for example. for 17a-ethynyl- tc~-nor-testosterone oenanthate in
`the control of fertility in women for 3 months 200 mg. Instead of 17a-ethynyl-l9-nor(cid:173)
`testosterone oenanthate, there may be used comparable depot gesta~ens. The quantity of
`comparable gestagens administered and the frequency of their admimstration may be such
`that their gestagenic activity, as measured. for example. by their effect on the cervical
`mucus of a human female. corresponds to that produced by the administration of 200 mg of
`17a-ethynyl-19-nor-testosterone oenanthate every three months.
`The volumes intramuscularly injected of the oily solutions of the present invention are
`normally 1 to 6 mi. The oily, solutions are thus advantageously made up in unit dosage form,
`each dosage unit having a volume within the range of from l to 6 mi. for example a volume
`of 1, 2, 3 or 4 mi. Each dosage unit may be contained in an ampoule.
`It is advantageous for every 1 to 6 ml of the oily solutions of the present invention to
`contain 50 to 500 mg of the gestagen. and more especially for every 2 to 4 ml of the solutions
`to contain 200 to 400 mg of the gestagen.
`.
`As oily solvents there are suitable those known to the expert for such purposes. for
`exam pi~ sesame oil and castor oil. For increasing the solubility of the gestagen there may be
`added to the oily solvents solubilizers. for example benzyl benzoate or benzyl alcohol. In
`addition to those mentioned above other vegetable oils. for example linseed oil. cottonseed
`oil, sunflower oil, ground nut oil. olive oil and wheat oil. may be used. Also suitable are
`synthetic oils. for example polyethylene glycol. triglycerides of higher saturated fatty acids
`and monoesters of higher fatty acids. A mixture of castor oil/benzyl benzoate in the ratio by
`volume of 6:4 is preferred as solvent.
`As indicated above. the oily solutions of the present invention can be used as
`contraceptives.
`The present invention accordingly further provides a method of contraception. wherein
`there is administered by intramuscular injection in a contraceptive dose to a female
`mammal. advantageously a female of the human species. an oily solution of a gesta~en. as
`hereinbefore defined, the solution being suitable for use as a depot preparatton by
`intramuscular injection .and containing the gestagen in a maximum concentration as
`hereinbefore defined.
`The various details of the oily solutions of the present invention discussed above also. of
`course, apply to the oily solutions used in the method of contraception of the present
`invention. Thus, for example, an advantageous embodiment of the method of contracep-
`tion of the present invention is the administration by intramuscular injection to a human 40
`female every 13 weeks of 1 to 6 ml of the oily solution. the I to 6 ml containing 50 to 500 mg
`of the gestagen;and preferably of 2 to 4 ml of the oily solution. the 2 to 4 ml containing 200
`to 400 mg of the gestagen.
`The present invention further provides a contraceptive pack which comprises an oily ·
`solution of a gesta~en. as hereinbefore defined. together with instructions, the instructions 45
`requiring the admmistration by intramuscular injection of the solution in a contraceptive
`dose to a female mammal. advantageously a female of the humari species. and the solution
`being suitable for use as a depot preparation by intramuscular injection and containing the
`.
`·
`gestagen in a maximum concentration as hereinbefore defined.
`The various details of the oily solutions of the present invention discussed above further 50
`apply to the oily solutions contained in the contraceptive packs of the present invention.
`Thus. the instructions in the packs advantageously require that there is administered to ~
`human female every 13 weeks 1 to 6 ml of the oily solution. the .t..I,Q 6 ml containing 50 to
`500 mg of the gestagen, and preferably 2 to 4 ml of the oily solution. the 2 to 4 ml containing
`200 to 400 mg of the gestagen.
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`1 569 286
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`The following Examples illustrate the invention:(cid:173)
`
`E.xample 1
`2000 mg of l?a-ethynyl-19-nor-testosterone oenanthate were dissolved in a mixture of
`castor oiVbenzyl benzoate (6:4 by volume). and the solution was then made up with a
`further amount of the same solvent to 20 mi. The solution was filtered under sterile
`conditions, and was introduced in the usual manner into 2 ml-ampoules under aseptic
`conditions. The ampoules were finally sterilized for 2 hours at l20°C.
`
`Example 2
`2000 mg of l?a-ethynyl-19-nor-testosterone oenanthate were dissolved in a mixture of
`castor oiVbenzyl benzoate (6:4 by volume). and the solution was then made up with a
`further amount of the same solvent to 30 mi. The solution was filtered under sterile
`conditions, and was introduced. in the usual manner into 3 ml-ampoules under aseptic
`conditions. The amJ:loules were· finally sterilized for 2 hours at l20°C.
`WHAT WE CLAIM IS:-
`1. An oily solution of gestagen, as hereinbefore defined. the solution being suitable for
`use as a depot preparation by intramuscular injection and containing the gestagen in a
`maximum concentration as hereinbefore defined.
`2. A solution as claimed in claim 1, wherein the gestagen is present in a preferred range
`of concentration as hereinbefore defined.
`3. A solution as claimed in claim 1 or 2. which contains as the solvent a mixture of
`castor oil and benzyl benzoate.
`4. A solution as claimed in claim 3. wherein the castor oil and benzyl benzoate are
`present in the mixture in the ratio by volume of 6:4.
`5. A solution as claimed in any one of claims 1 to 4. wherein the gestagen is at least one
`lipophilic steroid.
`6. A solution as claimed in claim 5. wherein the lipophilic steroid is a physiologically
`tolerable carboxylic acid ester of a steroid alcohol.
`7. A solution as claimed in claim 6~ wherein the carboxylic acid contains at least 4
`carbon atoms.
`·
`8. A solution as claimed in any one of claims 1 to 7. wherein the gestagen is an ester of
`19-nor-17-hydroxy-progesterone. 6a-methyl-17-hydroxy-progesterone. 6-methyl-6-
`dehydro-17-hydroxy-progesterone. 6-chloro- or 6-fluoro-6-dehydro-17-hydroxy(cid:173)
`progesterone, 6-chloro- or 6-fluoro-6-dehydro-l6a-methyl-17-hydroxy-progesterone,
`la.2a-methylene-6-chloro- or -6-
`6,16a-dimethyl-6-dehydro-17-hydroxy-progesterone.
`fluoro-6-dehydro-17 -hydroxy-progesterone .. 17a-ethynyl-19-nor-testosterone. l?a-ethynyl-
`18-methyl-19-nor-testosterone. 17a-ethynyl-6. 4-oestrene-3.171)-diol or 17a-ethynyl-6. 4-
`oestren-17~-ol.
`9. A solution as claimed in claim 8. wherein the gestagen is 17a-ethynyl-19-nor(cid:173)
`testosterone oenanthate.
`10. A solution as claimed in any one of claims I to 9. wherein every 1 to 6 ml of the
`solution contains 50 to 500 mg of the gestagen.
`11. A solution as claimed in claim 10. wherein every 2 to 4 ml of the solution contains
`200 to 400 mg of the gestagen.
`·
`12. A solution as claimed in any one of claims I to 11. which is in unit dosage form.
`13. A solution as claimed in claim 12. wherein each dosage unit has a volume within the
`range of from 1 to 6 mi.
`14. A solution as claimed in claim 13. wherein each dosage unit has a volume of 1. 2. 3
`or 4 mi.
`15. A solution as claimed in any one of claims 12 to 14. wherein each dosage unit is
`contained in an ampoule.
`16. A solution as cl\limed in claim 1 having a composition substamially as described in
`Example 1 or 2 herein.
`17. A process for the manufacture of an oily solution as claimed in any one of claims 1
`to 16, wherein the gestagen is dissolved in an amount of the solvent sufficient to form a
`substantially saturated solution of the gestag_en. t~e resultin~ sol_uti<;m i~ diluted with. a
`further amount of the solvent and the resulttnl! diluted solut1on IS f1lterld under stenle
`conditions. and. if desired. the resulting solutio~n is introduced into at.,leas"t one ampoule
`under aseptic conditions and sterilized.
`18. A process as claimed in claim 17. conducted substantially as described in Example 1
`or 2 herem.
`19. A method of contraception. wherein there is administered by intramuscular
`injection in a contraceptive dose to a female mammal an oily solution of a gestagen. as
`hereinbefore defined. the solution be in)! suitable for use· as a depot preparation by
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`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 4
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`1 569 286
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`intramuscular injection and containing the gestagen in a maximum concentration as
`hereinbefore defined.
`20. A method as claimed in claim 19. wherein the gestagen is present in the oily solution
`in a preferred range of concentration as hereinbefore defined.
`21. A method as claimed in claim 19 or 20. wherein the oily solution contains as the
`solvent a mixture of castor oil and benzyl benzoate.
`22. A method as claimed in claim 21. wherein the castor oil and benzyl benzoate are
`present in the mixture in the ratio by volume of 6:4.
`23. A method as claimed in any one of claims 19 to 22. wherein the gestagen is a
`physiologically tolerable, lipophilic carboxylic acid ester of a steroid alcohol.
`24. A method as claimed in claim 23, wherein the carboxylic acid contains at least 4
`carbon atoms.
`25. A method as claimed in any one of claims 19 to 24. wherein the gestagen is an ester
`of 19-nor-17-hydroxy-progesterone. 6a-methyl-17-hydroxy-progesterone' 6-methyl-6-
`dehydro-17-hydroxy-progesterone. 6-chloro- or 6-fluoro-6-dehydro-17-hydroxy(cid:173)
`progesterone, 6-chloro- or 6-fluoro-6-dehydro-16a-methyl-17-hydroxy-progesterone,
`6,16a-dimethyl-6-dehydro~17-hydroxy-progesterone. la-2a-methylene-6-chloro- or -6-
`fluoro-6-dehydro-17-hydroxy-progesterone, 17a-ethynyl-19-nor-testosterone, 17a-ethynyl-
`18-methyl-19-nor-testosterone, 17a-ethynyl-18-methyl-l9-nor-testosterone. 17a-ethynyl-
`6 4-oestrene-3,17~-diol or 17a-ethynyl-6 4~oestren-17f:i-ol.
`26. A method as claimed in claim 25, wherein the gestagen is l7a-ethynyl-19-nor(cid:173)
`testosterone oenanthate.
`27. A method as claimed in any one of claims 19 to 26. wherein the female mammal is a
`female of the human species.
`28. A method as claimed in claim 27. wherein there is administered to the human
`female every 13 weeks 1 to 6 ml of the oily solution. the l to 6 ml containing 50 to 500 mg of
`the gestagen.
`29. A method as claimed in claim 28. wherein there is administered to the human
`female every 13 weeks 2 to 4 ml of the oily solution. the 2 to 4 ml containing 200 to 400 mg
`· of the gestagen.
`·
`30. A method as claimed in claim 29, wherein there is administered to the human
`female every 13 weeks the contents of an ampoule having a composition substantially as
`described in Example 1 or 2 herein.
`31. A contraceptive pack which comprises an oily solution of a gestagen. as
`hereinbefore defined, together with instructions. the instructions requiring the administra(cid:173)
`tion of intramuscular injection of the solution in a contraceptive dose to a female mammal
`and the solution being suitable for use as a depot preparation by intramuscular injection
`and containing the ~estasen in a maximum concentration as hereinbefore defined.
`32. A pack as clatmed m claim 31. wherein the gestagen is present in the oily solution in
`a preferred range of concentration as hereinbefore defined.
`33. A pack as claimed in claim 31 or 32. wherein the oily solution contains as the solvent
`a mixture of castor oil and benzyl benzoate.
`34. A pack as claimed in claim 33. wherein the castor oil and benzyl benzoate are
`present in the mixture in the ratio by volume of 6:4.
`35. A pack as claimed in any one of claims 31 to 34. wherein the gestagen is a
`physiologically tolerable. lipophihc carboxylic acid ester of a steroid alcohol.
`36. A pack as claimed in claim 35. wherein the carboxylic acid contains at least 4 carbon
`atoms.
`.
`.
`37. A pack as claimed in any one of claims 31 to 36. wherein the gestagen is an ester of
`19-nor-17-hydroxy-progesterone. 6a-methyl-17-hydroxy-progesterone, 6-methyl-6-
`dehydro-17-hydroxy-progesterone. 6-chloro- or 6-fluoro-6-dehydro-17-hydroxy(cid:173)
`progesterone, 6-chloro- or 6-fluoro-6-dehydro-l6a-methyl-17.:!!..Ydroxy-progesterone,
`la.2a-metHyrene-6-chloro- or -6-
`6,16a-dimethyl-6-dehydro-17-hydroxy-progesterone.
`fluoro-6-dehydro-17-hydroxy-progesterone. 17a-ethynyl-l9-nor-testosterone. 17a-ethynyl-
`18-methyl-19-nor-testosterone. 17a-ethynyi~L::. ~ -oestrene-3 .1713-diol or l7a-ethynyl-6 4
`-
`oestren-17~-ol.
`38. A pack as claimed in claim 37. wherein the gestagen is 1#;1-ethynyl-19-nor(cid:173)
`testosterone oenanthate.
`39. A pack as claimed in any one of claims 31 to 38. wherein the'Miy solution is in unit
`dosage form.
`40. A pack as claimed in any one of claims 31 to 39. wherein the female mammal-is a
`female of the human species.
`41. A pack as claimed in claim 40. wherein the instructions require that there is
`administered to the human female every 13 weeks I to 6 ml _of the oily solution. the 1 to 6 ml
`containing 50 to 500 mg of the gestagen.
`
`5
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 5
`
`

`
`6
`
`5
`
`10
`
`1 569 286
`
`42. A pack as claimed in claim 41. wherein the instructions require that there is
`administered to the human female every 13 weeks 2 to 4 ml of the oily solution. the 2 to 4 ml
`containing 200 to 400 mg of the gestagen.
`43. A pack as claimed in claim 31. wherein the oily solution is in unit dosage form. each
`dosage unit being contained in an ampoule and the ampoule having a composition
`substantially as described in Example 1 or 2 herein. and the instructions require that there is
`administered to a human female every 13 weeks one of the dosage units.
`
`6
`
`5
`
`ABEL & IMRAY.
`Chartered Patent Agents.
`Northumberland House.
`303-306 High Holborn.
`London WClV 7LH.
`
`Printed lor Her Majesty's Stationery Office, by Croydon Printing Company Limite<~., Croydon, Surrey, 1980.
`Published by The Patent Office. 2' Southa!npton Buildings, London, WC2A lAy ,from
`wbic:ll copies may be obtained.
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 6
`
`

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`
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`
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`
`10
`
`1569286
`
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`
`COMPLETE SPECIFICATION
`This drawing Is o reproduction of
`the Original on a reduced scale
`
`THE SEPWTDI Of IIORETHISTEROf£ OEICA.Nl1CATE
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`Jmt4MUSQJUII ICJECTIOM Of 200mg. DISSOLVED
`IN CASTOII OIL/BEIIZYL BENZOATE 6:<4.
`
`HWI= STANDAAD D£VIATION Of EVEIIY 5
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`1 ·I I
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 7