Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-27
2001-02-27
Seaman, D. Margaret (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S123000
Reexamination Certificate
active
06194429
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the naphthyridone antibiotic alatrofloxacin mesylate essentially free of less polar impurities, to parenteral compositions of said alatrofloxacin mesylate and to processes for purifying alatrofloxacin mesylate.
Alatrofloxacin mesylate is the mesylate prodrug salt of related naphthyridone antibiotic trovafloxacin. Alatrofloxacin mesylate, prepared by methods currently available is produced in very high purity. However, alatrofloxain mesylate prepared by these current methods contains minute less polar impurities that tend to precipitate from parenteral compositions after standing for indefinite periods. These less polar impurities can not be adequately removed by commercially feasible methods such as recrystallization, standard chromatographic means using flash silica gel, solventisolvent extraction methods, or by treatment with diatomaceous earth. The present inventors have discovered that the impurities can be successfully removed by treating the crude reaction products, i.e. product prepared by any of the currently known literature methods, with a polystyrene resin.
It has been previously known that the quinolone antibiotic ciprofloxacin also possesses impurities rendering the product unsuitable for parenteral formulation. European Patent Publication 287,926, published Oct. 26, 1988, describes the purification of ciprofloxacin by treatment with diatomaceous earth so as to yield a product that is suitable for parenteral formulation. As stated above, treatment of alatrofloxacin mesyiate with diatomaceous earth does not adequately remove the less polar impurities.
The antibacterial activity and synthesis of the aforementioned alatrofloxacin are described in U.S. Pat. Nos. 5,164,402 and 5,229,396 issued Nov. 17, 1992 and Jul. 20, 1993, respectively, the disclosures of which are hereby incorporated herein by reference in their entirety. The foregoing patents are assigned in common with the present application.
lnternational Patent Publication WO 97/00268, published Jan. 3, 1997, claims an alternative process for preparing alatrofloxacin. The foregoing publication is hereby incorporated by reference in its entirely.
International Patent Publication WO 97/08191, published Mar. 6, 1997, describes a third process for the preparation, and polymorphs thereof, of alatrofloxacin, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing patent publication is assigned in common with the present application.
International Patent Publication WO 95/19361, published Jul. 20 1995; U.S. patent application No. 60/021,419, filed Jul. 9, 1996; and International Patent Application No. PCT/EP96/04782, filed Oct. 31, 1996, claim novel intermediates for preparing alatrofloxacin and trovafloxacin, the disclosures of which are hereby incorporated herein by reference in their entirety. The foregoing patent publications and applications are assigned in common with the present application.
U.S. Pat. No. 5,475,116, issued Dec. 12, 1995, and U.S. Pat. No. 5,256,791, issued Oct. 26, 1993, claim various azabicyclohexane intermediates useful in the synthesis of alatrofloxacin and trovafloxacin, the disclosures of which are hereby incorporated herein by reference in their entirety. The foregoing patents are assigned in common with the present application.
U.S. patent application Ser. No. 08/764,655, filed Dec. 2, 1996, refers to methods of treating
Helicobacter pylori
infections with alatrofloxacin and trovafloxacin, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing patent application is assigned in common with the present application.
International Patent Publication WO 96/39406, published Dec. 12, 1996 claims a novel crystal form of anhydrous 7-([1&agr;,5&agr;,6&agr;]-6-amino3-azabicyclo[3.1.0]hex-3-yl)6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt, a method of using said compound in the treatment of a bacterial infection in mammals, especially humans, and to pharmaceutical compositions, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing patent publication is assigned in common with the present application.
International Patent Application PCT/IB 96/00756, filed Jul. 29, 1996, claims zwitterionic forms of trovafloxacin which are useful for the administration of the drug as a suspension, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing patent application is assigned in common with the present application.
SUMMARY OF THE INVENTION
The present invention relates to a process of purifying a compound of the formula
comprising treating an impure reaction product containing an amount of said compound of formula I and less polar impurities, with a hydrophobic resin. Said less polar impurities are defined by their high pressure liquid chromatography (HPLC) retention times from injection of a sample in a Hewlett-Packard Model 1100 Series High Pressure Liquid Chromatographer® eluting with a mobile phase solution of 40% acetonitrile, 0.05M potassium dihydrogen phosphate (KH
2
PO
4
) and 0.3% perchloric acid (V/V) at a flow rate of about 2 ml per minute on a Puresil® 5 micron C
18
silica HPLC column (4.6×150 mm) with a 20 &mgr;l injection volume and with a Hewlett-Packard 1100 Series Diode Array Detector® with the detector set to record at a wavelength of 270 nm. The HPLC column is used at ambient temperature (20-25° C.). Said less polar impurities, defined by the aforesaid HPLC conditions, have a retention time of about 2.1 minutes to about 30 minutes. One particular undesirable less polar impurity has a retention time of 9-12 minutes, under the aforesaid HPLC conditions. The aforesaid impurity with the retention time of 9-12 minutes has the formula
(hereinafter also referred to as the “oligomer impurity”). Preferably, the less polar impurities, after treatment, comprise less than 500 ppm, more preferably less than 60 ppm, relative to the weight of the crude product. Most preferably, said impurities comprise less than 20 ppm. Preferably, the hydrophobic resin is a crosslinked polystyrene resin such as Diaion HP-20® or Amberchrom CG-161®.
The present invention also relates to a compound of the formula
substantially free of less polar impurities, more preferably substantially free of the compound of formula II.
The present invention also relates to a parenteral composition, comprising an antibacterially effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, substantially free of less polar impurities, preferably substantially free of a compound of formula II, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is water.
The present invention also relates to a parenteral composition, as described above, wherein the compound of formula I is a lyophylate.
The present invention also relates to a pharmaceutical composition, as described above, wherein the compound of formula I comprises about 10 mg to about 700 mg, preferably about 275 mg to about 500 mg of compound in a unit dosage container, most preferably about 300 mg.
The present invention also relates to a compound of the formula
The present invention also relates to a pharmaceutical composition, comprising an antibacterially effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating a bacterial infection, comprising administering to a subject affected by a bacterial infection an antibacterially effective amount of a compound according to formula II.
The present invention also relates to a compound of the formula
The present invention also relates to a pharmaceutical composition, comprising an antibacterially effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating a
Guhan Subramanian Sam
Guinn Robert Mark
Lambert John Francis
Walinsky Stanley Walter
Ginsburg Paul H.
Jacobs Seth H.
Pfizer Inc
Richardson Peter C.
Seaman D. Margaret
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