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US3248291A - Stabilized thioxanthene derivatives and method of using the same - Google Patents

Stabilized thioxanthene derivatives and method of using the same Download PDF

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US3248291A
US3248291A US303154A US30315463A US3248291A US 3248291 A US3248291 A US 3248291A US 303154 A US303154 A US 303154A US 30315463 A US30315463 A US 30315463A US 3248291 A US3248291 A US 3248291A
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thioxanthene
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Newmark Harold Leon
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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 stable pharmaceutical preparations. More particularly, the present invention relates to stable aqueous pharmaceutical solutions comprising thioxanthene compounds particularly well suited for use in preparing multiple dose containers.
  • the thioxanthenes suitable for the purposes of the present invention have the following formula 110 HsC HEN/ Hi (I) wherein X and X represent hydrogen, halogen such as chlorine, bromine, fluorine and iodine, a lower alkyl radical, for example, a straight or branched chain lower alkyl group with from about 1 to about 4 carbon atoms and a lower alkoxy radical preferably having a straight or branched alkyl chain with from about 1 to about 4 carbon atoms and represents a tertiary amino group which advantageously is a di-loWer-alkyl-amino, l-piperidyl, l-pyrrolidyl or 4- morpholinyl group.
  • X and X represent hydrogen, halogen such as chlorine, bromine, fluorine and iodine
  • a lower alkyl radical for example, a straight or branched chain lower alkyl group with from about 1 to about 4 carbon atoms and
  • Such thioxanthenes have been found to be efi'icacious in a broad range of emotional problems, especially for the relief of agitation associated with anxiety or depressive states.
  • the stable pharmaceutical preparations of the present invention containing the compounds of Formula I above, particularly those preparations adapted for parenteral use, are especially valuable as tranquilizing agents.
  • Preferred among the thioxanthenes of Formula I above for use in the pharmaceutical preparation of the present invention is 2-chloro-9-(3-dimethylaminopropylidene -thioxanthene.
  • Aqueous solutions of compounds of Formula I above have been employed in single dose ampoules.
  • the problems associated with the devising of a pharmaceutically acceptable ampoule are different from the problems connected with the use of an injectable material in a multiple dose vial.
  • an ampoule is a small hermetically sealed vessel containing a single dose of a solution for injection, whereas the contents of a multiple dose vial is of such amount as to enable its use in several separate treatments of one or more individuals with emotional problems.
  • the closure of a multidose vial is negotiated thereby permitting the extraction of a suitable amount of the contents thereof depending upon the individual dosage requirements, whereas the ampoule is entirely consumed with each treatment.
  • acids having the Formulas II and III above are diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, N-hydroxyethylenediaminetriacetic acid and 1,Z-diaminocyclohexane-N,N'-tetraacetic acid.
  • suitable salts of such acids can be-included the disodium dihydrogen salts, the tetra sodium salts, calcium disodium salts and the calcium dihydrogen salts.
  • compounds of Formulas II and III above and the pharmaceutically acceptable salts thereof be present in the aqueous solution of compounds of Formula I above in the range of from about 0.001 percent to about 0.1 percent, more preferably from about 0.007 percent to about 0.013 percent, still more preferably about 0.01 percent.
  • a preferred compound for use in the present invention is disodium dihydrogenethylenediaminetetraacetic acid.
  • the salts of the compounds of Formulas II and III above can be formed by known procedures.
  • the compounds of Formulas II and III above may be reacted with pharmaceutically acceptable bases in sufficient molar amounts to form mono-, di-, triand tetra-salts.
  • compounds of Formulas II and III above form nontoxic metallic salts such as the mono-, di-, triand tetra-sodium, potassium, calcium and aluminum salts thereof and the like.
  • Such salts are included within the scope of the present invention.
  • Compounds of Formula I above are basic in nature and thus they form salts with pharmaceutically acceptable acids.
  • the compound of Formula I above is present in an aqueous solution in its salt form.
  • Any pharmaceutically acceptable acid which is capable of rendering the compounds of Formula I above water soluble, can be utilized to form the pharmaceutically acceptable water soluble salts thereof suitable for the purposes of the present invention.
  • an acid selected from the group consisting of hydrochloric acid, acetic acid, methane sulfonic acid and ethane sulfonic acid is employed as the pharmaceutically acceptable acid.
  • an acid selected from the group consisting of hydrochloric acid and acetic acid is utilized as the solubilizing agent.
  • the present invention relates to a composition which comprises a water soluble pharmaceutically acceptable acid addition salt of compounds of Formula I above and a member selected from the group consisting of compounds of Formula II above, compounds of Formula III above and the pharmaceutically acceptable salts thereof.
  • the thioxanthene of Formula I above is present in the solution in the amount of from about 5 mg. per ml. to about 60 mg. per ml., more preferably from about mg. per ml. to about 50 mg. per ml., still more preferably from about 12.5 mg. per ml. to about 25 mg. per ml.
  • acetic acid is employed as the agent to solubilize the thioxanthene base of Formula I above.
  • a methyl or propyl paraben (the methyl or propyl ester of parahydroxy benzoic acid) may be advantageously employed in the preparation of the present invention.
  • Example 1 0.8 ml. of water were heated to in a glass lined vessel equipped with a mechanical stirrer. To the heated water was added 1.8 mg. of methyl paraben and 0.2 mg. of propyl paraben, with stirring. The resulting aqueous solution was cooled to room temperature. To the cooled solution, there was added, with stirring, 12.75 mg. of 2-chloro-9-(3 dimethylaminopropylidene)-thioxanthene, 0.0025 mg. of acetic acid (butter) and 0.1 mg. of disodium dihydrogen ethylenediaminetetraacetic acid. To the resultant mixture there was carefully added 0.0407 ml.
  • Example 2 A 1.0 ml. aqueous pharmaceutical preparation containing the acetic acid salt of 2-chloro-9-(3-dimethylarninopropylidene)-thioxanthene was prepared in the manner set out in Example 1 above utilizing the following materials:
  • Amount (per ml.) Mg. 2-chloro-9-(3-dimethylaminopropy1idene)- thioxanthene 51 acetic acid 25 Methyl paraben 1.8 Propyl paraben 0.2 Disodium dihydrogen ethylenediaminetetraacetic acid 0.1
  • Example 3 A 1.0 ml. solution containing the hydrochloride of 2- chloro-9 (3 dimethylaminopropylidene)-thioxanthene was formed in the manner set out in Example 1 above utilizing the following materials:
  • Example 4 80 l. of water are heated to 80 in a glass lined vessel equipped with a suitable mechanical stirrer. To the heated water are added 180 g. of methyl paraben and 20 g. of propyl paraben, with stirring. The heated solution is cooled to room temperature. 2,500 g. of 2-chloro- 9-(3-dimethylaminopropylidene)-thioxanthene, 500 ml. of
  • An aqueous composition which comprises a watersoluble pharmaceutically acceptable acid addition salt of a first compound having the formula diHC HaC HaN 1O wherein X and X represent a member selected from the group consisting of hydrogen, halogen, lower alkoxy and lower alkyl and compounds of the formula and pharmaceutieally acceptable salts thereof wherein n is a whole integer from 0 to 1 and R is selected from the group consisting of carboxy and hydroxy-lower alkyl there being present in the composition from about 5 mg. per ml. to about 60 mg. per ml. of the said first compound and from about 0.001 percent to about 0.1 percent of the said second compound for each part by volume of the said composition.
  • An aqueous pharmaceutical preparation which comprises a water-soluble pharmaceutically acceptable acid addition salt of 2 chloro 9 (3-dimethylaminopropylidene)-thioxanthene and a second compound selected from the group consisting of compounds having the formula o InJi-on HO-AiE-C Q! and pharmaceutically acceptable salts thereof wherein n is a whole integer from 0 to l and R is selected from the group consisting of carboxy and hydroxy-lower alkyl there being present in the pharmaceutical preparation from about 5 mg. per ml. to about 60 mg. per ml. of the thioxanthene and from about 0.001 percent to about 0.1 percent of the second compound for each part by volume of the aqueous pharmaceutical preparation.
  • An aqueous composition which comprises the acetic acid salt of 2-clfloro-9-(3-dimethylaminopropylidene)- thioxanthene and a second member selected from the group consisting of compounds having the formula compounds having the formula and pharmaceutically acceptable salts thereof wherein n is a whole integer from 0 to 1 and R is selected from the group consisting of carboxy and hydroxy-lower alkyl there being present in the composition from about 5 mg. per ml. to about 60 mg. per ml. of the thioxanethene and from about 0.001 percent to about 0.1 percent of the said second member for each part by volume of the said composition.
  • An aqueous composition which comprises from about 5 mg. per ml. to about 60 mg. per ml. of the acetic acid salt of 2-chloro-9-(3dimethylaminopropylidene)- thioxanthene and from about 0.001 percent to about 0.1 percent for each part by volume of the aqueous composition of dihydrogen disodium ethylenediaminetetraacetic acid.
  • An aqueous composition which comprises the hydrochloride of 2-chloro-9-(3-dimethylaminopropylidene)- thioxanthene and a second member selected from the group consisting of compounds having the formula compounds having the formula and pharmaceutieally acceptable salts thereof wherein n is a whole integer from 0 to 1 and R is selected from the group consisting of carboxy and hydroxy-lower alkyl there being present in the composition from about 5 mg. per ml. to about 60 mg. per ml.
  • X and X represent a member selected from the group consisting of hydrogen, halogen, lower alkoxy and lower alkyl;
  • n is a whole integer from 0 to 1 and R is selected from the group consisting of carboxy and hydroxy-lower alkyl.

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Description

United States Patent 0 The present invention relates to stable pharmaceutical preparations. More particularly, the present invention relates to stable aqueous pharmaceutical solutions comprising thioxanthene compounds particularly well suited for use in preparing multiple dose containers.
The thioxanthenes suitable for the purposes of the present invention have the following formula 110 HsC HEN/ Hi (I) wherein X and X represent hydrogen, halogen such as chlorine, bromine, fluorine and iodine, a lower alkyl radical, for example, a straight or branched chain lower alkyl group with from about 1 to about 4 carbon atoms and a lower alkoxy radical preferably having a straight or branched alkyl chain with from about 1 to about 4 carbon atoms and represents a tertiary amino group which advantageously is a di-loWer-alkyl-amino, l-piperidyl, l-pyrrolidyl or 4- morpholinyl group.
Such thioxanthenes have been found to be efi'icacious in a broad range of emotional problems, especially for the relief of agitation associated with anxiety or depressive states. Thus, the stable pharmaceutical preparations of the present invention, containing the compounds of Formula I above, particularly those preparations adapted for parenteral use, are especially valuable as tranquilizing agents. Preferred among the thioxanthenes of Formula I above for use in the pharmaceutical preparation of the present invention is 2-chloro-9-(3-dimethylaminopropylidene -thioxanthene.
Aqueous solutions of compounds of Formula I above have been employed in single dose ampoules. However, the problems associated with the devising of a pharmaceutically acceptable ampoule are different from the problems connected with the use of an injectable material in a multiple dose vial. This is true since an ampoule is a small hermetically sealed vessel containing a single dose of a solution for injection, whereas the contents of a multiple dose vial is of such amount as to enable its use in several separate treatments of one or more individuals with emotional problems. With each treatment, the closure of a multidose vial is negotiated thereby permitting the extraction of a suitable amount of the contents thereof depending upon the individual dosage requirements, whereas the ampoule is entirely consumed with each treatment. Such negotiation, obviously, permits atmospheric oxygen to enter the vial as well as any other materials present in the atmosphere which might cause deterioration of the preparation. Attendant with the problems resulting from the negotiating of the vial is the possibility that the vial closure will fail to return to its pre-negotiation 3,248,291 Patented Apr. 26, 1966 ice shape and/or position thereby permitting the continuous entry of air and the contaminants contained therein into the container portion of the vial. This is particularly true of containers of solutions intended for oral or other use, other than injectable.
Heretofore, the use of thioxanthene solutions in multiple dose vials has not been feasible. This is due to the fact that before any solution can be acceptable for use in multiple dose vials, it is essential that such solution be stable to changes in conditions inherent in any vial opening to remove a portion of the contents. Obviously, if a solution fails to evidence stability when exposed to the atmosphere introduced in serial withdrawal of doses at different intervals, it would be inoperative insofar as its use in a multiple dose vial is concerned. Solutions of thioxanthene compounds having the Formula I above have evidenced the propensity to deteriorate in the presence of atmospheric oxygen. Thus, heretofore when such solutions have been utilized in multiple dose vials, they tended to become discolored and/or develop a precipitate upon exposure to the atmosphere. Such discoloration and precipitation affects the purity of the product and the event of either generally necessitates that the remainder be discarded.
It is an object of the present invention to provide a stable solution of a thioxanthene compound having the Formula I above.
It is a further object of the present invention to provide a pharmaceutical solution containing a compound having the Formula I above which is stable and thus is insensitive to changes in environment thereby rendering such solutions suitable for use with multiple dose vials.
It is a further object of the present invention to provide an injectable pharmaceutical solution of compounds of Formula I above which is simple in constitution and preparation and which utilizes conveniently available materials therein and yet is characterized by good stability and relative freedom from excessive tissue irritation at the injection site.
In achieving these objects within the purview of the present invention, it has been discovered that the utilization of a member selected from the group consisting of compounds having the formula compounds having the formula (III) and pharmaceutically acceptable salts thereof wherein n is a whole integer from 0 to 1 and R is selected from the group consisting of carboxy and hydroxy-lower alkyl, preferably hydroxymethyl, in a solution of a compound of Formula I above, results in the efiicacious stabilization of such solutions against discoloration and precipitation due to oxidation, especially in partly used vials in which air has been permitted to enter when part of the contents have been consumed for its intended purpose.
Representative of acids having the Formulas II and III above, are diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, N-hydroxyethylenediaminetriacetic acid and 1,Z-diaminocyclohexane-N,N'-tetraacetic acid. Among the suitable salts of such acids can be-included the disodium dihydrogen salts, the tetra sodium salts, calcium disodium salts and the calcium dihydrogen salts. It is preferred that compounds of Formulas II and III above and the pharmaceutically acceptable salts thereof be present in the aqueous solution of compounds of Formula I above in the range of from about 0.001 percent to about 0.1 percent, more preferably from about 0.007 percent to about 0.013 percent, still more preferably about 0.01 percent. A preferred compound for use in the present invention is disodium dihydrogenethylenediaminetetraacetic acid.
The salts of the compounds of Formulas II and III above can be formed by known procedures. Thus, as the compounds of Formulas II and III above are acidic in nature, they may be reacted with pharmaceutically acceptable bases in sufficient molar amounts to form mono-, di-, triand tetra-salts. For example, compounds of Formulas II and III above form nontoxic metallic salts such as the mono-, di-, triand tetra-sodium, potassium, calcium and aluminum salts thereof and the like. Such salts are included within the scope of the present invention.
Compounds of Formula I above are basic in nature and thus they form salts with pharmaceutically acceptable acids. In a preferred aspect, the compound of Formula I above is present in an aqueous solution in its salt form. Any pharmaceutically acceptable acid which is capable of rendering the compounds of Formula I above water soluble, can be utilized to form the pharmaceutically acceptable water soluble salts thereof suitable for the purposes of the present invention. Advantageously, an acid selected from the group consisting of hydrochloric acid, acetic acid, methane sulfonic acid and ethane sulfonic acid is employed as the pharmaceutically acceptable acid. In a preferred embodiment, an acid selected from the group consisting of hydrochloric acid and acetic acid is utilized as the solubilizing agent.
Thus, the present invention relates to a composition which comprises a water soluble pharmaceutically acceptable acid addition salt of compounds of Formula I above and a member selected from the group consisting of compounds of Formula II above, compounds of Formula III above and the pharmaceutically acceptable salts thereof.
The thioxanthene of Formula I above is present in the solution in the amount of from about 5 mg. per ml. to about 60 mg. per ml., more preferably from about mg. per ml. to about 50 mg. per ml., still more preferably from about 12.5 mg. per ml. to about 25 mg. per ml. Preferably, when solutions of about 50 mg. per ml. and above are employed, acetic acid is employed as the agent to solubilize the thioxanthene base of Formula I above.
The manner in which the ingredients which comprise the solution are blended is not critical. Thus, any conventional mixing technique may be advantageously employed to form the stable solutions hereinafter more particularly described.
Other materials may be utilized in forming the solutions of the present invention, for example, a methyl or propyl paraben (the methyl or propyl ester of parahydroxy benzoic acid) may be advantageously employed in the preparation of the present invention.
The present invention will be described more fully in conjunction with the following examples. It will be understood, however, that these examples are given by way of illustration only and that the invention is not to be construed as limited in spirit or in scope by the details set forth. All temperatures stated are in degrees centigrade.
Example 1 0.8 ml. of water were heated to in a glass lined vessel equipped with a mechanical stirrer. To the heated water was added 1.8 mg. of methyl paraben and 0.2 mg. of propyl paraben, with stirring. The resulting aqueous solution was cooled to room temperature. To the cooled solution, there was added, with stirring, 12.75 mg. of 2-chloro-9-(3 dimethylaminopropylidene)-thioxanthene, 0.0025 mg. of acetic acid (butter) and 0.1 mg. of disodium dihydrogen ethylenediaminetetraacetic acid. To the resultant mixture there was carefully added 0.0407 ml. of l N hydrochloric acid, with stirring, whereby the hydrochloride salt of 2-chloro-9-( 3-dimethylaminopropylidene)-thioxanthene was formed. Sufiicient water was added to bring the volume of the resultant solution to 1.0 ml. This solution was found to evidence good stability against discoloration and precipitation due to oxygen, especially in partly used vials in which air has been permitted to enter when part of the contents have been utilized for its intended purpose.
Example 2 A 1.0 ml. aqueous pharmaceutical preparation containing the acetic acid salt of 2-chloro-9-(3-dimethylarninopropylidene)-thioxanthene was prepared in the manner set out in Example 1 above utilizing the following materials:
Component: Amount (per ml.) Mg. 2-chloro-9-(3-dimethylaminopropy1idene)- thioxanthene 51 acetic acid 25 Methyl paraben 1.8 Propyl paraben 0.2 Disodium dihydrogen ethylenediaminetetraacetic acid 0.1
Water Remainder The resultant solution evidenced excellent chemical stability and acceptable physical stability.
Example 3 A 1.0 ml. solution containing the hydrochloride of 2- chloro-9 (3 dimethylaminopropylidene)-thioxanthene was formed in the manner set out in Example 1 above utilizing the following materials:
This pharmaceutical solution evidences stability, and its effect on local tissue insofar as the irritation thereof is concerned, is good.
Example 4 80 l. of water are heated to 80 in a glass lined vessel equipped with a suitable mechanical stirrer. To the heated water are added 180 g. of methyl paraben and 20 g. of propyl paraben, with stirring. The heated solution is cooled to room temperature. 2,500 g. of 2-chloro- 9-(3-dimethylaminopropylidene)-thioxanthene, 500 ml. of
glacial acetic acid and 10 g. of disodium dihydrogen ethylenediaminetetraacetic acid were added with stirring. 8 l. of hydrochloric acid were added slowly to the resulting mixture, with stirring, to dissolve the 2-chloro-9- (3 -dimethylaminopropylidene)-thioxanthene. The volume of the resultant solution was brought to l. by the addition of a suitable amount of water. The final solution was agitated by a mechanical mixer to insure uniform blending.
I claim: 1. An aqueous composition which comprises a watersoluble pharmaceutically acceptable acid addition salt of a first compound having the formula diHC HaC HaN 1O wherein X and X represent a member selected from the group consisting of hydrogen, halogen, lower alkoxy and lower alkyl and compounds of the formula and pharmaceutieally acceptable salts thereof wherein n is a whole integer from 0 to 1 and R is selected from the group consisting of carboxy and hydroxy-lower alkyl there being present in the composition from about 5 mg. per ml. to about 60 mg. per ml. of the said first compound and from about 0.001 percent to about 0.1 percent of the said second compound for each part by volume of the said composition.
2. An aqueous pharmaceutical preparation which comprises a water-soluble pharmaceutically acceptable acid addition salt of 2 chloro 9 (3-dimethylaminopropylidene)-thioxanthene and a second compound selected from the group consisting of compounds having the formula o InJi-on HO-AiE-C Q! and pharmaceutically acceptable salts thereof wherein n is a whole integer from 0 to l and R is selected from the group consisting of carboxy and hydroxy-lower alkyl there being present in the pharmaceutical preparation from about 5 mg. per ml. to about 60 mg. per ml. of the thioxanthene and from about 0.001 percent to about 0.1 percent of the second compound for each part by volume of the aqueous pharmaceutical preparation.
3. An aqueous composition which comprises the acetic acid salt of 2-clfloro-9-(3-dimethylaminopropylidene)- thioxanthene and a second member selected from the group consisting of compounds having the formula compounds having the formula and pharmaceutically acceptable salts thereof wherein n is a whole integer from 0 to 1 and R is selected from the group consisting of carboxy and hydroxy-lower alkyl there being present in the composition from about 5 mg. per ml. to about 60 mg. per ml. of the thioxanethene and from about 0.001 percent to about 0.1 percent of the said second member for each part by volume of the said composition.
4. An aqueous composition which comprises from about 5 mg. per ml. to about 60 mg. per ml. of the acetic acid salt of 2-chloro-9-(3dimethylaminopropylidene)- thioxanthene and from about 0.001 percent to about 0.1 percent for each part by volume of the aqueous composition of dihydrogen disodium ethylenediaminetetraacetic acid.
5. An aqueous composition which comprises the hydrochloride of 2-chloro-9-(3-dimethylaminopropylidene)- thioxanthene and a second member selected from the group consisting of compounds having the formula compounds having the formula and pharmaceutieally acceptable salts thereof wherein n is a whole integer from 0 to 1 and R is selected from the group consisting of carboxy and hydroxy-lower alkyl there being present in the composition from about 5 mg. per ml. to about 60 mg. per ml. of the thioxanthene and from about 0.001 percent to about 0.1 percent of the said second mem- HO H20 HaN wherein X and X represent a member selected from the group consisting of hydrogen, halogen, lower alkoxy and lower alkyl; and
is selected from the group consisting of di-lower alkyl-amino, l-piperidyl, l-pyrrolidyl and 4-rnorpholinyl; and a stabilizing compound selected from the group consisting of compounds of the formula compounds of the formula 0 11 ll 110-0-0 H: /cmc-0H 5 NC Hr-C Hx- IIIC Il -{1 Hz -N (I? It:-C H: 0 HI 0 HrC-OH c=o (9H [1 10 and pharmaceutically acceptable salts thereof wherein n is a whole integer from 0 to 1 and R is selected from the group consisting of carboxy and hydroxy-lower alkyl.
References Cited by the Examiner UNITED STATES PATENTS 2,799,619 7/ 1957 Seifter 167-65 2,864,844 12/1958 Davisson 260-433. 2,928,767 3/ 1960 Gulesich 167-65 3,088,868 5/1963 Windsor 167-55 3,113,137 12/1963 Schaeren 260-327 3,115,502 12/ 1963 Schlapfer 260-328 3,132,073 5/1964 Farlane 167-78 OTHER REFERENCES Haydn, Chem. Abst., vol. 56, p. 13513(b), 1962.
Hilfer, Drug and Cosmetic Industry, January 1949, pages 40 and 41.
Martell, Chemistry of the Metal Chelate Compounds, Prentice-Hall, 1956, pp. 536-537.
Nielsen, Acta Pharmacol. et Toxicol, vol. 15, p. 335, 1959.
Roche, Chem. Abst., vol. 57, 1373(d), 1962.
Sir, I. Am. Chem. Soc., vol. 73, p. 4057, August 1951.
Swallow, The Am. J. of Pharmacy, vol. 124, No. 8, page 287, August 1952.
Thompson, Am. Prof. Pharm, vol. 19, No. 6, p. 468, June 1953.
JULIAN S. LEVITT, Primary Examiner.
LEWIS GO'ITS, Examiner. PAUL SABATINE, SAM ROSEN, Assistant Examiners.

Claims (1)

1. AN AQUEOUS COMPOSITION WHICH COMPRISES A WATERSOLUBLE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT OF A FIRST COMPOUND HAVING THE FORMULA
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0298192A1 (en) * 1987-07-06 1989-01-11 Teva Pharmaceutical Industries Limited Stable, injectable solutions of vincristine salts
WO1999055375A1 (en) * 1998-04-27 1999-11-04 Arzneimittelwerk Dresden Gmbh Stable mitoxantron solutions

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US2864844A (en) * 1955-02-02 1958-12-16 Lilly Co Eli Stabilized thimerosal
US2928767A (en) * 1957-07-17 1960-03-15 Smith Kline French Lab Stabilized phenothiazine preparations
US3088868A (en) * 1958-08-18 1963-05-07 Riker Laboratories Inc Orally-active therapeutic compositions and process for using same
US3113137A (en) * 1959-06-30 1963-12-03 Hoffmann La Roche Method for isomerizing stereoisomeric xanthene and thioxanthene compounds via the use of oxalic acid
US3115502A (en) * 1959-06-19 1963-12-24 Hoffmann La Roche Method of isomerizing basically substituted stereoisomeric thioxanthenes
US3132073A (en) * 1962-03-14 1964-05-05 Lilly Co Eli Measles vaccine

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US2864844A (en) * 1955-02-02 1958-12-16 Lilly Co Eli Stabilized thimerosal
US2799619A (en) * 1955-11-17 1957-07-16 American Home Prod Anti-excitatory compositions
US2928767A (en) * 1957-07-17 1960-03-15 Smith Kline French Lab Stabilized phenothiazine preparations
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US3115502A (en) * 1959-06-19 1963-12-24 Hoffmann La Roche Method of isomerizing basically substituted stereoisomeric thioxanthenes
US3113137A (en) * 1959-06-30 1963-12-03 Hoffmann La Roche Method for isomerizing stereoisomeric xanthene and thioxanthene compounds via the use of oxalic acid
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Cited By (2)

* Cited by examiner, † Cited by third party
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EP0298192A1 (en) * 1987-07-06 1989-01-11 Teva Pharmaceutical Industries Limited Stable, injectable solutions of vincristine salts
WO1999055375A1 (en) * 1998-04-27 1999-11-04 Arzneimittelwerk Dresden Gmbh Stable mitoxantron solutions

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