[11]
`
`1
`
`4,212,863
`
`[19]
`United States Patent
`[45] Jul. 15, 1980 '
`Cornelius
`
`
`
`
`
`[54] HIGHLY CONCENTRATED
`PHARMACEUTICAL FORMULATIONS OF
`STEROIDS AND PROCESSES FOR THEIR
`PREPARATION
`
`[75]
`
`Inventor:
`
`Lammert Cornelius, Boxmeer,
`Netherlands
`
`[73] Assignee: Akzo N.V., Arnhem, Netherlands
`
`[21] Appl. No.: 953,877
`
`[22] Filed:
`
`Oct. 23, 1978
`
`Foreign Application Priority Data
`[30]
`Oct. 29, 1977 [NL] Netherlands ..'....................... 7711916
`
`
`Int. Cl.2 ........... .._............................... .. A61K 31/56
`[51]
`[52] US. Cl.
`.............. ..
`[58] Field of Search ..................,........... .. 424/240, 284
`
`[56]
`
`References Cited
`
`2,791,609
`3,025,311
`3,085,939
`3,149,037
`3,636,195
`
`U.S. PATENT DOCUMENTS
`5/1957 Kaplan ................................. 424/240
`3/1962 Gutsell, Jr. et a1.
`424/240
`......
`4/1963 Wruble et a1.
`424/240
`
`. ..... 167/81
`9/1974 Aiello et a1.
`. . ..
`1/1972 Monson ................................ 424/240
`
`FOREIGN PATENT DOCUMENTS,
`
`2240187 2/1974' Fed. Rep. of Germany .
`1081667 4/1966 United Kingdom .
`1453239 10/1976 United Kingdom .
`
`OTHER PUBLICATIONS
`
`Chemical Abstracts, vol. 82, No. 4 (1975) Paragraph 21,
`826(3).
`
`Primary Examiner—Elbert L. Roberts
`Attorney. Agent, or Firm—Stevens, Davis, Miller &
`Mosher
`
`[57]
`
`ABSTRACT,
`
`The invention relates to highly concentrated liquid
`phannaceutical formulations of steroids of the ceatrane,
`androstane and (19-nor-)pregnane series comprising
`tocol or a derivative thereof that is fluid at normal tem-
`perature, or mixtures thereof, in an amount of at least
`10% by weight of the formulation, and optionally one
`or more of the usual fluid carriers, such as vegetable oil,
`benzyl benzoate and/or benzyl alcohol.
`
`'10 Claims, No Drawings
`
`1 InnoPharma Exhibit 1112.0001
`
`

`

`I
`
`4,212,863
`
`HIGHLY CONCENTRATED PHARMACEUTICAL
`FORMULATIONS OF STEROIDS AND
`PROCESSES FOR THEIR PREPARATION
`
`The invention relates to highly concentrated pharma-
`ceutical formulations of steroids of the oestrane, andro-
`stane and (19-nor-)pregnane series, the said formula~
`tions being fluid at normal temperature, and to pro-
`cesses for their preparation.
`Injection preparations of steroids are known. Such
`preparations usually consist of solutions of the steroids
`in oily carriers, such as arachis oil, sesame oil, olive oil
`and similar carriers, to which yet other excipients may,
`if desired, be added, such as benzyl alcohol and benzyl
`benzoate. Such fluid preparations may be injected al-
`most without damage to tissues, and absorption of the
`active substance by the organism takes place from the
`subcutaneous or intramuscular depot thus obtained. The
`extent and the duration of the absorption depends on
`various factors including the dosage and concentration
`of the steroid and the physical properties of the steroid,
`such as lipophilicity. The upper limit of the concentra-
`tion is naturally governed by the solubility of the steroid
`in the carrier. If this solubility is not very great, achieve-
`ment of the desired effect will necessitate repeating
`injections at shorter intervals or injecting larger vol-
`umes, and there are of course objections to both of these
`procedures.
`It is known that the solubility of steroids in vegetable
`or animal oils can be increased by the addition of excipi-
`ents such as benzyl alcohol and benzyl benzoate. An
`objection to the use of such excipients, and specifically
`benzyl alcohol in somewhat higher concentration,
`is
`that these agents may irritate the tissues.
`Other ways of administration to give higher concen-
`trations in the subcutaneous or intramuscular depot are
`the injection of crystal suspensions or the implantation
`of solid formulations. The preparation of stable crystal
`suspensions may give rise to problems, while the surgi-
`cal intervention, though minor, constitutes an objection
`to the implantation.
`When the preparation and use of a highly concen-
`trated long-acting injection preparation of steroids is
`therefore desired, for example an injection preparation
`for the inhibition of ovulation in animals or man, one or
`more of the above-noted objections will be valid to a
`greater or lesser extent.
`The administration of steroids in solution, for exam-
`ple a solution in oil, by the oral route is also known; see
`for example
`the Dutch Patent Application No.
`7402689.(=British Pat. No. 1,500,374).
`The administration of fluid pharmaceutical prepara-
`tions by the oral route may be realized in various ways.
`The prescribed quantity, for example a number of drops
`or ml, may be taken per spoon, on a sugar lump or
`together with food. The solution may also be taken
`“sealed” in a soft gelatine capsule or in microcapsules.
`With the oral administration of certain steroids in
`solution, for example testosterone and esters thereof,
`the problem may also arise that the solubility (and there-
`fore the amount of active agent per dosage unit) in the
`known solvents is relatively low, so that either more or
`larger dosage units must be administered on each occa-
`sion or the administration of the preparation must be
`repeated at shorter intervals. There are objections to
`both procedures. In such cases there is an obvious need
`for solutions with greater concentrations.
`
`5
`
`10
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`15
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`20
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`25
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`30
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`35
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`45
`
`50
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`65
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`.
`2
`It has now surprisingly been found that highly con-
`centrated formulations of steroids, said formulations
`being fluid at normal temperature, and said steroids
`being of the oestrane, androstane and (l9-nor-)pregnane
`series, may be prepared by dissolving the steroids in
`tocol or in a derivative thereof which is liquid at normal
`temperature (15°—30° C.), or in a mixture of two or more
`of these derivatives whereby the quantity of tocol or
`derivative thereof in the formulation is at least 10% by
`weight.
`Hence, the invention relates to the highly concen-
`trated steroid formulations thus obtained, and to the
`processes for their preparation.
`Tocol and the derivatives liquid at normal tempera-
`ture may be represented by the general formula:
`
`
`
`where
`R1=H, CH3 0r C2H5;
`R2=H, CH3 or C2H5;
`R3=H, CH3 or Csz;
`R4=H, 0H, O-acyl (1—2 atoms) or O-alkyl (1—2 C-
`atoms); and
`the dotted lines denote the optional presence of a car-
`bon-carbon double bond.
`‘
`The compounds in which the side-chain in the for-
`mula given above contain one or two isoprene residues
`
`CI
`
`(-c-c—c-_-c-)
`
`less than indicated are also included amongst the tocol
`derivatives noted above.
`.
`For tocol itself, R1=R2=R3=H, R4=OH and the
`side-chain is saturated. Examples of tocol derivatives
`are: 5-methyltocol, 7-methyltocol, 8-methyltocol, 5,7-
`dimethyltocol, 5,8-dimethyltocol, 7,8-dimethy1tocol,
`5,7,8-trimethyltocol, 8-methyltocotrienol, 7,8-dimethyl-
`tocotrienol, 5,8-dimethyltocotrienol, 5,7,8-trimethyl-
`tocotrienol,
`5,7-di—ethyltocol,
`5,7-dimethyl-8-ethyl-
`tocol, 5,7-di-ethyl-8-methyltocol, the formates and ace-
`tates, as well as the methyl and ethyl esters of these
`compounds, and 6-desoxytocol. Use is preferably made
`of
`tocol, 5,7,8-trimethyltocol(a-tocopherol) or
`8-
`mcthyltocol(6-tocopherol). In practice use is generally
`made of the racemates dl-tocol, dl-a-tocopherol and
`dl—6—tocopherol.
`During the preparation of a formulation according to
`the invention, excipients such as benzyl alcohol or ben-
`zyl benzoate may optionally also be used, or a quantity
`of an oily carrier such as arachis oil or sesame oil may be
`added. Such a use or addition may be desirable in the
`preparation of injection formulations in order to lower
`the viscosity and in this way make the preparation eas-
`ier to inject; in other words, to enable the formulation to
`be injected through a needle of the desired bore.
`The amount of tocol or derivative thereof in the
`
`least 25% w/w, which
`preparation is preferably at
`means that at least 100 mg and preferably 250 mg tocol
`
`InnoPharma Exhibit 1112.0002
`
`

`

`3
`or derivative thereof is present in a milliliter (about 1000
`mg) of solution. The upper limit of the quantity of tocol
`or derivative thereof is of course determined by the
`amount of steroid which can be dissolved in the carrier,
`and depends to some extent on both the steroid and the
`carrier; it lies between 50 and 90% w/w and is generally
`between 60 and 80% w/w. This means that the maxi-
`mum amount of steroid per ml solution (about 1000 mg),
`again depending on the steroid and the carrier, will be
`between 100 and 500 mg and generally may be 200—400
`mg.
`The process offers particular advantages for steroids
`of the oestrane, androstane and (l9-nor-) pregnane se-
`ries containing at least a 3-oxo-A4-group and an option-
`ally esterified hydroxy group at position 17 and/or 21
`(if present), since with these steroids much higher con-
`centrations can be achieved than is possible with the
`known solvents and concentrations of 100 to 400 mg in
`the absolute sense are furthermore possible; for certain
`steroids with the characteristics noted, even concentra-
`tions up to 500 mg per ml tocol or derivative thereof are
`possible.
`Examples of oestrane, androstane and (19-nor-) preg-
`nane compounds with at least a 3-oxo-A4-group and an
`optionally esterified hydroxy group at position 17 and-
`/or 21 (when present) are: testosterone, l9-nor-testost-
`erone (nandrolone), progesterone, l9-nor-progesterone,
`l7a—hydroxyprogesterone,
`17a-hydroxy-19-nor-prog-
`esterone, 21-hydroxy-progesterone, 21-hydroxy-l9-nor-
`progesterone,
`l6a—ethy1-2l-hydroxy-progesterone,
`l6a-ethyl-21—hydroxy—19-noruprogesterone, 16-methy-
`lene-17a-hydroxy-progesterone, corticosterone, desox-
`ycorticosterone, cortisone, hydrocortisone, predniso-
`lone, aldosterone and the 17 and/or 21 esters of these
`steroids derived from organic mono- or di-carboxylic
`acids with 1 or 2, respectively, to 18 carbon atoms.
`Examples of such organic mono- and di- carboxylic
`acids are aliphatic carboxylic acids such as propionic
`acid, butyric acid, isocaproic acid, decanoic acid, a-
`methyldecanoic acid, lauric acid, myristic acid, oleic
`acid, palmitic acid,
`trimethylacetic acid, undecenoic
`acid, malonic acid, succinic acid, glutaric acid and tar-
`taric acid, cycle-aliphatic carboxylic acids, such as oy-
`clohexane-carboxylic acid, cyclopentylpropionic acid
`and cyclohexylbutyric acid, araliphatic carboxylic acids
`such as phenylacetic acid and phenylpropionic acid,
`and aromatic carboxylic acids such as benzoic acid.-
`The steroids named may also be further substituted at
`positions 6, 7 and/or 11, for example by a methyl, ethyl
`or methylene group, and/or may contain a further dou-
`ble bond, for example a A6 bond.
`The preparations obtained according to the inven-
`tion, depending on the steroid present, may be used for
`various indications. Preparations based on testosterone
`and esters thereof may be used as androgenically active
`preparations in substitution therapy. Preparations based
`on oestrogens may be used in cases of oestrogen defi-
`ciency. Preparations containing nandrolone or esters
`thereof can find use as anabolic preparations or ovula-
`tion-inhibiting preparations. Preparations based on pro-
`gesterone or progesterone derivatives may be used as
`progestagenic preparations, not only for the mainte-
`nance of a pregnancy but also for prevention of preg—
`nancy (ovulation inhibiting action) and they may fur-
`thermore be used for the treatment of endometrial car-
`cinoma. For use as ovulation inhibitors,
`long-acting
`esters of l7a-hydroxy-progesterone, such as for exam—
`ple, l7a-hydroxy-progesterone caproate and medroxy-
`
`10
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`15
`
`20
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`25
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`30
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`35
`
`4o
`
`45
`
`50
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`55
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`60
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`65
`
`4,212,863
`
`4
`progesterone acetate, are used. Preparations containing
`corticosteroids may‘ be used in those cases in which
`mineralocorticoid, glucocorticoid, anti-inflammatory,
`anti-allergic, anti-shock or analgesic activity is desired.
`An interesting application of those preparations ac-
`cording to the invention based on nandrolone esters, in
`particular nandrolone esters derived from organic car-
`boxylic acids with more than 7 carbon atoms, for exam-
`ple nandrolone phenylpropionate, is the use as an injec-
`tion preparation for the regulation of oestrus in animals.
`Such an injection preparation offers particular advan-
`tages for the suppression of oestrus in domestic animals
`such as dogs. Since it is possible, in accordance with the
`invention, to prepare injection formulations containing
`well over 300 mg nandrolone ester, for example nandro-
`lone palmitate, per ml, it is possible to suppress oestrus
`in dogs for more than 3 months with a single injection of
`1 m1. Only concentrations of 50 to 100 mg per m1 can be
`obtained with the known solvents such as arachis oil,
`while the addition of benzyl benzoate and/or benzyl
`alcohol enables concentrations of 100 to 200 mg per ml
`to be reached with certain nandrolone esters, for exam-
`ple nandrolone palmitate. For the suppression of oes-
`trus, therefore, either a larger volume (2 to 5 ml) would
`have to be injected, or the injection would have to be
`repeated at an earlier date, and there are objections to
`both these procedures.
`On using injection preparations according to the in-
`vention based on nandrolone esters for the suppression
`of oestrus in animals it was furthermore shown that,
`specifically with the preparations based on nandrolone
`esters derived from aliphatic carboxylic acids with 9——18
`carbon atoms, an additional depot effect (prolonged
`activity or sustained release effect) appears, so that the
`very high concentration in the depot, particularly dur-
`ing the initial phase, does not result in an undesirably
`high blood level; unwanted side-effects as a result of
`excessively high blood levels do not therefore occur.
`Another interesting use of the preparations according
`to the invention is the oral administration in the form of
`soft gelatine capsules containing a highly concentrated
`solution of the steroids in tocol or a derivative thereof.
`This use is specifically of importance for the oral admin-
`istration of testosterone and nandrolone, in particular
`the esters of these steroids derived from organic carbox-
`ylic acids.
`The activity of both testosterone and nandrolone is
`much lower on oral administration than on parenteral
`administration. It is true that this difference proves to be
`smaller for the esters of these compounds, but it may
`nevertheless still constitute an adequate reason for
`choosing the parenteral administration form in prefer-
`ence to the oral form, particularly in those cases where
`the doses to be administered are relatively high, as, for
`example, in androgen substitution therapy, and a large
`number of dosage units or a relatively large dosage unit
`(swallowing problem!) have or has, respectively, to be
`given on each occasion or alternatively the dosage has
`to be repeated at shorter intervals. In such cases, use of
`the highly concentrated solutions according to the in-
`vention can weigh the scales in favour of the medically
`and technically easier oral dosage form, such as the soft
`gelatine capsule containing the concentrated solution
`of, for example, a testosterone or nandrolone ester.
`Such an oral administration form furthermore offers the
`advantage that the active agent is made available to the
`organism in a lipoid solution, which has a favourable
`effect on the activity of the preparation. In this connec-
`
`w I
`
`nnoPharma Exhibit 1112.0003
`
`

`

`4,212,863!
`
`.
`-
`6'
`way usual in the pharmaceutical technique, this solution
`was-"encapsulated under aSeptic Conditions in soft gela-
`tinchapsulels with a volume (contents) of 0.24 ml, so
`that the testosterone undecanoate content wasz5'0'rn‘g
`per capsule. The capsule Wall-(113 mg) consisted of
`gelatine (77 mg), glycerine (17.5 mg), sorbitol (15.5 mg),
`pai'abens (0.5 mg), TiOz (0.6 mg) and ‘Cochineal Red A
`(1.9 mg; dye).
`.
`V.
`,,
`.
`‘
`v
`r
`A number of other steroids were dissolved in tocol
`and encapsulated in soft gelatine capsules in a similar
`way.lDetails are given in Table B.
`Table B
`
`v
`
`Steroid
`
`Capsule
`content (ml)
`
`mg steroid '
`per capsule
`
`Testosterone a-methyldecanoate
`Nandrolone 'decanoate
`Nandrolone ‘a-methyl-B-cyclo-
`hexylpropionate
`'
`
`Dinandrolone oxydiacetate
`0.24 ,
`25
`
`0.12
`0.18
`’ 0.08
`
`25
`50
`20
`
`EXAMPLE IV
`
`Injection formulations of a number of steroids in a
`Solution based on tocol, benzyl alcohol, benzyl benzoate
`and arachis oil (50:5:20z25) were prepared in the usual
`way (see Example II) and filled into 1 ml capsules. The
`steroids are given in Table C, together with their con-
`centrations in mg per ml solution.
`Table C
`
`
`Steroid
`mg per m1
`Nandrolone phenylpropionate
`200
`lfia-ethyl-2 l-hydroxyprogesterone-Zl-decanoate
`350
`Dinandrolone oxydiacetate
`75
`Oestradiol phenylpropionate
`50
`l7a~hydroxyprogesterone caproate
`150
`
`Nandrolone palmitate/laurate (2:1) 300
`
`I claim:
`
`1. A highly concentrated liquid pharmaceutical ste-
`roid formulation comprising (1) at least one steroid of
`the oestrane, androstane or (l9-‘nor-)pregnane series
`containing at least a 3-oxo-A‘-group and an hydroxy
`group at position '17 and or 21 (if present) and (2) a
`solvent for said steroid comprising at lent one of tocol
`or a derivative thereof that is fluid at normal tempera-
`tures and of the formula:
`
`
`
`where
`R1=H, CH3, or C2H5;
`R2=H, CH3, or C2H5;
`R3=H, CH3, or Csz;
`R4=H, OH, 0-C1.2 acyl, OCH3, or 02115; and
`n: l, 2, or 3;
`'
`the dotted lines indicate the optional presence of a car-
`bon atom double bond, with the proviso that said tocol
`or derivative constitutes at least 10% by weight of said
`formulation.
`"
`
`InnoPharma Exhibit 1112.0004
`
`5.
`
`10
`
`15.
`
`20.
`
`25
`
`35
`
`4s
`
`'50
`
`55
`
`60
`
`‘65
`
`tion see the Belgian Patent Specifications Numbers
`826086 and 845613.
`It is known that certain tocol derivatives possess
`vitamin E activity. For many applications,'such>‘as sup-
`pression of oestrus in animals; this is not objectionable,
`but for applications innthelhuman sector the. vitamin B
`activity of a preparation according to the invention may
`be a drawback. It is however known that the various
`tocols possess differing vitamin E activities, and that
`tocol itself and certain derivatives, for example 5,7-die-
`thyltocol and 6-desoxytocol, possess little-"or novitamin
`E activity, so that a formulation" withvthe desired 10w
`vitamin E activity or a formulation devoidlo'f vitamin E
`activity can be preparedvaccording to the choice-of
`carrier.
`‘ a,
`o
`The invention is illustrated by meansofthe following
`examples.
`2.-
`.;
`.
`.
`m.
`
`‘ EXAMPLE '1‘“
`
`'
`
`Saturated solutions ofa number .of‘steroidsin 5,7,8-
`trimethyltOcol (a—ztOCOpherol') were prepared=-at,..12l°zv.C.-
`The concentration of steroid inmg pergml solution is
`given in column a of Table A. Column b gives the con:
`centration of steroid in mg per .ml in a saturated solution
`in a solvent comprising equal parts by~volume of q:
`tocopherol and arachisoil, whilefor comparison col-
`umn c shows the concentration of steroidin mg per. ml.
`in a standard solution in arachis oil... ».
`'
`
`>
`-
`'
`- Table A
`i
`i
`'6'_
`40 ,
`’ 2“
`l'
`‘
`"200
`
` _
`
`'
`
`'
`
`'
`
`a H
`100
`'40:
`"
`$500
`
`M
`‘
`
`'
`
`c,
`55
`_l
`‘
`-
`"
`.50
`
`I
`
`-
`
`Steroid
`testosterone
`V
`.
`I
`corticosterone
`léa—ethyl-Zl-hydroxy-progesteronév
`21-decanoate
`r
`a
`U
`'
`r
`16a-ethyl-21-hydroxy-progesterone-
`140
`>225
`>225
`21—heptanoate
`10
`20
`120
`dinandrolone oxydiacetate
`2
`85
`180
`dinandrolone adipate
`85
`>225
`>225
`testosterone undecanoate
`
`nandrolone palmitate 75 400 200
`
`
`
`EXAMPLE II
`
`300 g nandrolone palmitate and 250 g a-tocopherol
`were added to a mixture of 100 g benzyl alcohol and 250.
`g benzyl benzoate which had been warmed to 70° C.
`After stirring for a while, a clear solution was obtained.
`The solution was cooled to room temperature after
`which the volume was adjusted to 1000 ml by addition,
`with stirring, of arachis oil (about 100 g). The solution
`thus obtained was filled into 1000 vials in a volume of 1
`ml solution each, after which the vials were closed with
`oil-resistant rubber stoppers and so-called open “Ci-
`liatto” capsules. The vials were finally heated at 121° C.
`for 30 minutes in an autoclave.
`
`In a similar way, but using tocol instead of a-toco-
`pherol, and in another batch 6-tocopherol instead of
`a-tocopherol, solutions were prepared and vials were
`filled with 1 ml solution containing 300 mg nandrolone
`palmitate.
`The injection preparations thus obtained proved to be"
`eminently suitable for use in the suppression of oestrus
`in dogs, a single injection of 1 ml made using a syringe
`fitted with a 19 G needle giving suppression cf oestrus
`lasting at least 3 months.
`-
`EXAMPLE III
`
`A sterile solution of testosterone undecanoate in
`tocol, containing 208.35 g per liter, was made. In the
`
`

`

`4,212,863
`
`
`
`'
`where
`R|=H, CH3, or Csz;
`R2'=H, CH3, or C2115;
`R3=H, CH3, or Csz;
`R4==H, OH, O—C1.z acyl, or C2H5; and
`n: l, 2, or 3;
`the dotted lines indicate the optional presence of a car—
`bon atom double bond, with the proviso that said tocol
`or derivative constitutes at least 10% by weight of said
`formulation.
`7. Process according to claim 6, characterized in that
`said tocol or derivative thereof is selected from the
`group consisting of tocol, a-tocopherol and 74000-
`pherol.
`8. The process of claim 6 wherein the hydroxy group
`of the steroid is esterified.
`9. The process of claim 6 comprising further adding
`at least one fluid carrier selected from the group consist-
`ing of vegetable oils, benzyl benzoate, and benzyl alco-
`hol to the formulation with the proviso that said tocol
`or derivative constitutes at least 10% by weight of said
`formulation.
`10. Process according to claims 6, 7, 8 or 9, character-
`ized in that said tocol or derivative thereof constitutes
`at least 25% by weight of said formulation.
`.
`$
`*
`i
`*
`
`7
`2. The formulation of claim 1, wherein said tocol or
`
`derivative thereof is selected from the group Consisting
`
`of tocol, a—tocopherol and 6-tocopherol.
`
`3. The formulationof claims 1 or 2, ‘wherein said
`
`tocol or derivative thereof constitutesvat least 25% by
`weight of said formulation.
`'
`4. The steroid formulation of claim 1 where the hy-
`
`10
`
`droxy group of the steroid is esterified.
`5. The steroid formulation of claim 1 further contain-
`
`15
`
`ing at least one fluid carrier selected from the group
`
`consisting of vegetable oils, benzyl benzoate, and benzyl
`
`alcohol with. the‘proviso that said tocol or derivative
`
`constitutes at least 10% by weight of said formulation.
`6. A process for preparing a highly concentrated
`
`pharmaceutical steroid formulation comprising dis-
`
`solving at least one steroid of the oestrane, androstane,
`
`or (19-nor-) pregnane series containing at least a 3-oxo-
`
`A4-group and an hydroxy- group at position 17 and or 21
`
`(if present) in at least one of tocol or a derivative thereof
`
`that is liquid at normal temperatures and of the formula:
`
`20
`
`25
`
`30
`
`3‘5
`
`45
`
`50
`
`55
`
`60
`
`65
`
`7 InnoPharma Exhibit 11125005
`
`

`

`[___________________..__._.
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENTNO.
`
`DATED
`
`:
`
`3
`
`4,212,863
`
`July 15, 1980
`
`[
`
`nchmmdmmmmrwmmsthamw—MWMEdMEMaMtMtMMmeummt
`are hereby corrected as shown below:
`
`INVENT0R(S)I Lammert CORNELIUS
`
`Line 3 of the Abstract, change "comprising" to ——containing——.
`
`Column 2,
`
`line 51, change "esters" to -—ethers——.
`
`Column 6,
`
`line 63,
`
`in claim 1, change "CZHS" to read -—OC2H5«—.
`
`Column 8,
`
`line 14,
`
`in claim 6, change "or C2H5" to read
`
`-—OCH3 or C2H5—— .
`
`Signed and Scaled this
`Fourth Day of May I982
`
`|SEAL|
`
`A (test:
`
`GERALD .I. MOSSINGHOFF
`
`Arresting Officer
`
`Commissioner of Patents and Trademarks
`
`InnoPharma Exhibit 1112.0006
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`?
`
`PATENT N0.
`
`DATED
`
`:
`
`:
`
`4.212.863
`
`July 15, 1980
`
`1NVENTOR(S)
`
`: Lammert CORNELIUS
`
`It is certified that error appears in the above-identified patent and that said Letters Patent
`are hereby corrected as shown below:
`
`Column 8, line 14. in claim 6. change "OCH3 or CZHS" to read
`
`~—0CH3 or 0C2 51w“
`Signed and Scaled this
`
`Twentieth Day of
`
`July 1902
`
`mm”
`
`Arrest:
`
`GERALD J. MOSSINGHOFF
`
`Arresting Officer
`
`Commissioner of Patenls and Trademarks
`
`
`
`InnoPharma Exhibit 1112.0007
`
`