Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1997-02-04
1999-01-12
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514247, 514249, 514408, A61K 3158, A61K 3150, A61K 31495, A61K 3140
Patent
active
058589996
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is a cosolvent parenteral pharmaceutical formulation of lazaroid compounds.
2. Description of the Related Art
International Publication No. WO87/01706 based on International Patent Application No. PCT/US86/01797 and U.S. Pat. No. 5,175,281 disclose hylpregna-1,4,9(11)-triene-3,20-dione (EXAMPLE 83), which is known as tirilazad, and the mesylate salt (EXAMPLE 109) which is known as tirilazad mesylate for use as neurological agents.
The Journal of Pharmacology and Experimental Therapeutics, 269, 145-50 (1994), International Journal of Clinical Pharmacology and Therapeutics, 32, 223-230 (1994) and Pharmaceutical Research, 11(2) 341 (1994) disclose hyl-5.alpha.-pregna-1,9(11)-diene-3,20-dione (5.alpha.-tirilazad).
U.S. patent application Ser. No. 08/278,633 discloses hyl-5.alpha.-pregna-1,9(11)-diene-3,20-dione (5.alpha.-tirilazad) and the 5.beta.-isomer (5.beta.-tirilazad) and pharmaceutically acceptable salts thereof.
U.S. patent application Ser. No. 08/361,818 discloses yl!-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione (6.alpha.-hydroxytirilazad) and l!-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione (6.beta.-hydroxytirilazad) and pharmaceutically acceptable salts thereof.
U.S. Pat. No. 4,968,675 discloses a parenteral formulation of tirilazad mesylate in citrate buffer. The present invention in addition uses a cosolvent which causes less irritation and pain when used as intended (diluted).
Cosolvents have become widely used as a means for solubilizing drugs for non-parenteral and parenteral (both IV and IM) administration. The effect is dependent primarily upon the polarity of the drug with respect to the solvent (water) and the cosolvent. The degree to which the solubility of a drug can be increased for a particular cosolvent is dependent upon the nonpolarity of the drug and the nonpolarity of the cosolvent. The most frequently used cosolvents are propylene glycol, ethanol, glycerine, and polyethylene glycol. The solubilization curves of a number of pharmaceutically important solutes in cosolvent systems is known, Techniques of Solubilization of Drugs, edited by S. H. Yalkowsky, Marcel Dekker, INC 1981, more particularly see Solubilization of Drugs by Cosolvents, p 91-134.
U.S. Pat. No. 4,794,117 and International Publication No. WO85/04106 disclose that solubilization of hydrophobic pharmaceuticals, e.g. steroids, may be accomplished by solution in polyethylene glycol and addition of aqueous solutions of controlled pH and buffering.
Buffers in parenteral formulations are known.
Journal of Pharmaceutical Science and Technology, 48, 86-91 (1994) discloses that for that particular drug lower acetate buffer concentration caused less irritation than higher acetate buffer concentration. It was further disclosed that citrate buffer concentration of 0.01M caused less irritation than acetate buffer concentration at 0.005M with the particular drug used.
SUMMARY OF INVENTION
Dislosed is a sterile aqueous pharmaceutical composition for parenteral administration which comprises:
(1) about 0.9 to about 90 mg/ml of a lazaroid or a pharmaceutically acceptable salt thereof,
(2) about 0.002 to about 2.0M citrate,
(3) up to about 80% of a cosolvent selected from the group consisting of propylene glycol, polyethylene glycol, glycerol, ethanol, DMSO, DMAC, DMI and M-PYROL,
(4) water at a pH of about 2.4 to about 3.5.
Also disclosed is a sterile aqueous pharmaceutical composition for parenteral administration which comprises:
(1) 25 mg/ml of hylpregna-1,4,9(11)-triene-3,20-dione mesylate,
(2) 0.25M citrate,
(3) 40% propylene glycol,
(4) water at a pH of about 2.7 to about 3.1.
DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutical agents tirilazad, 5.alpha.-tirilazad, 5.beta.-tirilazad, 6.alpha.-hydroxytirilazad, 6.beta.-hydroxytirilazad and pharmaceutically acceptable salts will be collectively referred to as "lazaroids". It is preferred that the lazaroid be tirilazad; it is more preferred that the lazaroid be tirilazad mesylate.
Lazaroids a
REFERENCES:
patent: 4794117 (1988-12-01), Corbiere
patent: 4968675 (1990-11-01), Su
patent: 5124154 (1992-06-01), Babcock et al.
patent: 5175281 (1992-12-01), McCall et al.
patent: 5614515 (1997-03-01), Rodgers et al.
The Journal of Pharmacology & Experimental Therapeutics, 269, 145-50 (1994).
International Journal of Clinical Pharmacology & Therapeutics, 32, 223-230 (1994).
Pharmaceutical Research, 11(2) 341 (1994).
Solubilization of Drugs by Cosolvents, "Techniques of Solubilization of Drugs", edited by S. H. Yalkowsky, Marcel Dekker, INC., pp. 91-134 (1981).
Journal of Pharmaceutical Science and Technology, 48, pp. 86-91 (1994).
Baker David S.
Machkovech Susan M.
Su Ching-Chiang
Pharmacia & Upjohn Company
Stein Bruce
Weddington Kevin E.
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