Patented Jan. 5, 1965 United States Patent Office
`
`3,164,529
`
`1
`
`3 164 520
`INJECTABLE STEROID? C0’MPOSITIONS CONTAIN-
`ING AT LEAST 75% BENZYL BENZOATE
`Raymond Charles Huber, Martinsville, N.J., assignor to A
`Olin Mathieson_ Chemical Corporation, New York,
`N.Y., a corporation of Virginia
`No Drawing. Filed Oct. 29, 1962, Ser. No. 233,931
`4 Claims.
`‘
`(Cl. 167-58)
`
`This invention relates to compositions of matter and
`more particularly to new parenterally administrable phar-
`maceutical compositions comprising one or more active
`medicaments and a physiologically acceptable non—toxic
`pharmaceutical vehicle, comprised essentially of benzyl
`benzoate.
`~
`The active medicament which may be incorporated in
`the novel compositions of this invention may be any one
`which is administered for use in comparatively large unit
`dosages, for example, 10 mg./ml. to 500 mg./ml. and
`which is soluble in benzyl benzoate. Examples of the
`medicaments which may bekemployed in this invention
`include inter alia, steroid hormones, especially those ste-
`roid hormones which exhibit anabolic, estrogenic, andro-
`genic and proigestational activity, for example,
`l7—hy-
`droxyprogesteroiie and the esters thereof,
`testosterone,
`estradiol and the acid esters thereof, progesterone and its
`derivatives and A1~testololactone and its derivatives.
`In
`the most preferable embodiment of this invention the ac-
`tive medicament
`is a steroid hormone although other
`pharmaceutically active compounds may also be em-
`ployed, with satisfactory results.
`Heretofore it has been well recognized in the prepara-
`tion of, parenterally administrable pharmaceutical com-
`positions that a suitable solvent must be employed to
`render
`the composition injectable. However, as the
`science of medicine has progressed -it has been found that
`increasingly higher dosages of certain medicaments must
`be employed in the treatment of certain ailments in order
`to achieve several advantages. Among these advantages
`can be numbered the prolongation of activity of _the me-
`dicaments involved and the lessening of the total number
`of individual injections which are needed to obtain the
`same results.
`,
`Additionally,
`it '-has been found that new chemical
`modifications of medicaments are continually being dis-
`covered and the solubility of these modified medicaments
`in the solvents commonly employed, appears to be more
`and more limited and it has therefore become increas-
`ingly difficult to dissolve these new modified medicaments
`in parenterally acceptable vehicles.
`It is well-known that
`certain pharmawutical vehiclesyield satisfactory results
`at low level medicament concentrations when employed
`in compositions for parenteral administration. Such ve-
`hicles are the vegetable oils such as cotton seed oil, pea-
`nut oil, sesame oil, or corn oil, in combination with small
`amounts of benzyl benzoate. However, when an in-
`creased dosage level of the medicaments ‘is employed,
`along with a correspondingly necessary increased amount
`of pharmaceutical vehicle it has been found that certain
`undesirable disadvantages exist.
`'
`j
`The undesirable disadvantages which are present when
`the prior art vehicles are employed with a high dosage
`level of medicaments, are many.
`In addition to the prior
`art vehicles being incapable of solubilizing any great
`quantities of the medicaments, it has been found that the
`compositions heretofore employed produce an undue
`amount of irritation at the site of injection, when paren-
`terally administered into the animal being treated.
`It has now been found that the disadvantages encoun-
`tered in the parenteral administration of high dosage
`levels of the medicaments of this invention can be avoided
`by employing the novel pharmaceutical compositions of
`
`this invention.
`
`2
`It has been found that these disadvan-
`
`tages can be overcome by employing benzyl benzoate as
`the essential component of the pharmaceutical vehicle of
`parenterally administrable compositions. The benzyl
`benzoate has been found to be capable of dissolving great
`quantities of the medicaments of this invention‘ and the
`resulting parenterally administrable composition employ-
`ing this vehiclc does not produce undue irritation when
`injected into the animals being treated.
`’
`The amount of benzyl benzoate which may be em-
`ployed in thecompositions of this invention while still
`yielding satisfactory results has been found to range from
`about 75% to 100% by volume of the pharmaceutical ve-
`hicle employed. Thus the ratio of benzyl benzoate pres-
`ent
`in the pharmaceutical vehicle as compared to any
`other ingredients therein must be at least 3 to 1.
`In the
`most preferable embodiment of this invention it has been
`found that a pharmaceutical vehicle consisting essentially
`of pure benzyl benzoate yields the best results although
`at lowerlevels satisfactory results are also obtained.
`As is common in the art of preparing parenterally ad-
`ministrable pharmaceutical compositions other additives
`such as preservatives, antioxidants or anesthetics, such as
`benzyl -alcohol and the other like well known additives
`may also be included in the pharmaceutical compositions
`of this invention. However, their use herein is permis-
`sive and not mandatory as their incorporation or omission
`in the final product of this invention does not substan-
`tially aifect the results herein obtained.
`,
`The compositions of this invention are easily prepared
`by merely taking the desired amount of medicament and
`dissolving it in the pharmaceutical vehicle of this inven-
`tion by any means known in the art, for example, by
`mere stirring.
`The final compositions of this invention are parenter-
`ally administrable to the animal being treated. The ad-
`ministration of theicomposition may be accomplished
`intramuscularly, subcutaneously or in any other manner
`known to the art as may be determined in the individual
`cases wherein this invention is employed.
`It hasbeen
`generally found that the most preferable results are ob-
`tained when an -intramuscular route of administration is
`employed, although other methods of administration, will
`also give satisfactory results.
`The invention is more ‘particularly illustrated by the
`following examples:
`,
`,
`Example 1
`
`Two g. of the acetophenone derivative of l6,l7-dihy-
`droxy-progesterone are dissolved in 10 ml. of benzyl ben-
`zoate with stirring and warming. The resultant solution
`is then filled in vials of 5 ml. each and sterilized by auto-
`claving at 121° C. for two hours.
`_
`0.25 ml. of the resulting solution is then injected into
`the vastus lateralis muscle of a rabbit producing a lesion
`at thesite of the iniection having the size of about 640
`cubic millimeters after two days.
`When 2 g. of the acetophenone derivative of 16,17-di-
`hydroxyprogesterone are dissolved in 4.5 ml. of benzyl
`benzoate and 5.5 ml. of castor oil in accordance with the
`procedure of Example 1 and 0.25 ml. of the resultant
`solution is injected intramuscularly into the rabbit a lesion
`at the site of injection having a size of 967 cubic milli-
`meters after two days.
`’
`
`10
`
`15
`
`20
`
`[0O1
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`Example 2
`
`70
`
`The procedure of Example 1 is followed except that 2
`g. of testosterone palmitate are substituted for the aceto-
`phenone derivative of 16,17-dihydroxyprogesterone of
`Example 1.
`0.25 ml. of the resultant solution is injected intramus-
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`Astrazeneca Ex. 2124 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB lPR20l6-01325
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`

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`3,161,520
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`3
`cularly into a rabbit producing a lesion at the site of in-
`jection having the size of about 420 cubic millimeters
`after two days. When 2 g. of testosterone palmitate are
`dissolved in a vehicle consisting of 40% castor oil and
`60% benzyl benzoate and the resultant solution is in-
`jected intramuscularly into the rabbit, a lesion at the site
`of injection having a size of 610 cubic millimeters is pro-
`duced after two days.
`
`Example 3
`
`A 25% solution of progesterone is prepared by dissolv-
`ing 2.5 g. of progesterone in benzyl benzoate to make 10
`ml. Sterilization is obtained by autoclaving the solution
`at 121° C. for 2 hours. When 0.25 mg. of this solution
`is injected into the vastus lateralis muscle of the rabbit,
`a lesion is produced which, after 2 days,»measures 672
`cubic millimeters.
`‘
`When 2.5 g. of ‘progesterone are dissolved to make 10
`ml. in a mixture of 50% benzyl benzoate and 50% Castor
`oil as the vehicle, and 0.25 ml. of this solution is injected
`into the rabbit muscle, a lesion size of 898 cubic milli-
`meters is produced after two days.
`Example 4
`
`A 50% solution of hormones isprepared by dissolving
`2.5 g. of progesterone, and 2.5 g. of 17-hpydroxyprogestep
`one caproate in benzyl benzoate to make 10 ml. of final
`After autoclaving at 121° C. for 2 hours to
`product.
`sterilize, 0.25 ml. of the solution is injected into a rabbit
`muscle and the lesion size is measured after'2 days. A
`lesion consisting of 572 cubic millimeters was produced.
`When this same hormone combination in the same pro-
`portions was dissolved in a vehicle consisting of 46%
`benzyl benzoate and 54% castor oil, a rabbit muscle
`lesion size of 1047 cubic millimeters is produced 2 days
`after injection of 0.25 ml. of test material.
`
`‘Example 5
`A 40% solution of testosterone enanthate is prepared
`:by dissolving 4.0 g. in benzyl benzoate to make 10 ml. of
`final volume. After autoclaving at 121° C. for 2 hours
`to sterilize, 0.25 ml. of the solution is injected into the
`vastus lateralis muscle of the rabbit and the lesion size
`is measured after 2 days. A lesion consisting of 847
`cubic millimeters is produced.
`'
`When this same quantity of hormone is dissolved in a
`vehicle consisting of 20% benzyl rbenzoate and 80%
`sesame oil and 0.25 ml. is injected a lesion size of 1441
`cubic millimeters is produced.
`Example 6
`
`A 5% solution of»Af-testololactone is prepared by dis-
`
`4
`in benzyl benzoate and after auto-
`solving 50 mg./ml.
`claving to sterilize, 0.25 ml. of the solution is injected _
`intoa rabbit muscle.
`fter 2 days a lesion size of only
`483 cubic millimeters is produced.
`
`Example 7
`
`10
`
`15
`
`20
`
`30
`
`35
`
`40
`
`45
`
`50
`
`15 mg. of A1-testololactone is dissolved in a solution
`comprised of 7.5 ml. of benzyl benzoate and 2.5 ml. of
`castor oil. The resultant solution is sterilized, then filled
`in vials of 5 ml. each and sterilized by autoclaving at
`121° C. for 2 hours. The injectable solution may then
`be administered to the patient being treated.
`This invention may be variously otherwise embodied
`within the scope of the appended claims.
`What is claimed is:
`»
`1. A parenterally administrable pharmaceutical com-
`position cornpris-ing, the acetophenonide of 16,l7-dihy-
`droxyprogesterone and a physiologically acceptable non-
`toxic pharmaceutical vehicle wherein at
`least 75% by
`volume of said vehicle is benzyl benzoate.
`2. A parenterally administrable pharmaceutical com-
`position comprising testosterone palmitate and a physio-
`logically acceptable non-toxis pharmaceutical vehicle
`wherein at least 75% by volume of said vehicle is benzyl
`benzoate.
`3. A’ parenterally administrable pharmaceutical com-
`position comprising testosterone enanthate and a phys-
`iologically acceptable non-toxic pharmaceutical vehicle
`wherein at least 75 % by volume of said vehicle is benzyl
`benzoate.
`4. A method of administering a large single dosage of
`a steroid which comprises parenterally administering to
`the patient being treated a composition comprising a ste-
`roid selected from the group consisting of 17-hydroxy-
`progesterone, the caproate ester of 17-hydroxyprogester-
`one, testosterone, the enanthate ester of testosterone, the
`palmitate ester of testosterone, estradiol, progesterone,
`and A1-testololactone, and a pharmaceutical carrier, said
`carrier being at least 7 5% by volume of benzyl benzoate.
`
`References Cited in the file of this patent
`Chemical Abstracts, vol. 52, p. 7620b, 1958 (abstr. of
`Gerosa et al., Ann. Chim., Rome, 47, pp. 1388-1393
`(1957)).
`Chemical Abstracts, vol. 42, p. 9084g, 1948.
`Chemical Abstracts, vol. 47, p. 6611d, 1953.
`Merck Index, 7th ed., 1960, p. 137.
`_
`U.S. Dispensatory, 25th ed., 1955, p. 160.
`Sax: Handbook of Dangerous Materials, p. 45, Rein-
`hold, New York, 1951.
`A
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`AstraZeneca Ex. 2124 p. 2