Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2002-07-11
2003-12-23
Peselev, Elli (Department: 1628)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
Reexamination Certificate
active
06667393
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical compositions comprising an equilibrium mixture of isomers of an azalide antibiotic compound and to methods for preparing them. This invention further relates to stabilized forms of the aforementioned compositions and to methods of stabilizing them. This invention further relates to methods for treating a mammal comprising administering to a mammal in need of such treatment a pharmaceutical composition of the invention.
Macrolide antibiotic agents active against a wide variety of bacterial and protozoa infections in mammals, fish and birds have been previously reported (see, e.g., International Patent Publications WO 98/56802 and WO 99/12552). These compounds generally have a macrocyclic lactone ring of 12 to 22 carbon atoms to which one or more sugar moieties are attached. Macrolide antibiotics act on the 50S ribosomal subunit to inhibit protein synthesis in microorganisms. Examples of macrolide antibiotics include lincomycin, azithromycin, which is a derivative of erythromycin A, and other azalide compounds.
Development of pharmaceutical compositions containing azalide compounds as the active ingredient has presented significant challenges. Some azalides are capable of isomerizing in solution. Consequently, the production of a reproducible antibiotic composition comprising a single isomer or a fixed ratio of isomers has been difficult. Second, a composition containing a fixed amount of a particular azalide isomer may change over time. Third, the lactone ring and sugars of azalides are easily hydrolyzed in even mildly acidic or basic pH environments, decreasing the potency and shelf-life of an antibiotic composition.
Accordingly, it is an object of the present invention to provide antibiotic compositions, and methods for preparing them, that overcome the above-mentioned disadvantages.
Citation of any reference herein shall not be construed as indicating that such reference is prior art to the present invention.
SUMMARY OF THE INVENTION
In a first embodiment, the present invention relates to a composition comprising: (a) the compound of formula I
and the compound of formula II:
in a ratio of about 90% ±4% to about 10%±4%, respectively; (b) water; and (c) one or more acids present at a total concentration of from about 0.2 mmol to about 1.0 mmol per mL of the composition.
The present invention relates to a method for obtaining a composition comprising: (a) the compound of formula I and the compound of formula II in a ratio of about 90%±4% to about 10%±4%, respectively; (b) water; and (c) one or more acids present at a total concentration of from about 0.2 mmol to about 1.0 mmol per mL of the composition, comprising the step of heating to a temperature of about 50° C. to about 90° C. a mixture comprising: (i) the compound of formula (I), (ii) water, and (iii) one or more acids in a total amount ranging from about 0.2 mmol to about 1.0 mmol per mL of the mixture.
The present invention relates to a composition comprising: (a) a mixture comprising: (i) the compound of formula (I) and the compound of formula (II) in a ratio of about 90%±4% to about 10%±4%, respectively; (ii) water; and (iii) one or more acids present at a total concentration of from about 0.2 mmol to about 1.0 mmol per mL of the mixture; and (b) one or more water-miscible co-solvents present in a total amount of from about 250 to about 750 mg per mL of the composition.
The present invention relates to a method for obtaining a composition comprising: (a) a mixture comprising: (i) the compound of formula (I) and the compound of formula (II) in a ratio of about 90%±4% to about 10%±4%, respectively; (ii) water; and (iii) one or more acids present at a total concentration of from about 0.2 mmol to about 1.0 mmol per mL of the mixture; and (b) one or more water-miscible co-solvents present in a total amount of from about 250 to about 750 mg per mL of the composition, comprising heating to a temperature of about 50° C. to 90° C. a mixture comprising the compound of formula (I), water and one or more acids in an amount ranging from about 0.2 mmol to about 1.0 mmol per mL of the mixture, wherein one or more water-miscible co-solvents is added before, during or after the heating step, in an amount of from about 250 to about 750 mg per mL of the composition. In a preferred embodiment, the water-miscible co-solvent is added after the heating step.
The present invention relates to a method for preserving the structural integrity of the compound of formula I or the compound of formula II comprising the step of forming a composition by adding one or more water-miscible co-solvents to a mixture comprising: (a) the compound of formula (I) and the compound of formula (II); (b) water; and (c) one or more acids present in a total amount of from about 0.2 mmol to about 1.0 mmol per mL of the mixture, the amount of added water-miscible co-solvent being about 250 to about 750 mg per mL of the composition.
In an embodiment of any of the above methods, the pH of the mixture ranges from about 5.0 to about 8.0, and more preferably, from about 5.0 to about 6.0.
In an embodiment of any of the above methods, the heating takes place for about 0.5 to about 24 hours, and more preferably, from about 1 to about 8 hours.
In an embodiment of any of the compositions or methods of the invention, the concentration of the compound of formula (I) in the mixture, i.e., before the heating step, ranges from about 50 mg to about 500 mg per mL of the mixture. In a preferred embodiment thereof, the concentration ranges from about 50 mg/mL to about 200 mg/mL.
In an embodiment of any of the compositions or methods of the invention the concentration of the first mixture (of compound I and compound II) in the composition ranges from about 50 mg/mL to about 200 mg/mL of the composition. In a preferred embodiment thereof, the concentration of the first mixture in the composition ranges from about 75 to about 150 mg/mL, and more preferably from about 90 mg/mL to about 110 mg/mL of the composition.
In an embodiment of any of the compositions or methods of the invention, the one or more acids are selected from the group consisting of acetic acid, benzenesulfonic acid, citric acid, hydrobromic acid, hydrochloric acid, D- and L-lactic acid, methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, D- and L-tartaric acid, p-toluenesulfonic acid, adipic acid, aspartic acid, camphorsulfonic acid, 1,2-ethanedisulfonic acid, laurylsulfuric acid, glucoheptonic acid, gluconic acid, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, 2-hydroxyethanesulfonic acid, malic acid, mucic acid, nitric acid, naphthalenesulfonic acid, palmitic acid, D-glucaric acid, stearic acid, maleic acid, malonic acid, fumaric acid, benzoic acid, cholic acid, ethanesulfonic acid, glucuronic acid, glutamic acid, hippuric acid, lactobionic acid, lysinic acid, mandelic acid, napadisylic acid, nicotinic acid, polygalacturonic acid, salicylic acid, sulfosalicylic acid, tryptophanic acid, and mixtures thereof. In a preferred embodiment thereof, the one or more acids is citric acid. In a more preferred embodiment thereof, the ctiric acid is present in an amount of from about 0.02 mmol to about 0.3 mmol per mL of composition. In another preferred embodiment thereof, the one or more acids are citric acid and hydrochloric acid. In a more preferred embodiment thereof, citric acid is present in an amount of from about 0.02 mmol to about 0.3 mmol per mL of composition and the hydrochloric acid is present in an amount sufficient to achieve a composition pH of about 5 to about 6.
In an embodiment of any of the compositions or methods of the invention, the one or more water-miscible co-solvents are selected from the group consisting of ethanol, isopropanol, diethylene glycol monomethyl ether, diethylene glycol butyl ether, diethylene glycol monoethyl ether, diethylene glycol dibutyl ether, polyethylene glycol-300, polyethylene glycol-400, propylene glycol, glycerine, 2-pyrrolidone
Benson Gregg C.
Lee Christine S.
Peselev Elli
Pfizer Inc.
Richardson Peter C.
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