Magnesium quinolone antibiotics

Details Magnesium quinolone antibiotics Magnesium quinolone antibiotics

1998-11-20

2001-09-11

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06288080

ABSTRACT:

FIELD OF THE INVENTION
This invention is related to the field of quinolone antibiotics and involves the use of Mg2+ ions plus an antibiotic quinolone to create a superior injectable formulation.
INFORMATION DISCLOSURE
U.S. Pat. No. 4,730,000, issued Mar. 8, 1988. Chu, Daniel T., “Quinoline Antibacterial Compounds.”
U.S. Pat. No. 4,772,605 issued Sep. 20, 1988. Naik, Arundev H., et al. “Basic Formulations of Quinolonecarboxylic Acids.”
U.S. Pat. No. 5,023,257 issued Jun. 11, 1991. Pöllinger, N., et al., “Intramuscular Injection Forms of Gyrase Inhibitors.”
U.S. Pat. No. 5,084,276 issued Jan. 28, 1992. Yunker, Martin H., et al., “Quinolone Carboxylic Acid Compositions with Polymeric Additive to Reduce Vein Irritation.”
U.S. Pat. No. 5,225,413 issued Jul. 6, 1993. Naik, Arundev H., “PH-Neutral Aqueous Solutions of Quinolone-Carboxylic Acids.”
U.S. Pat. No. 5,290,794 issued Mar. 1, 1994. Mehta, Surendra C., et al., “Soluble Calcium Lactate Antibacterial Complexes as Non-Irritating Parenteral Forms.”
U.S. Pat. No. 5,304,559 issued Apr. 19, 1994. Rozier, A., “Compositions Containing a 4-Quinolone Derivative Complexed with a Divalent Metal Ion.”
U.S. Pat. No. 5,334,589 issued Aug. 2, 1994. Al-Razzak, L. A., et al., “Quinolone Carboxylic Acid-Metal Ion-Acid Complexes.”
U.S. Pat. No. 5,425,935 issued Jun. 20, 1995. Solanki, K. K., “Imaging of Infections.”
International Publication No. WO91/09525 published Jul. 11, 1991. Al-Razzak, L., et al., “Quinolone Carboxylic Acid-Metal Ion-Acid Complexes.”
International Publication No. WO93/05816 published Apr. 1, 1993. Yusuf, A., et al., “Compositions Containing Quinolone Antibiotics and Sulfonate of Polystyrol.”
International Publication No. WO94/20075 published Sep. 15, 1994. Derrieu, G., et al., “Controlled Release Microcapsules, Process for their Preparation and Pharmaceutical or Veterinary Compositions Containing Same.”
International Publication No. WO94/26110 published Nov. 24, 1994. Gupta, P. K., et al., “Stable Quinolone and Naphthyridine Premix Formulations.”
Spanish Patent ES 2 010 633 published Nov. 16, 1989. López Molina, Isidro, et al.,.
German Patent DE 3635062 published Apr. 21, 1988. Grohe, K.
Chapman, John S., et al.,
Antimicrobial agents and chemotherapy,
32,(4) “Routes of Quinolone Permeation in
Escherichia coli
,” pp. 438-442 (1988).
Cole, A., et al.,
Inorganica Chimica Acta,
92, “The Complexation of Transition Series Metal Ions by Nalidixic Acid,” pp. 91-97 (1984).
Valiseana, S., et al.,
Biochemical Pharmacology,
40, “Relevance of Ionic Effects on Norfloxacin Uptake by
Escherichia Coli
,” pp. 431-436 (1990).
Smith, J. T. and Ratcliffe, N. T., “Effect of pH and magnesium on the in vitro activity of ciprofloxacin.”
Ross, Danna L. and Riley, Christopher M.,
International Journal of Pharmaceutics,
93, pp 121-129 (1993).
Escribano, E., et al.,
Antimicrobial Agents and Chemotherapy,
pp 1996-2000 (1997).
BACKGROUND
Fluoroquinolone derivatives are well known for their inhibitory activity on the synthesis of bacterial deoxyribonucleic acid, and consequently are good bactericides. Most fluoroquinolones are also poorly soluble in water and poor aqueous solubility of a drug can make it difficult to deliver that drug in an efficacious manner to a patient. Researchers have made various attempts to either improve the aqueous solubility of fluoroquinolones or to create suspensions of fluoroquinolone drug that can then be delivered to a patient. For example, U.S. Pat. No. 5,304,559 suggests the use of a divalent metal ion such as Cu++, Zn++, or Mg2+ and acids, to create salts that are then maintained as stable suspensions for use as parenteral or more preferably as ophthalmic formulations. U.S. Pat. No. 5,225,413 recommends the use of calcium ions and adjusting the pH to 6.5 to 7.5 to create a water soluble solution of quinolone that can be used for egg dipping.
Quinolone carboxylic acid—metal ion—acid complexes are described in U.S. Pat. No. 5,334,589 to describe compositions of quinolone carboxylic acids plus metal ions plus acid to form an acid complex that can then be used in intravenous administrations. As an added benefit, this quinolone—metal ion—acid complex is also said to have decreased venous irritation upon injection. In contrast to this suggestion, others have reported that divalent metal ions, in particular Mg2+ ions, have a pronounced inhibitory effect on an animal's uptake of quinolone, apparently the metal ion complex reduces the bioavailability of quinolones. See, S. Valisena, et. al. “Relevance of Ionic Effects on Norfloxacin Uptake by
E. Coli
.” Biochemical Pharmacology, vol. 40. no. 3, pp. 431-436 (1990) and John S. Chapman and Nafsika H. Georgopapadakou, “Antimicrobial Agents and Chemotherapy,” vol 32. no. 4, pp. 438-442, (1988).
This disclosure provides novel quinolone complexes with surprising and unexpectedly improved properties over previously disclosed compositions.
SUMMARY OF THE INVENTION
Unique Mg-quinolone complexes are disclosed. They are relatively highly soluble, they may exist as a solution without a precipitate forming and without any need for additional acid or base additions to adjust pH, they may be administered as a subcutaneous or intramuscular injection with a low injection site irritation profile, and they are rapidly absorbed and taken up into the bloodstream.
This invention comprises selected quinolones described in U.S. Pat. No. 5,563,155, combined with Mg. More specifically, the quinolones described in U.S. Pat. No. 5,563,155, in solution, with Mg2+ ions, in a range from ratios of 1:4 to 3:1 parts of Mg2+ ion to quinolone. With ratios of 1:1 and 2:1 being more preferred embodiments and a ratio of 2:1 Mg2+ ion to quinolone being the most preferred embodiment with the more preferred quinolones being 8 position cyclopropyl derivatives and most preferred is 3R, 1S-1-cyclopropyl-7-(3(1-(methylamino)ethyl)-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, see, Formula 1, and its esters, in the form of the zwitterion, also disclosed in claim
8
of U.S. Pat. No. 5,563,155, incorporated by reference. Methods of preparing the complexes, methods of using them to treat animals and methods of preparing medicaments are all disclosed.


REFERENCES:
patent: 4730000 (1988-03-01), Chu
patent: 4772605 (1988-09-01), Naik et al.
patent: 5023257 (1991-06-01), Pöllinger et al.
patent: 5084276 (1992-01-01), Yunker et al.
patent: 5225413 (1993-07-01), Naik
patent: 5290794 (1994-03-01), Mehta
patent: 5304559 (1994-04-01), Rozier
patent: 5334589 (1994-08-01), Al-Razzak et al.
patent: 5425935 (1995-06-01), Solanki
patent: 5563155 (1996-10-01), Domagala et al.
patent: 3635062 (1988-04-01), None
patent: 2 010 633 (1989-11-01), None
patent: WO 91/09525 (1991-07-01), None
patent: WO 93/05816 (1993-04-01), None
patent: WO 94/22075 (1994-09-01), None
patent: WO 9426110 (1994-11-01), None
JS Chapman, et al, Antimicrobial agents and chemotherapy, 32,(4) “Routes of Quinolone Permeation inEscherichia coli” pp. 438-442 (1988).
A. Cole., et al.,Inorganica Chimica Acta,92, “The Complexation of Transition Series Metal Ions by Nalidixic Acid” pp. 91-97 (1984).
S. Valiseana, et al.,Biochemical Pharmacology,40, “Relevance of Ionic Effects on Norfloxacin Uptake byEscherichia Coli,” pp. 431-436 (1990).
JT Smith and NT Ratcliffe, “Effect of pH and magnesium on the in vitro activity of ciprofloxacin”.
Danna L. Ross and Christopher M. Riley,International Journal of Pharmaceutics,93, pp. 121-129 (1993).
E. Escribano, et al.,Antimicrobial Agents and Chemotherapy,pp 1996-2000 (1997).

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