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US2675342A - Supersaturated oil solutions of steroid hormones - Google Patents

Supersaturated oil solutions of steroid hormones Download PDF

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Publication number
US2675342A
US2675342A US187844A US18784450A US2675342A US 2675342 A US2675342 A US 2675342A US 187844 A US187844 A US 187844A US 18784450 A US18784450 A US 18784450A US 2675342 A US2675342 A US 2675342A
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hormone
steroid
oil
injectable
solution
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US187844A
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Lee Slaughter Warren
Dichter Emanuel Richard
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Merck Sharp and Dohme LLC
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Schering Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to injectable hormone preparations of androgenic, estrogenic and other types.
  • Emulsions are unstable and difficult to sterilize without the use of stabilizing agentsof unknown or questionable physiological properties, particularly as these stabilizing; agents usu ally consist of substances which are quite foreign to body chemistry.
  • Pellet implantation permits the introduction of a high concentration of hormone, but this mode of administration has the serious disadvantage that it requires a minor surgical operation.
  • cases have been reported wherein pellet implantation has resulted in hormone rejection by the. tissue.
  • the hormone In an aqueous suspension, the hormone is in the solid condition and its absorption into the blood stream by way of the aqueous medium is slow and the rate of absorption is difiicult to control. Dosage control is also difficult in such case, and difficulty is also experienced occasionally in injecting such preparations owing to the coagulation or agglomeration of the particles and clogging of the hypodermic needles.
  • the concentration of a steroid hormone in an injectableliquid can be very considerably increased by the simple expedient of adding totheliquid another non-toxic steroid compound.
  • the steroid compound can be completely neutral physiologically or it may have a mild or even a high physiological action which does not interfere with that of the hormone, and it may even have a hormone activity similar to that of the hormone: to be injected.
  • the increase in solubility efiected by our steroid solubili'zercan be as much as 159 to 400% and even more.
  • solubility was quite unexpected and appears to be contrary to the common ion theory of solubility in the caseof ionizing substances; for in such case it is known that ionizingcompounds like salts have a reduced solubility in aliquid which already has in solution a compound having an ion in commen with the salt. While steroid hormones are different substances from ionizable salts, nevertheless it was to be expected that a steroid compound would have a lowenrather than a greater, solubility in a solvent already containing another steroid compound.
  • steroid compounds which either are without physiological efiiect; at the. concentrations necessary for improying the solubility ot the administered hormone, or are of such low physiologicalaction that at. they indicated con centration their activityxoan beneglected, are cholesterol, sitosterol, 'dehydroandrosterone, d'ehydroand-rosterone acetate, ,pregnandiol, regnandiol acetate and other esters, desoxycholic acid, wool fat alcohols.
  • hormones of steroid character can be utilized as the administered hormone whose concentration in the numerous other inert steroids.
  • injectable medium is to be increased.
  • various adrenal hormones and related steroid hormones together with steroid substances of intermediate charac ter which are apparently utilized by the body in building up various hormones. Included among these are cortisone and other steroid horterone propionate in, for example, sesame oil, is
  • the injectable liquid is preferably a vegetable oil like sesame, peanut and corn oils. These oils may be used singly or in mixtures. While the solubilities of the different steroids in these difierent oils will vary, there is in all cases a very substantial increase in the solubility of the administered hormone due to the presence of the other steroid.
  • Example I in sesame oil free from other steroids (see Example II), it will be seen that the presence of the small proportion of unesterified testosterone increased the solubility of the ester by over 150%.
  • Example II 50 cc. of sesame oil were saturated with testosterone propionate. The resulting solution conof' the testosterone by over 400%, since the solubility of testosteron in sesame 011' (Example I) is only 9 mg./cc.
  • the solubilizing steroid should be dissolved first in the liquid injection medium, and the hormone only thereafter; but where the hormone is not to be used at maximum concentration, more or less simultaneous solution of the two steroids will give satisfactory results.
  • An injectabl hormone composition composition comprising a solution of asteroid hormone in an injectable oil containing another, added non-toxic steroid compound in solution, the concentration of the hormone being greater than its saturation concentration in such oil in the absence of the added steroid compound.
  • An injectable hormone composition comprising a solution of an androgenic steroid hormone in an injectable oil containing another, added non-toxic steroid compound in solution, the concentration of the hormone being greater than its saturation concentration in such oil in the absence of the added steroid compound.
  • An injectable hormone composition comprising a solution of an estrogenic steroid hormone in an injectable oil containing another, added non-toxic steroid compound in solution, the concentration of the hormone being greater than its saturation concentration in such oil in the absence of the added steroid compound.
  • composition as defined in claim 1, wherein the added steroid compound is in substantially saturated solution in the oil.
  • composition as defined in claim 1 wherein the steroid hormone is in substantially saturated solution in the solution of the added steroid compound.
  • composition as defined in claim 1, wherein the injectable oil is a vegetable oil.
  • composition as defined in claim 1, wherein the imectable oil is sesame oil.
  • composition as defined in claim 1, wherein the added non-toxic steroid compound has hormone properties similar to that of the steroid hormone.
  • composition as defined in claim 1 wherein the hormone is a testosterone ester and the added steroid compound is testosterone, and wherein the injectable oil is sesame oil.
  • An injectable hormone composition con prising asolution of progesterone in an injectahle oil containing another, added non-toxic steroid compound insolution, the concentration of progesterone being greater than its saturation concentration in such oil in the absence of the added steroid compound.
  • An injectable hormone composition comprising a solution of methyl androstendiol in an 'injectable oil containing cholesterol in solution, the concentration of methyl androstendiol being greater than its saturation concentration in such oil in the absence of the added cholesterol.
  • An injectable hormone composition comprising a solution of a pregnenolone ester in an injectable oil containing added pregnenolone in solution, the concentration of pregnenolone ester being greater than its saturation concentration in such oil in the absence of the added pregnenolone.
  • An injectable hormone composition comprising a substantially saturated'solution of pregnenolone acetate in an injectable oil which is substantially saturated with added pregnenolone.
  • An injectable androgenic hormone composition comprising a solution of a male hormone having a high androgenic activity in an injectable oil which is substantially saturated with an added steroid compound having a low androgenic activity, the concentration of the male hormone being greater than its saturation concentration in such oil in the absence of the said added steroid compound.
  • An injectable estrogenic hormone composition comprising a solution of a steroid hormone having a high estrogenic activity in an injectable oil which is substantially saturated with an added steroid compound of relatively low estrogenic activity, the concentration of the estrogenic hormone being greater than its saturation concentration in such oil in the absence of the said added steroid compound.
  • composition as defined in claim 1 wherein both the added steroid hormone and the steroid compound are present in substantially saturation concentration.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Patented Apr. 13, 1954 SUPERSATURATED OIL SOLUTIONS OF STEROID HOBMONES Slaughter Warren Bee, Short Hills, N. J}, and Emanuel: Richard Dichte'r; New York, N. Y., 'assignorsto- Scherihg Corporation, Bloomfield,
L, a, corporation of New Jersey No Drawing, Application Septemher30, 1950,
Serial No. 187,844
21 Claims. 1
The present invention relates to injectable hormone preparations of androgenic, estrogenic and other types.
It is the general object of the invention to pro Vida injectable liquid preparations having unusually high concentrations of the androgenic, estrogeni c or other hormones It is a further object or the invention to provld-e inleotabl'e liquid hormone preparations in which the solubility of the hormone has been increased by the presence. in the liquid of another steroid compound is non -toxi'c i'n character and which itself mayor may not have hormone activity.
It is a still: further object of the invention to provide injectable hormone preparations in which an increased concentration of the hormone in the ini'ectable liquid is made possible by the use of substancesv which are similar chemically to the hormone compound and are easily tolerated by the body, and without the aid of substances which are. foreign to body metabolism.
The extremely low solubility of the steroid hormones, including the androgenic: and estrogenic hormones, in the liquids usually employed for injection has given rise to various efiorts and expedients for introducing increased concentrations of the hormones into the-body. Resorthas most commonly been had to theuse o t emulsions, pellet implantation, aqueous. suspensions, and solvent mixtures, but none of these has proved entirely satisfactory. The amount of hormone that can be. suspended in an emulsion is quite limited, and the use of emulsions is therefore not satisfactory when large concentrations are l desired. Emulsions: are unstable and difficult to sterilize without the use of stabilizing agentsof unknown or questionable physiological properties, particularly as these stabilizing; agents usu ally consist of substances which are quite foreign to body chemistry. Pellet implantation permits the introduction of a high concentration of hormone, but this mode of administration has the serious disadvantage that it requires a minor surgical operation. Moreover, cases have been reported wherein pellet implantation has resulted in hormone rejection by the. tissue. In an aqueous suspension, the hormone is in the solid condition and its absorption into the blood stream by way of the aqueous medium is slow and the rate of absorption is difiicult to control. Dosage control is also difficult in such case, and difficulty is also experienced occasionally in injecting such preparations owing to the coagulation or agglomeration of the particles and clogging of the hypodermic needles.
Many efforts have been made to find improved solvents for hormones which are non-toxic in character, but without any noteworthy success. At the present time the best solvents used in conjunction with sesame oil seem to be benayl benzoate and benzyl alcohol, but their use has been very limited because they are exceedin ly irritating when employed in amounts sulii'cient to increase materially the concentration of the hormones.
We have found that the concentration of a steroid hormone in an injectableliquid can be very considerably increased by the simple expedient of adding totheliquid another non-toxic steroid compound. The steroid compound can be completely neutral physiologically or it may have a mild or even a high physiological action which does not interfere with that of the hormone, and it may even have a hormone activity similar to that of the hormone: to be injected. The increase in solubility efiected by our steroid solubili'zercan be as much as 159 to 400% and even more. increased solubility was quite unexpected and appears to be contrary to the common ion theory of solubility in the caseof ionizing substances; for in such case it is known that ionizingcompounds like salts have a reduced solubility in aliquid which already has in solution a compound having an ion in commen with the salt. While steroid hormones are different substances from ionizable salts, nevertheless it was to be expected that a steroid compound would have a lowenrather than a greater, solubility in a solvent already containing another steroid compound.
Among the steroid compounds which either are without physiological efiiect; at the. concentrations necessary for improying the solubility ot the administered hormone, or are of such low physiologicalaction that at. they indicated con centration their activityxoan beneglected, are cholesterol, sitosterol, 'dehydroandrosterone, d'ehydroand-rosterone acetate, ,pregnandiol, regnandiol acetate and other esters, desoxycholic acid, wool fat alcohols. isoa'ndrosterone and isoandrosterone acetate, benzoataaand other esters, and dehydroisoandrosterone and its acetate, benzoate and other esters.v Numerous other steroid compounds fulfill the. requirements of substantial physiological inertness, particularly at low concentrations, and can be: used preparing the compositions of our invention.
In addition to the androgenic; and estrogenic ormon s; above referred to, also other hormones of steroid character can be utilized as the administered hormone whose concentration in the numerous other inert steroids.
injectable medium is to be increased. Among these may be mentioned the various adrenal hormones and related steroid hormones, together with steroid substances of intermediate charac ter which are apparently utilized by the body in building up various hormones. Included among these are cortisone and other steroid horterone propionate in, for example, sesame oil, is
increased by over 150%. With methyl androstendiol there can be employed cholesterol and The injectable liquid is preferably a vegetable oil like sesame, peanut and corn oils. These oils may be used singly or in mixtures. While the solubilities of the different steroids in these difierent oils will vary, there is in all cases a very substantial increase in the solubility of the administered hormone due to the presence of the other steroid.
The invention will be further described by way of the following examples which are, however,
presented only by way of illustration and not as indicating the limits of the invention.
7 Example I .in sesame oil free from other steroids (see Example II), it will be seen that the presence of the small proportion of unesterified testosterone increased the solubility of the ester by over 150%.
Example II 50 cc. of sesame oil wer saturated with testosterone propionate. The resulting solution conof' the testosterone by over 400%, since the solubility of testosteron in sesame 011' (Example I) is only 9 mg./cc.
The 'aboveexamples show that it is not the specific character of the steroid, but the fact that it is taken up in a solvent already containing another steroid in solution, that accounts for the increase in solubility of the first steroid; and
we have found this principle to be of wide application with the greatest variety of steroid combinations.
It will beapparent that it will not always be necessary to saturate the solution containing the solubilizing steroid with the steroid to be administered, since an adequate concentration of tained 82 mg. of the ester per cc. of the oil. This 7 solution was then saturated with testosterone, V and 46 mg./cc. went into solution. It will thus be seen that the prior saturation of the oil with testosterone propionate increased the solubility the latter may be achieved below saturation in such solution, but above the normal saturation concentration in th absence of the steroid solubilizing agent. In certain cases it may not even be necessary to use the solubilizing agent at saturation to produce a supersaturated solution or the hormone to be administered (with reference to the saturation concentration of such hormone in the injectable liquid alone).
The above examples show that to attain maximum concentration of the administered hormone, the solubilizing steroid should be dissolved first in the liquid injection medium, and the hormone only thereafter; but where the hormone is not to be used at maximum concentration, more or less simultaneous solution of the two steroids will give satisfactory results.
1 We claim:
1. An injectabl hormone composition composition comprising a solution of asteroid hormone in an injectable oil containing another, added non-toxic steroid compound in solution, the concentration of the hormone being greater than its saturation concentration in such oil in the absence of the added steroid compound.
2. An injectable hormone composition comprising a solution of an androgenic steroid hormone in an injectable oil containing another, added non-toxic steroid compound in solution, the concentration of the hormone being greater than its saturation concentration in such oil in the absence of the added steroid compound.
3. An injectable hormone composition comprising a solution of an estrogenic steroid hormone in an injectable oil containing another, added non-toxic steroid compound in solution, the concentration of the hormone being greater than its saturation concentration in such oil in the absence of the added steroid compound.
4. A composition as defined in claim 1, wherein the added steroid compound is in substantially saturated solution in the oil.
5. A composition as defined in claim 1, wherein the steroid hormone is in substantially saturated solution in the solution of the added steroid compound.
6. A composition as defined in claim 1, wherein the injectable oil is a vegetable oil.
'7. A composition as defined in claim 1, wherein the imectable oil is sesame oil.
8. A composition as defined in claim 1, wherein the added non-toxic steroid compound has hormone properties similar to that of the steroid hormone.
9. A composition as defined in claim 1, wherein the hormone is a testosterone ester and the added steroid compound is testosterone.
10. A composition as defined in claim 9, wherein the testosterone ester is the propionate.
11. A composition as defined in claim 1, wherein the hormone is a testosterone ester and the added steroid compound is testosterone, and wherein the injectable oil is sesame oil.
12. An injectable hormone composition con prising asolution of progesterone in an injectahle oil containing another, added non-toxic steroid compound insolution, the concentration of progesterone being greater than its saturation concentration in such oil in the absence of the added steroid compound.
13. An injectable hormone composition comprising a solution of methyl androstendiol in an 'injectable oil containing cholesterol in solution, the concentration of methyl androstendiol being greater than its saturation concentration in such oil in the absence of the added cholesterol.
14. An injectable hormone composition comprising a solution of a pregnenolone ester in an injectable oil containing added pregnenolone in solution, the concentration of pregnenolone ester being greater than its saturation concentration in such oil in the absence of the added pregnenolone.
15. An injectable hormone composition comprising a substantially saturated'solution of pregnenolone acetate in an injectable oil which is substantially saturated with added pregnenolone.
16. An injectable androgenic hormone composition comprising a solution of a male hormone having a high androgenic activity in an injectable oil which is substantially saturated with an added steroid compound having a low androgenic activity, the concentration of the male hormone being greater than its saturation concentration in such oil in the absence of the said added steroid compound.
17. An injectable estrogenic hormone composition comprising a solution of a steroid hormone having a high estrogenic activity in an injectable oil which is substantially saturated with an added steroid compound of relatively low estrogenic activity, the concentration of the estrogenic hormone being greater than its saturation concentration in such oil in the absence of the said added steroid compound.
18. A composition as defined in claim 1, wherein both the added steroid hormone and the steroid compound are present in substantially saturation concentration. a
19. Process for the preparation of injectable hormone compositions which comprises substantially saturating an injectable oil with an added non-toxic steroid compound, then dissolving in the solution a quantity of a steroid hormone in References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 1,978,297 Eldred Oct. 23, 1934 2,055,083 Klein Sept. 22, 1936 2,061,934 Jacobson June 1, 1937 2,190,183 Friedrich Feb. 13, 1940 FOREIGN PATENTS Number Country Date 56,856 Austria June 1, 1912 515,671 Great Britain Mar. 2, 1938 651,597 Germany Oct. 16, 1937 686,721 Germany Jan. 15, 1940 OTHER REFERENCES McBain et al. article in J. A. C. 8., October 1940, volume 62, page 2880 and 2881.
Unlisted Drugs, September 30, 1949, page 111.
Heard in Recent Progress in Hormone Researc volume IV, 1949, pages to 53. Brockelsby: Marine Animal Oils, 1941, pages 83 to 85.
Margolese in J. Clin. Endocrinology. volume 4, 1944, pages 394 to 399.

Claims (1)

1. AN INJECTABLE HORMONE COMPOSITION COMPOSITION COMPRISING A SOLUTION OF A STEROID HORMONE IN AN INJECTABLE OIL CONTAINING ANOTHER, ADDED NON-TOXIC STEROID COMPOUND IN SOLUTION, THE CONCENTRATION OF THE HORMONE BEING GREATER THAN ITS SATURATION CONCENTRATION IN SUCH OIL IN THE ABSENCE OF THE ADDED STEROID COMPOUND.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2840508A (en) * 1951-05-17 1958-06-24 Schering Ag Injectable steroid hormone preparations and method of making same
US2855341A (en) * 1954-07-02 1958-10-07 Ciba Pharm Prod Inc Testosterone compositions
US2983649A (en) * 1957-10-15 1961-05-09 Francesco Vismara Societa Per Ricinoleic acid ester solutions of adreno-cortical hormones
US4900734A (en) * 1987-08-27 1990-02-13 Maxson Wayne S Novel pharmaceutical composition containing estradiol and progesterone for oral administration
US5140021A (en) * 1986-04-16 1992-08-18 Genesis Systems Corporation Method and dosage form for treatment of premenstrual syndrome

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT56856B (en) * 1910-06-10 1912-12-27 Farbenfab Vorm Bayer F & Co Process for the manufacture of cholesterol preparations suitable for injection.
US1978297A (en) * 1927-08-17 1934-10-23 Reed & Carnrick Testicular hormone and method of producing the same
US2055083A (en) * 1932-07-13 1936-09-22 Winthrop Chem Co Inc Pharmaceutical preparation
US2081934A (en) * 1935-11-23 1937-06-01 Jacobson Jacob Cinnamic preparations for therapeutic uses
DE651597C (en) * 1929-04-23 1937-10-16 Schering Kahlbaum Ag Process for the preparation of durable hormone preparations
GB515671A (en) * 1937-03-02 1939-12-11 Shering A G Process for the manufacture of highly concentrated aqueous solutions of germ-gland hormones and their derivatives
DE686721C (en) * 1938-04-22 1940-01-15 Schering Ag Process for the preparation of hormone solutions
US2190183A (en) * 1936-12-19 1940-02-13 Winthrop Chem Co Inc Stable suspension of hormone preparations

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT56856B (en) * 1910-06-10 1912-12-27 Farbenfab Vorm Bayer F & Co Process for the manufacture of cholesterol preparations suitable for injection.
US1978297A (en) * 1927-08-17 1934-10-23 Reed & Carnrick Testicular hormone and method of producing the same
DE651597C (en) * 1929-04-23 1937-10-16 Schering Kahlbaum Ag Process for the preparation of durable hormone preparations
US2055083A (en) * 1932-07-13 1936-09-22 Winthrop Chem Co Inc Pharmaceutical preparation
US2081934A (en) * 1935-11-23 1937-06-01 Jacobson Jacob Cinnamic preparations for therapeutic uses
US2190183A (en) * 1936-12-19 1940-02-13 Winthrop Chem Co Inc Stable suspension of hormone preparations
GB515671A (en) * 1937-03-02 1939-12-11 Shering A G Process for the manufacture of highly concentrated aqueous solutions of germ-gland hormones and their derivatives
DE686721C (en) * 1938-04-22 1940-01-15 Schering Ag Process for the preparation of hormone solutions

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2840508A (en) * 1951-05-17 1958-06-24 Schering Ag Injectable steroid hormone preparations and method of making same
US2855341A (en) * 1954-07-02 1958-10-07 Ciba Pharm Prod Inc Testosterone compositions
US2983649A (en) * 1957-10-15 1961-05-09 Francesco Vismara Societa Per Ricinoleic acid ester solutions of adreno-cortical hormones
US5140021A (en) * 1986-04-16 1992-08-18 Genesis Systems Corporation Method and dosage form for treatment of premenstrual syndrome
US4900734A (en) * 1987-08-27 1990-02-13 Maxson Wayne S Novel pharmaceutical composition containing estradiol and progesterone for oral administration

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