Bristol-myers Squibb Compnay

Bristol-myers Company

Other

Bristol-myers

Joseph B Bogardus

Murray A Kaplan

Robert K Perrone

Shreeram N Agharkar

Robert A Lipper

Rajesh Babulal Gandhi

Lawan Phusanti

Miriam K Franchini

Sheeram N Agharkar

Michael W Lovell

Mehdi Paborji

Nageswara R Palepu

William P Coppola

Kenneth J Wilcox

Timothy R Marr

Munir N Nassar

Kenneth W Douglas, Sr

Scott R Stenberg

Ubrani V Venkataram

Peter M Garofalo

Provided are very highly water soluble, stable, crystalline salts of 2&prime;,3&prime;-dideoxy-2&prime;,3&prime;-didehydrothymidine (&ldquo;d4T&rdquo;), 2&prime;,3&prime;-dideoxyinosine (&ldquo;ddI&rdquo;), and 2&prime;,3&prime;-dideoxy-2&prime;-fluoroinosine (&ldquo;F-ddI&rdquo;). Such salts are useful as intermediates or as antiviral agents.

Antiviral, highly water soluble, stable, crystalline salts of 2&prime;, 3&prime;-dideoxyinosine, 2&prime;, 3&prime;-dideoxy-2&prime;, 3&prime;-didehydrothymidine and 2&prime;, 3&prime;-dideoxy-2&prime;-fluoroinosine

The present invention concerns a novel process using controlled cooling for obtaining d.sub.4 T polymorphic Form I from a mixture containing one or more of polymorphic Forms I, II and III. Compound d.sub.4 T has been approved for use in the treatment of AIDS.

d.sub.4 T polymorphic Form 1 process

Stable solutions of rebeccamycin analog consist essentially of (a) water, (b) 8-N-(diethylaminoethyl)rebeccamycin in an effective dosage amount, and (c) pharmaceutically acceptable acid such that the presence of a molar equivalence thereof would solubilize (b), said acid being present in excess of said molar equivalence to provide a stabilizing pH ranging from 3 to 4, preferably from 3.0 to 3.6. A preferred solution contains 10 mg/ml of the free base and tartaric acid in equimolar amount with the free base to provide a pH of 3.5. Preferably, the solution is prepared by forming a suspension of 8-N-(diethylaminoethyl)rebeccamycin in water and adding acid to provide a pH ranging from 3 to 4.

Stable solutions of rebeccamycin analog

Solutions of carboplatin and other malonato platinum(II) antitumor agents are prepared containing stabilizing amounts of 1,1-cyclobutanedicarboxylic acid or salt at pH 4-8. The stabilizers inhibit unacceptable discoloration and precipitation. The solutions may also be stabilized by purging the carrier with air or oxygen and, optionally, blanketing the headspace with air or oxygen.

Stabilized solutions of platinum(II) antitumor agents

A stable solution of mitomycin C in propylene glycol or propylene glycol/water is disclosed. The solutions have an acceptable shelf-life of greater than 24 months at 4.degree. C. and can be injected directly or diluted with water or other aqueous parenteral vehicle for parenteral administration.

Stable solutions of mitomycin C

Platinum complexes are disclosed in which the formula is ##STR1## wherein A and B are each independently ammine or monodentate amine, or A and B taken together represent a bidentate amine, and A and B are coordinated to the platinum atom through their nitrogen atom; X and Y are each independently halogen; R' is C.sub.1 -C.sub.20 alkanoyl, aroyl, heteroaroyl, or a group selected from the group consisting of ##STR2## wherein u' is an integer from 1 to 5; and R' is hydrogen with the proviso that A, B, X, and Y are structually equatorial substituents with respect to OR'--Pt--OR'. These platinum complexes show antitumor activity with relatively lower kidney or bone marrow toxicity.

Water and solvent soluble axial hydroxy and mono- and di- carboxylic

The invention relates to chemically stable, concentrated solutions of cis-diamminedinitratoplatinum which are pH-stabilized with nitric acid and are readily convertible to parenteral cisplatin solutions by addition of sources of chloride ion.

Concentrated, stabilized cis-diamminedinitratoplatinum solutions for

Stable, injectable, aqueous solutions of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(substituted)alkoxy]benzamid e antiemetic agents are prepared by adding, as stabilizing agent, a pharmaceutically acceptable, water-miscible, hydroxylic organic solvent or water-soluble polyhydric alcohol or sugar which decreases the polarity of the solution.

Stable injectable antiemetic compositions

Amorphous solid formed by lyophilization or cosolvent precipitation of an aqueous solution of 7-[.alpha.-(2-aminothiazol-4-yl)-.alpha.-(Z)-methoximinoacetamido]-3-[(1-m ethyl-1-pyrrolidinio)-methyl[-3-cephem-4-carboxylate zwitterion and a salt or mixture of salts from a selected particular group is a broad spectrum antibiotic composition and has better temperature stability at least up to 45.degree. C. than the zwitterion. The salt is one wherein the cation is selected from the group consisting of sodium, lithium, calcium, and magnesium and the anion is selected from the group consisting of chloride, bromide, and iodide. The molar ratio of zwitterion to salt ranges from about 0.5:1 to about 2:l.

Lyophilized or precipitated cephalosporin zwitterion and salt combination

A stable solution of etoposide in 1-methyl-2-pyrrolidinone is disclosed. The solution can be diluted with a parenteral vehicle to yield an infusion solution containing up to 10 mg/ml etoposide activity without rapid etoposide crystallization. Solutions having etoposide concentration of as high as 500 mg/ml can also be prepared and used to fill gelatin capsules.

Etoposide solution in NMP

The antibiotic 7-[D-2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-1-propenyl]ceph-3-em-4-c arboxylic acid (BMY-28100) forms imidazolidinone derivatives on reaction with ketones. These derivatives are useful in pharmaceutical dosage forms and as intermediates for separation thereof from mixtures containing the [(E)-1-propenyl]isomer of the antibiotic.

3-Propenzl cephalosporin isomer separation process and derivative

Crystalline adducts of 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido-3-[(1-methyl-1-pyrr olidinium)methyl]-3-cephem-4-carboxylate selected from the group consisting of the di(1-methyl-2-pyrrolidinone) adduct and the di(N-formyl pyrrolidine) adduct and salt complexes thereof have been found to be stable at even high temperatures. The crystalline adducts are prepared by forming an admixture of adducting agents, zwitterions and seed adduct crystals and inducing crystallization followed by isolating the crystals. A process for preparing adduct salt complexes is also disclosed. Crystalline zwitterion can be formed by slurrying the adducts in a solvent which removes the adducting agents.

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Manlius, NY, United States of America

Joseph B Bogardus