NZ727638B2 - Antimicrobial compositions with effervescent agents - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising a quinolone carboxylic acid derivative antimicrobial agent and an effervescent agent. These compositions have improved gastrointestinal tolerability and/or reduced potential to cause gastrointestinal side effects. These compositions are useful for oral administration, for treating, preventing, or reducing the risk of microbial infections.

Description

ANTIMICROBIAL COMPOSITIONS WITH EFFERVESCENT AGENTS REFERENCE TO RELATED APPLICATIONS This application claims the bene?t of priority of United States Provisional Patent Application No. ,786, ?led June 20, 2014, the entire disclosure of which is incorporated herein by reference.

FIELD OF THE ION The present invention relates to pharmaceutical compositions comprising a quinolone carboxylic acid derivative antimicrobial agent and an effervescent agent. These compositions have ed gastrointestinal tolerability. These compositions are useful for oral administration, for treating, preventing, or reducing the risk of microbial infections.

BACKGROUND Antibiotics are widely available, inexpensive, and seen as routine agents for combatting bacterial infections. However, over-prescription and es in patient compliance (e.g., to complete a ?lll cycle of antibiotics as prescribed) has given rise to antibiotic-resistant bacteria, known as "superbugs." See, e.g., "Antibiotics Crisis Prompts Rethinking On Risks, Rewards," Medscape Mar. 18, 2013. Reports of the steady rise in reports of "superbugs," in combination with the decreasing number of als ofnew ic otics has prompted ational concern. See id. For example, methicillin- resistant Staphylococcus aureus "), is ted to kill about 40,000 people every year in the United States and Europe, while totally drug resistant tuberculosis, untreatable strains of gonorrhea and "super superbugs" having the New Delhi metallo-beta-lactamase (NDM l) mutation are become more prevalent around the globe. Id. Accordingly, a need exists for new antibiotic drugs.

An appropriate pharmaceutical carrier system is generally a requirement for the safe and effective delivery of a pharmaceutical drug active. The entire pharmaceutical composition, z'.e. the pharmaceutical drug active formulated in a pharmaceutical carrier, can affect the bioavailability and also the pharmacokinetics and pharmacodynamics of the drug active. It is therefore important that a pharmaceutical ition be carefully developed and manufactured to deliver the desired pharmaceutical drug active in a safe and effective manner.

The delivery of antimicrobial agents for treating or preventing microbial infections can present l challenges. To provide eutic ef?cacy, it is lly desired that the antimicrobial agent be administered to the patient to achieve systemic concentrations in the tream or target organs above a minimum inhibitory concentration for a suf?cient time against the particular microbial organism or organisms being targeted.

Consequently, an antimicrobial agent that otherwise exhibits an effective antimicrobial pro?le in vitro can be ineffective, or even l, unless properly ated for in viva administration.

The challenge of developing suitable antimicrobial compositions is further complicated for the development of compositions for oral administration. For example, antimicrobial agents can affect the ?ora of the gastrointestinal tract, particularly in the small and large intestine, which can result in untoward gastrointestinal side effects such as diarrhea, nce, and general abdominal fort. Furthermore, antimicrobial agents can exert a selective pressure on the resident bacteria of the gastrointestinal tract resulting in the emergence of ia resistant to the antimicrobial agent. The gastrointestinal side effects can affect patient compliance with the antimicrobial dosing regimen, therefore compromising drug effectiveness and potentially subjecting the patient to recurring or more ant infections. In severe cases, the gastrointestinal side effects can result in disruption or even total discontinuation of therapy.

The potential development of bacterial resistance is a broader public health concern. In n instances, because of the selective pressure of the antimicrobial agent on the bacterial ?ora of the gastrointestinal tract, the patient receiving crobial therapy can become colonized by bacteria resistant to the antimicrobial agent. The resultant resistant bacteria can not only be harmful to the patient but can be further disseminated into and become established in the community.

It is believed by those skilled in the art that the gastrointestinal side effects and resistance problems are caused by residual antimicrobial agent that is not absorbed from the gastrointestinal tract into the blood . In such instances, it is believed that the antimicrobial agent that remains in and passes through the gastrointestinal tract, particularly the antimicrobial agent that passes into the cecum and colon, can cause these gastrointestinal side effects and resistance problems. Additionally, the antimicrobial agent that is ed into the blood stream can, depending on the particular pharmacokinetics of the antimicrobial agent, be excreted from the liver through the bile and back into the gastrointestinal tract to further augment the gastrointestinal side effects and resistance problems.

There is thus a need to develop formulations which minimize the presence of residual or ed antimicrobial agent in the intestinal tract. In particular there is a need to develop formulations which minimize the presence of residual or unwanted crobial agent in the cecum and colon. There is also a need to develop oral formulations which minimize the undesirable gastrointestinal side effects and the development of antibiotic resistance. ore, the present invention addresses the foregoing and other needs by providing itions and methods.

BRIEF DESCRIPTION OF THE FIGURES shows a powder X-ray diffraction (XRPD) pattern of crystalline D-glucitol, l-deoxy- l -(methylamino)-, l-(6-amino-3 ,5-di?uoropyridinyl)chloro?uoro- l ,4- dihydro(3-hydroxyazetidin- l -yl)oxo-3 -quinolinecarboxylate. shows a powder X-ray diffraction pattern of crystalline D-glucitol, l- deoxy- l -(methylamino)-, l-(6-amino-3 ,5-di?uoropyridinyl)chloro?uoro- l ,4- dihydro(3-hydroxyazetidin- l -yl)oxo-3 -quinolinecarboxylate trihydrate. shows a Modulated Differential Scanning Calorimetry (mDSC) thermogram of crystalline D-glucitol, l-deoxy-l-(methylamino)-, l-(6-amino-3,5- di?uoropyridinyl)—8-chloro?uoro- l ,4-dihydro(3-hydroxyazetidin- l -yl)oxo-3 - quinolinecarboyxlate. shows a dissolution profile for certain formulations according to the present disclosure.

Y OF THE INVENTION The present invention is based, in part, on the surprising discovery that pharmaceutical compositions comprising a quinolone carboxylic acid derivative crobial agent and an effervescent agent have improved gastrointestinal tolerability. These compositions are useful for oral stration, for treating, preventing, or reducing the risk of microbial infections.

It is understood that any of the embodiments described below can be combined in any desired way, and any embodiment or combination of embodiments can be applied to each of the aspects described below, unless y exclusive.

In one aspect, the invention provides a pharmaceutical composition comprising: (a) a one carboxylic acid derivative or a pharmaceutically acceptable salt or ester f; and (b) an effervescent agent.

In some embodiments, the one carboxylic acid derivative corresponds to the following structure of Formula 1 R6 o R4 COORl | | R5 W i n \X Formulal wherein R1 represents a hydrogen atom or a carboxyl tive group; R2 represents a hydroxyl group, a lower alkoxy group, or a substituted or unsubstituted amino group; R3 represents a hydrogen atom or a halogen atom; R4 represents a hydrogen atom or a halogen atom; R5 represents a halogen atom or an optionally substituted saturated cyclic amino group; R6 ents a hydrogen atom, a n atom, a nitro group, or an optionally protected amino group; X, Y and Z may be the same or different and respectively represent a nitrogen atom, -CH= or -CR7=; R7 represents a lower alkyl group, a halogen atom, or a cyano group, with the o that at least one of X, Y and Z represent a nitrogen atom, and W represents a nitrogen atom or -CR8= ; wherein R8 represents a hydrogen atom, a halogen atom, or a lower alkyl group, or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, when R1 represents a hydrogen atom, R2 represents an amino group, R3 and R4 represent a ?uorine atom, R6 represents a hydrogen atom, X . 7 . 7 . represents a nitrogen atom, Y represents -CR = wherein R represents a ?uorine atom, Z represents —CH=, and W is -CR8= wherein R8 represents a ne atom, then R5 is not a 3- hydroxyazetidine-l-yl group, or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the quinolone carboxylic acid derivative corresponds to the following compound (A) F COOH LN N CI F HO \ or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the quinolone carboxylic acid derivative is a D-glucitol, l- deoxy- l -(methylamino)-, mino-3 ,5-di?uoropyridinyl)—8-chloro?uoro- l ,4- dihydro(3-hydroxy- l -azetidinyl)oxo-3 -quinolinecarboxylate.

In some embodiments, the quinolone carboxylic acid derivative is a lline D- glucitol, l-deoxy- l -(methylamino)-, l-(6-amino-3 ,5 -di?uoropyridinyl)chlorofluoro- l ydro(3 -hydroxy-l dinyl)oxoquinolinecarboxylate characterized, wherein the pattern is ed from a copper radiation source with Cu-Kd radiation, by the X-ray powder diffraction pattern shown in FIGURE 1.

In some embodiments, the quinolone carboxylic acid derivative is D-glucitol, l- deoxy- l -(methylamino)-, l-(6-amino-3 ,5-di?uoropyridinyl)—8-chloro?uoro- l ,4- o(3-hydroxy- l -azetidinyl)oxo-3 -quinolinecarboxylate trihydrate.

In some embodiments, the quinolone carboxylic acid derivative is lline D- glucitol, l-deoxy- l -(methylamino)-, l-(6-amino-3 ,5 -di?uoropyridinyl)chlorofluorol ,4-dihydro(3-hydroxy- l -azetidinyl)oxoquinolinecarboxylate trihydrate , characterized, when measured at about 25 0C with Cu-Ku radiation, by the X-ray powder diffraction pattern shown in FIGURE 2.

In some embodiments, the effervescent agent comprises one or more of sodium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate (also known as disodium phosphate or disodium hydrogen phosphate), sodium dihydrogen phosphate (also known as sodium phosphate monobasic or monosodium phosphate), sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydrogen phosphate (also known as dipotassium phosphate or dipotassium hydrogen phosphate), potassium dihydrogen phosphate (also known as potassium phosphate monobasic or monopotassium phosphate), potassium hydroxide, magnesium ate, ium bicarbonate, magnesium hydroxide, magnesium oxide, calcium carbonate, calcium bicarbonate, calcium oxide, citric acid.

In some embodiments, the composition further comprises a compound ed from the group consisting of citric acid, sodium citrate, ium e, maleic acid, maleic ide, sodium malate, potassium malate, tartaric acid, sodium tartrate, potassium tartrate, fumaric acid, sodium fumarate, potassium ?Jmarate, ascorbic acid, sodium ascorbate, potassium ascorbate, and mixtures thereof.

In some embodiments, the effervescent agent comprises a mixture of sodium bicarbonate, sodium en phosphate and citric acid.

In some embodiments, the effervescent agent comprises a mixture of sodium bicarbonate, sodium dihydrogen phosphate and citric acid.

In some embodiments, the pharmaceutical ition further comprises a polyhydroxyamine compound.

In some embodiments, the polyhydroxyamine nd is meglumine.

In another aspect, the invention es a pharmaceutical composition comprising: (a) from about 0.01% to about 80% by weight of a quinolone carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, as ed to the total weight of the composition on an acid basis; and (b) from about 0.1% to about 50% by weight of an escent agent, as compared to the total weight of the composition.

In another aspect, the invention provides a pharmaceutical composition comprising: (a) from about 0.01% to about 80% by weight of a quinolone carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; (b) from about 0.1% to about 50% by weight of meglumine, as compared to the total weight of the ition; and (c) from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the ition.

In another aspect, the invention provides a pharmaceutical composition comprising: (a) from about 0.01% to about 50% by weight of dela?oxacin, or a pharmaceutically acceptable salt thereof, as ed to the total weight of the composition on an acid basis; and (b) from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the composition.

In another aspect, the invention provides pharmaceutical composition comprising: (a) from about 0.01% to about 50% by weight of dela?oxacin, or a pharmaceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; (b) from about 0.1% to about 50% by weight of meglumine, as ed to the total weight of the composition; and (c) from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the composition.

In another aspect, the invention provides pharmaceutical composition comprising: (a) from about 0.01% to about 50% by weight of dela?oxacin, or a pharmaceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; and (b) from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the composition, the effervescent agent comprising the mixture of sodium bicarbonate, sodium ogen phosphate, and citric acid.

In another aspect, the invention provides a pharmaceutical composition comprising: (a) from about 0.01% to about 50% by weight of dela?oxacin, or a pharmaceutically acceptable salt thereof, as ed to the total weight of the composition on an acid basis; (b) from about 0.1% to about 50% by weight of meglumine, as compared to the total weight of the composition; and (c) from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the composition, the effervescent agent comprising the e of sodium bicarbonate, sodium dihydrogen ate, and citric acid.

In another aspect, the invention provides a ceutical composition sing: (a) from about 100 mg to about 750 mg of dela?oxacin, on an acid active basis; and (b) from about 100 mg to about 500 mg of an escent agent.

In another aspect, the invention provides pharmaceutical composition comprising: (a) from about 100 mg to about 750 mg of dela?oxacin, on an acid active basis; and (b) from about 100 mg to about 500 mg of an effervescent agent sing the e of sodium bicarbonate, sodium dihydrogen phosphate, and citric acid.

In another aspect, the invention provides pharmaceutical composition comprising: (a) about 400 mg of dela?oxacin meglumine, on an acid active basis; and (b) about 150 mg of an effervescent agent comprising the mixture of sodium bicarbonate, sodium dihydrogen phosphate, and citric acid.

In another aspect, the invention provides a pharmaceutical composition comprising: (a) about 450 mg of dela?oxacin, (b) about 199 mg of meglumine; and (c) about 150 mg of an effervescent agent comprising the e of sodium bicarbonate, sodium phosphate, and citric acid.

In some embodiments, the ition has improved gastrointestinal tolerability.

In some ments, the composition has reduced potential to cause gastrointestinal side effects.

In some embodiments, the ition has improved gastrointestinal tolerability or has reduced potential to cause gastrointestinal side effects as evaluated in a mini pig model.

In some embodiments, the composition has improved gastrointestinal tolerability or has reduced potential to cause gastrointestinal side effects as evaluated in humans.

In some embodiments, the composition has diminished potential to cause bacterial resistance.

In some embodiments, the composition is in the form of a dry mixture, an aqueous solution, an aqueous suspension, a non-aqueous solution, a non-aqueous suspension, or an emulsion.

In some embodiments, the composition is a unit .

In some embodiments, the composition is in the form of a tablet.

In some embodiments, the composition is in the form of a single layer tablet.

In some embodiments, the composition is in the form of a r tablet comprising a ?rst layer and a second layer. In some embodiments, the ?rst layer comprises the one carboxylic acid derivative or a pharmaceutically acceptable salt thereof and the second layer comprises the effervescent agent. In some embodiments, the second layer is a d e layer, Where the second layer is released in the gastrointestinal tract downstream from the stomach.

In some embodiments, the composition is in the form of a capsule.

In another aspect, the invention provides a method for treating, preventing, or reducing the risk of a bacterial infection comprising administering to a patient in need f an ive amount of the ition described herein.

In some embodiments, the invention provides a method for treating a bacterial infection comprising administering to a patient in need thereof an effective amount of the composition described herein. In some embodiments, the invention provides a method for preventing a bacterial infection comprising administering to a patient in need thereof an effective amount of the composition described herein. In some embodiments, the invention provides a method for reducing the risk of a bacterial infection comprising administering to a patient in need thereof an effective amount of the composition described .

In some embodiments, the method has ed gastrointestinal tolerability. In some embodiments, the method has reduced potential to cause gastrointestinal side s.

In one , the invention provides a method for treating, preventing, or reducing the risk of a bacterial infection, While reducing the potential for causing gastrointestinal side effects, comprising administering to a patient in need thereof an effective amount of the composition described herein.

In one aspect, the invention provides a method for treating, preventing, or reducing the risk of a bacterial infection, While reducing the potential for g bacterial resistance, sing administering to a t in need f an effective amount of the composition of described herein.

In one aspect, the invention provides a pharmaceutical composition for use in the manufacture of a ment for ng, preventing or reducing the risk of infection in a patient in need thereof, the composition comprising: (a) a quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof; and (b) an escent agent.

DETAILED DESCRIPTION OF THE INVENTION In the present invention, it has surprisingly been found that the combination of a quinolone carboxylic acid tive antimicrobial agent and an effervescent agent are found to e a desired balance of antimicrobial activity and improved gastrointestinal toleration and also may reduce the potential for bacterial resistance. Without being limited by theory, the ?nal drug product formulation may be the result of a complex interplay of solubility, stability, and toleration.

The present invention relates to pharmaceutical compositions comprising a quinolone carboxylic acid derivative and an effervescent agent. It has been found that these itions have improved gastrointestinal tolerability. These compositions are useful for oral administration, for treating, preventing, or reducing the risk of a microbial infection.

The present invention relates to a pharmaceutical composition sing a quinolone carboxylic acid tive or a pharmaceutically acceptable salt or ester thereof, and an effervescent agent. These compositions are useful for oral administration for treating, preventing, or reducing the risk of infection. These compositions have enhanced patient gastrointestinal toleration when stered orally. The present invention provides compositions having enhanced gastrointestinal toleration compared to what would otherwise be achievable not employing the present invention. Enhanced intestinal patient toleration is important, because the invention provides compositions that are safe and well tolerated. It is not suf?cient for a pharmaceutical composition to be ef?cacious, it is important that y be achieved at an appropriate safety and toleration level. Therefore, the compositions of the present ion provide an advantage over the state of the art.

In one aspect, the ion relates to a method for treating, preventing, or reducing the risk of a bacterial infection in a patient in need thereof a ition as taught herein, wherein said composition has improved gastrointestinal tolerability.

In one aspect, the invention s to a method for treating, preventing, or reducing the risk of a bacterial infection in a patient in need thereof a composition as taught , wherein said composition has the reduced potential to cause gastrointestinal side s. The intestinal side effects in the foregoing are selected from diarrhea, ?atulence, nausea, vomiting, abdominal pain, dyspepsia, belching, bloating, gastritis, and general nal fort.

In one aspect, the invention relates to a method for treating, preventing, or reducing the risk of a bacterial infection in a patient in need thereof a composition as taught herein, wherein said composition has the reduced potential to cause gastrointestinal side effects and wherein said composition has the reduced potential to cause bacterial resistance.

The gastrointestinal side effects in the foregoing are selected from diarrhea, ?atulence, nausea, vomiting, abdominal pain, dyspepsia, ng, ng, gastritis, and general abdominal discomfort.

In one embodiment, the present invention relates to a pharmaceutical composition which comprises (a) a one carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof, and (b) an effervescent agent.

In other ments, the present invention relates to a composition wherein said quinolone carboxylic acid derivative corresponds to the following structure of Formula 1: R6 o R4 COORl | | R5 W i n \X Formulal wherein R1 represents a hydrogen atom or a carboxyl protective group; R2 represents a hydroxyl group, a lower alkoxy group, or a substituted or unsubstituted amino group; R3 represents a hydrogen atom or a halogen atom; R4 represents a hydrogen atom or a n atom; R5 represents a halogen atom or an optionally substituted ted cyclic amino group; R6 represents a hydrogen atom, a halogen atom, a nitro group, or an optionally protected amino group; X, Y and Z may be the same or different and respectively represent a nitrogen atom, -CH= or -CR7= (wherein R7 represents a lower alkyl group, a n atom, or a cyano group), with the proviso that at least one of X, Y and Z represent a nitrogen atom, and W represents a nitrogen atom or -CR8= (wherein R8 represents a hydrogen atom, a halogen atom, or a lower alkyl group); with the proviso that R1, R2, R3, R4, R5, R6, R7, R8, W, X, Y, and Z as de?ned as described in this paragraph are de?ned for Formula 1.

In one embodiment, when R1 ents a hydrogen atom, R2 represents an amino group, R3 and R4 represent a ?uorine atom, R6 represents a hydrogen atom, X ents a nitrogen atom, Y represents -CR7= in R7 represents a ?uorine atom), Z represents — CH=, and W is -CR8= (wherein R8 represents a chlorine atom), then R5 is not a 3- hydroxyazetidine- l -yl group; In other embodiments, the present invention relates to a composition wherein said quinolone carboxylic acid derivative corresponds to the following compound (A), F COOH //:/N N CI F HO \ or a pharmaceutically acceptable salt or ester thereof.

In other embodiments, the present invention relates to a composition wherein said one carboxylic acid derivative is a D-glucitol, l-deoxy-l-(methylamino)-, l-(6-amino- 3 ,5 -difluoro-2—pyridinyl)chloro?uoro- l ,4-dihydro(3-hydroxy- l -azetidinyl)oxo-3 - quinolinecarboxylate. In other embodiments, the present invention relates to a composition wherein said quinolone carboxylic acid derivative is a crystalline D-glucitol, l-deoxy-l- (methylamino)-, l-(6-amino-3 uoropyridinyl)chlorofluoro- l ,4-dihydro(3 - hydroxy-l-azetidinyl)oxoquinolinecarboxylate. In yet other embodiments, the present ion relates to a composition wherein said quinolone carboxylic acid tive is a crystalline D-glucitol, l-deoxy-l-(methylamino)-, l-(6-amino-3,5-di?uoropyridinyl)—8- chloro?uoro- l ydro(3-hydroxy- l -azetidinyl)oxo-3 -quinolinecarboxylate terized, wherein the pattern is obtained from a copper radiation source with Cu-KOL radiation, by the X-ray powder diffraction pattern shown in FIGURE 1.

In other embodiments, the present invention relates to a composition wherein said quinolone carboxylic acid derivative is D-glucitol, l-deoxy-l-(methylamino)-, l-(6-amino- 3 ,5 -difluoro-2—pyridinyl)chloro?uoro- l ydro(3-hydroxy- l -azetidinyl)oxo-3 - quinolinecarboxylate trihydrate. In other embodiments, the present invention relates to a composition n said quinolone carboxylic acid derivative is crystalline itol, l- deoxy- l -(methylamino)-, l-(6-amino-3 ,5-di?uoropyridinyl)—8-chloro?uoro- l ,4- dihydro(3-hydroxy-l-azetidinyl)oxoquinolinecarboxylate trihydrate. In yet other embodiments, the present invention relates to a composition wherein said quinolone carboxylic acid derivative is crystalline D-glucitol, l-deoxy-l -(methylamino)-, l-(6-amino- 3 ,5 -difluoro-2—pyridinyl)chloro?uoro- l ,4-dihydro(3-hydroxy- l -azetidinyl)oxo-3 - quinolinecarboxylate trihydrate characterized, when measured at about 25 0C with Cu-Ku radiation, by the x-ray powder diffraction pattern shown in FIGURE 2.

In other embodiments, the invention relates to a pharmaceutical composition wherein said effervescent agent is that releases carbon dioxide upon contact with water or a gastrointestinal ?uid.

In other embodiments, the present ion s to a composition wherein said composition provides a measurable improvement in gastrointestinal toleration. In other embodiments, the present invention relates to a composition wherein said gastrointestinal tion is ed in an animal model. In other embodiments, the present invention relates to a composition wherein said gastrointestinal toleration is measured in a mini-pig model. In other embodiments, the present ion relates to a ition wherein said gastrointestinal tion is measured in humans.

In other embodiments, the present invention relates to a pharmaceutical composition comprising (a) from about 100 mg to about 500 mg of dela?oxacin meglumine, and (b) from about 100 mg to about 500 mg of an effervescent agent.

In other embodiments, the t invention relates to a method for treating, preventing, or reducing the risk of a bacterial infection comprising administering to a patient in need thereof a composition as described herein. 1. De?nitions The term nt", as used herein, means the human or animal (in the case of an , more typically a mammal) subject. The term "mammal" includes a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human e, such as a monkey, chimpanzee, baboon or rhesus. In one embodiment, the mammal is a human. The patient is usually one that is in need of the compositions or methods bed herein. "In need of," can mean that the patient has or is diagnosed as having an infection, e.g., a microbial infection, or that the patient is at risk of contracting an infection due to an injury, a l or surgical procedure, or microbial exposure, or could be in a position that could subject the patient to such exposure. Such infections can be due to, e.g., a skin ion, nosocomial nia, post-viral pneumonia, an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt ion, a vascular access infection, meningitis, infection due to surgical or invasive medical procedures, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus infection, a vancomycin-resistant Enterococcz' infection, a linezolid-resistant sm infection, tuberculosis, a quinolone ant Gram-positive ion, a cipro?oxacin resistant illin resistant (MRSA) infection, bronchitis, a complicated skin and skin structure infection (cSSSI), an uncomplicated skin and skin structure infection (uSSSI), a community respiratory-tract infection, and a multi-drug resistant (MDR) Gram-negative infection.

The term "preventing", as used herein, means, e.g, to completely or almost completely stop an infection from occurring, for example when the patient is predisposed to an infection or at risk of contracting an infection.

The term "reducing the risk of", as used herein means, e.g, to lower the likelihood or probability of an infection occurring, for example when the patient is predisposed to an infection or at risk of cting an infection.

The term "treating" as used herein means, e.g., to cure, inhibit, arrest the development, relieve the ms or effects of, ameliorating, or cause the regression of an infection in a patient haVing an infection.

It should be recognized that the terms "preventing", "reducing the risk of", and "treating" are not ed to limit the scope of the ion and that there can be overlap amongst these terms.

As used herein, the term "effective amount" means an amount of a pharmaceutically active compound, z'.e. a drug active, e.g., a quinolone carboxylic acid derivative or ceutically able salt f, given to a recipient patient sufficient to elicit biological ty, for example, anti-infective activity, e.g., anti-microbial actiVity.

The term "prophylactically effective amount" means an amount of a pharmaceutically active compound, z'.e. a drug active, e.g., a quinolone carboxylic acid derivative given to a recipient patent suf?cient to prevent or reduce the risk of a microbial infection.

As used herein, the phrase "pharmaceutically acceptable" refers to those nds, materials, itions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is d by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the tional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, c, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, lyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, ine, methane sulfonic, napsylic, , oxalic, , pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the ly occurring amine acids, e.g, glycine, alanine, phenylalanine, arginine, etc.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. lly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the riate base or acid in water or in an organic solvent, or in a mixture of the two. In one embodiment, non-aqueous media, for example ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are useful for g salts of the present compounds. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 18th ed. (Mack Publishing y, 1990). For e, salts can include, but are not limited to, the hydrochloride and acetate salts of the aliphatic amine-containing, hydroxyl amine-containing, and imine-containing compounds of the present invention.

Additionally, the nds of the present invention, for example, the salts of the nds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent les. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, As used herein, aceutically able esters" refer to derivatives of the disclosed compounds wherein the parent compound is modified by an alcohol ester of a carboxylic acid or a carboxylic acid ester of an alcohol. The compounds of the present invention can also be prepared as , for example pharmaceutically acceptable esters. For example a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl, or other ester. Also, an alcohol group in a compound can be ted to its corresponding ester, e.g., an e, propionate, or other ester. In the present invention, particularly useful esters are the C1-C6 alkyl alcohol , i. e. the C1-C6 straight, ed, and cyclic alkyl esters, the phenyl ester, and the benzyl ester.

Examples of these esters include the methyl ester, the ethyl ester, the n-propyl ester, the isopropyl ester, the n-butyl ester, and so forth.

As used herein, the term "unit dosage" or "unit dosage form", means a single dose of a pharmaceutical composition that is intended to be administered in its entirety. A unit dosage or unit dosage form is a convenient form for administering a premeasured amount of a drug active.

In the speci?cation, the singular forms also include the plural, unless the context clearly dictates otherwise. Unless de?ned otherwise, all technical and scienti?c terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of con?ict, the present speci?cation will control.

All percentages and ratios used herein, unless otherwise ted, are by weight.

As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a le which is inherently uous, the variable can be equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 can take the values 0, 1 or 2 if the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values 2 0 and S 2 if the variable is inherently continuous.

As used herein, unless speci?cally indicated otherwise, the word "or" is used in the inclusive sense of "and/or" and not the exclusive sense of "either/or." Throughout the description, where itions are described as having, including, or comprising speci?c components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. rly, where methods or processes are bed as having, including, or comprising speci?c process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing n actions is immaterial so long as the invention remains operable. er, two or more steps or actions can be conducted simultaneously. 2. Compositions of the present invention The itions of the present invention comprise all or some of the following components. The compositions can be de?ned either prior to or after mixing of the components.

Suitable components are described in e.g., Eds. R. C. Rowe, et al., Handbook of ceutical Excipients, Fifth Edition, ceutical Press (2006); Remington ’s ceutical es, 18th ed. (Mack Publishing Company, 1990); and Remington: The Science and Practice ofPharmacy, 20th n, Baltimore, MD: Lippincott Williams & Wilkins, 2000, which are incorporated by reference herein in their entirety. Even though a onal category can be provided for many of these carrier components, such a functional category is not intended to limit the ?anction or scope of the component, as one of ordinary skill in the art will recognize that a component can belong to more than one functional category and that the level of a specific component and the presence of other components can affect the functional properties of a component. a. one Carboxylic Acid Derivative The itions of the t invent comprise a quinolone carboxylic acid derivative (alternatively known as, inter alia, a pyridonecarboxylic acid derivative or a pyridone ylic acid derivative), or a pharmaceutically acceptable salt thereof, as an antimicrobial compound, i. e. as the active pharmaceutical ingredient, or API, of the compositions of the present invention. The invention further provides methods for synthesizing any one of the compounds of the present invention. The invention also provides pharmaceutical compositions comprising an effective amount of one or more of the compounds of the present invention and a pharmaceutically acceptable carrier. The present invention ?thher provides methods for making these compounds, carriers, and pharmaceutical compositions.

Quinolone carboxylic acid derivatives, useful herein are described, including their syntheses, formulation, and use, in US. Patent No. 6,156,903, to Yazaki et al., issued December 5, 2000 and its cates of tion ofNovember 13, 2001 and December 11, 2001; US. Patent No. 6,133, 284, to Yazaki et al., issued October 17, 2000; US. Patent No. ,998, 436, to Yazaki et al., issued December 7, 1999 and its certi?cates of correction of January 23, 2001, October 30, 2001, and December 17, 2002; PCT Application No. WO 2006/1 10815, to Abbott tories, published October 19, 2006; PCT Application No. WO 2006/042034, to Abbott Laboratories, published April 20, 2006, PCT Application No. WO 2006/015194, to Abbott Laboratories, published February 9, 2006; PCT Application No. WO 01/34595, to Wakunaga ceutical Co., Ltd., published May 17, 2001; and PCT Application No. WO 97/11068, to ga Pharmaceutical Co., Ltd., published March 27, 1997, the contents of each of which are hereby incorporated by reference in their ties.

Quinolone carboxylic acid tives useful in the methods, compositions, and uses of the present invention include compounds corresponding to Formula 1 R6 o R4 COORl | | R5 W i n \X Formula 1, wherein with respect to Formula 1, R1 represents a hydrogen atom or a carboxyl protective group; R2 represents a hydroxyl group, a lower alkoxy group, or a substituted or unsubstituted amino group; R3 represents a hydrogen atom or a halogen atom; R4 represents a hydrogen atom or a halogen atom; R5 represents a halogen atom or an optionally substituted saturated cyclic amino group; R6 represents a hydrogen atom, a halogen atom, a nitro group, or an optionally protected amino group; X, Y and Z may be the same or different and respectively represent a nitrogen atom, -CH= or -CR7= in R7 represents a lower alkyl group, a halogen atom, or a cyano group), with the proviso that at least one of X, Y and Z represent a nitrogen atom, and W represents a nitrogen atom or -CR8= (wherein R8 represents a hydrogen atom, a halogen atom, or a lower alkyl group).

In one embodiment, when R1 ents a hydrogen atom, R2 represents an amino group, R3 and R4 represent a ?uorine atom, R6 represents a hydrogen atom, X represents a nitrogen atom, Y represents -CR7= (wherein R7 represents a ?uorine atom), Z represents — CH=, and W is -CR8= (wherein R8 represents a chlorine atom), then R5 is not a 3- hydroxyazetidine-l-yl group; or a pharmaceutically acceptable salt, ester, or g thereof.

When R1 is a carboxyl protective group, it may be any carboxylate ester residue which cleaves relatively easily, such as in vivo, to generate the corresponding free carboxyl group. Exemplary carboxyl protective groups include those which may be eliminated by hydrolysis, catalytic ion, and other treatments under mild conditions such as lower alkyl groups such as methyl group, ethyl group, n-propyl group, yl group, n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group, and heptyl group; lower alkenyl groups such as vinyl group, allyl group, l-propenyl group, butenyl group, pentenyl group, hexenyl group, and heptenyl group; aralkyl groups such as benzyl group; and aryl groups such as phenyl group and naphthyl group; and those which may be readily eliminated in the body such as lower alkanoyloxy lower alkyl groups such as ymethyl group and pivaloyloxymethyl group; lower alkoxycarbonyloxy lower alkyl group such as methoxycarbonyloxymethyl group and l-ethoxycarbonyloxyethyl group; lower alkoxymethyl group such as methoxymethyl group; lactonyl group such as phthalidyl; di-lower alkylamino lower alkyl group such as l-dimethylaminoethyl group; and (5-methyloxo-l,3-dioxole yl)methyl group.

In one embodiment, R1 in Formula 1 is H.

In one embodiment, R2 in Formula 1 is —NH2.

In one embodiment, R3 in a 1 is halogen.

In another embodiment, R3 in a 1 is ?uorine.

In one embodiment, R4 in a 1 is halogen.

In r embodiment, R4 in Formula 1 is ?uorine.

In one embodiment, R5 in a 1 is a substituted cyclic amino group.

In one embodiment, R5 in Formula 1 is In one embodiment, R6 in Formula 1 is hydrogen.

In one embodiment, X in Formula 1 is a nitrogen atom.

In one embodiment, Y in Formula 1 is =CR7-.

In one embodiment, R7 in Formula 1 is a halogen.

In another embodiment, R7 in Formula 1 is ?uorine.

In one embodiment, Z in Formula 1 is =CH-.

In one embodiment, W in a 1 is =CR8-.

In one embodiment, R8 in Formula 1 is a n.

In another embodiment, R8 in Formula 1 is chlorine.

It is noted that the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, A, J1, J2, J3, W, X, Y, Z, e, f, and g are de?ned herein for convenience with t to the chemical ure for the quinolone carboxylic acid derivatives, for example for Formula 1.

In other embodiments, the present invention relates to a method, composition, or use for a compound of Formula 1, wherein W is -CR8=, wherein R8 represents a hydrogen atom, a halogen atom, or a lower alkyl group.

In other embodiments, the t invention relates to a method, composition, or use for a quinolone carboxylic acid derivative of Formula 1, wherein R5 is a group represented by the following formula (a) or (b): wherein A represents an oxygen atom, sulfur atom or NR9 (wherein R9 represents en atom or a lower alkyl group), e represents a number from 3 to 5, f represents a number from 1 to 3, g represents a number from 0 to 2, J1, J2 and J which may be the same or different from one r, ent a hydrogen atom, hydroxyl group, lower alkyl group, amino lower alkyl group, amino group, lower alkylamino group, lower alkoxy group, or a halogen atom.

In other embodiments, the present invention relates to a method, composition, or use for a quinolone carboxylic acid tive of a 1, wherein R5 is a group represented by formula (a): (CH2)e N— In other embodiments, the present invention relates to a method, composition, or use for a quinolone carboxylic acid derivative of structure Quinolone Carboxylic Acid Derivative of Formula 1, wherein e in the formula (a) is 3 or 4: (CH2)e N— In other embodiments, the present invention relates to a method, composition, or use for a quinolone carboxylic acid derivative of structure Quinolone Carboxylic Acid Derivative of Formula 1, wherein R1 is a hydrogen atom; R2 is an amino group, lower alkylamino group, or a er alkylamino group; R3 is a halogen atom; R4 is a halogen atom; R6 is hydrogen atom; X is a nitrogen atom; Y and Z are —CH= or -CR7= (wherein R7 is a lower alkyl group or a halogen atom); and W is -CR8= (wherein R8 is a n atom or a lower alkyl .

In other embodiments, the present invention relates to a method, composition, or use for a quinolone carboxylic acid derivative of structure Quinolone Carboxylic Acid . . . 2 Derivative of Formula 1, wherein R . . 3 . . 4 . . is amino group; R is ?uorine atom; R is a ?uorine atom; Y is —CF=; Z is —CH=; W is -CR8= (wherein R8 is a chlorine atom, bromine atom or a methyl group), and e in formula (a) is 3.

(CH2)eVN— In other embodiments, the present ion relates to a method, composition, or use wherein said one carboxylic acid corresponds to the compound (A): (A) 9 or a pharmaceutically acceptable salt, ester, or prodrug thereof. This foregoing quinolone carboxylic acid derivative, compound (A), is also known by the USAN, dela?oxacin, the publicly disclosed code names RX-334l, ABT-492 and WQ 3034, and also by, inter alia, the chemical name l-(6-amino-3 ,5-di?uoropyridinyl)chloro?uoro-l ,4-dihydro(3 - hydroxy-l-azetidinyl)oxoquinolinecarboxylic acid or l-(6-amino-3,5-di?uoro pyridinyl)chloro?uoro- l ,4-dihydro(3 xyazetidin- l -yl)oxo-3 - quinolinecarboxylic acid. This carboxylic acid form of the compound ponds to the CAS Registry Number 1892791. Furthermore, the l-deoxy-l-(methylamino)-D-glucitol salt of this compound, also known as D-glucitol, l- deoxy- l -(methylamino)-, l-(6-amino-3 ,5-di?uoropyridinyl)chloro?uoro- l ,4- dihydro(3-hydroxy-l-azetidinyl)oxoquinolinecarboxylate and the trihydrate of the l-deoxy-l-(methylamino)-D-glucitol salt of this compound, also known as D-glucitol, l- deoxy(methylamino)-, 1-(6-amino-3 ,5-di?uoropyridinyl)chloro?uoro- 1 ,4- dihydro(3-hydroxyazetidinyl)oxoquinolinecarboxylate rate. The 1-deoxy- 1-(methylamino)-D-glucitol salt and the y(methylamino)-D-glucitol salt trihydrate pond to the CAS Registry Numbers 35245 88 and 8831050, respectively. 1- Deoxy(methylamino)-D-glucitol corresponds to the CAS Registry Number 0-8. 1- Deoxy(methylamino)-D-glucitol is also known by the name meglumine. D-glucitol, 1- deoxy(methylamino)-, mino-3 ,5-di?uoropyridinyl)chloro?uoro- 1 ,4- dihydro(3-hydroxyazetidinyl)oxoquinolinecarboxylate, which is the meglumine salt of dela?oxacin, is also known as dela?oxacin meglumine. D-glucitol, 1-deoxy (methylamino)-, 1-(6-amino-3 ,5-di?uoropyridinyl)chlorofluoro- 1 ,4-dihydro(3 - hydroxy-l-azetidinyl)oxoquinolinecarboxylate trihydrate, which is the trihydrate of the meglumine salt of dela?oxacin, is also known as dela?oxacin meglumine trihydrate. WO 2006/042034 also discloses a crystalline form of the 1-deoxy(methylamino)-D-glucitol salt characterized when measured at about 25 0C with Cu-Ku radiation, by the X-ray powder diffraction pattern disclosed therein and a crystalline form of the 1-deoxy(methylamino)- D-glucitol salt trihydrate when measured at about 25 0C with Cu-Ku Cu-Kuradiation, by the X-ray powder diffraction pattern shown in (see WO 42034, which is hereby incorporated by reference in its entirety). These 1-deoxy(methylamino)-D-glucitol salts are useful in the present invention. Also, see A.R. Haight et al. "Synthesis of the Quinolone ABT-492: Crystallizations for Optimal Processing", Organic Process Research & Development (2006), 10(4), 751-756, which is hereby incorporated by reference in its entirety. onally other pharmaceutically acceptable salts of the forgoing compound, dela?oxacin, include the potassium salt and the tris salt. Tris is a common abbreviation for ydroxymethyl)aminomethane, which is known by the IUPAC name 2-Amino hydroxymethyl-propane- 1 ,3 -diol.

In some embodiments, the quinolone carboxylic acid derivative comprises from about 0.01% to about 50% by weight of the composition. In further ments, the quinolone carboxylic acid tive comprises from about 0.25% to about 20% by weight of the composition. In yet further embodiments, the quinolone carboxylic acid derivative comprises from about 0.5% to about 10% by weight of the composition. In yet further ments, the quinolone ylic acid derivative comprises from about 1% to about % by weight of the composition. The weight percentage of the quinolone carboxylic acid tive is determined on an active weight basis of the parent compound. In other words, appropriate adjustments and ations well known to one of ordinary skill in the art can be readily performed to determine the active weight basis. As a non-limiting example, if the parent free carboxylic acid of dela?oxacin, z'.e. l-(6-amino-3,5-di?uoropyridinyl) chloro?uoro- l ydro(3-hydroxy- l -azetidinyl)oxo-3 -quinolinecarboxylic acid, is used, its weight would have to be adjusted if a salt such as the sodium salt were to be used, because the molecular weight of the compound would increase by about 21.9, although the amount of active compound delivered is the same.

In some embodiments, the quinolone carboxylic acid derivative is present in the pharmaceutical compositions described herein in the amount of from about 0.1 mg to about 1500 mg. In some embodiments, the quinolone carboxylic acid tive is present in the pharmaceutical compositions described herein in the amount of from about 100 mg to about 750 mg. In some embodiments, the one carboxylic acid derivative is t in the pharmaceutical compositions described herein in the amount of from about 250 to about 500 mg. In some embodiments, the quinolone carboxylic acid tive is present in the pharmaceutical compositions described herein in the amount of about 300 mg. In some embodiments, the quinolone ylic acid derivative is present in the pharmaceutical compositions described herein in the amount of about 400 mg. In some embodiments, the one carboxylic acid derivative is t in the ceutical compositions described herein in the amount of about 450 mg. In some embodiments, the quinolone carboxylic acid derivative is present in the pharmaceutical compositions described herein in the amount of from about 0.1 to about 10 mg, from about 10 mg to about 20 mg, from about 20 mg to about 501ng,?on1about501ngtoabout1001ng,?on1about1001ngtoabout2001ng,?oniabout 2001ngtoabout5001ng,?on1about5001ngtoabout10001ngor?oniabout10001ngto about 1500 mg. In some embodiments, the quinolone carboxylic acid derivative is present in the pharmaceutical compositions described herein in the amount of about 5 mg, about 10 mg, aboutlSrng,about201ng,about251ng,about501ng,about75rng,about1001ng,about125 rng,about1501ng,aboutl751ng,about2001ng,about225rng,about2501ng,about2751ng, about3001ng,about3251ng,about3501ng,about3751ng,about4001ng,about4251ng, about4501ng,about475rng,about5001ng,about5251ng,about5501ng,about5751ng, about6001ng,about625rng,about6501ng,about675rngabout7001ng,about7251ng, about7501ng,about775rng,about8001ng,about8251ng,about8501ng,about8751ng, about9001ng,about925rng,about9501ng,about9751ng,about10001ng,about10251ng, about1050,rng,about10751ng,aboutllOOrng,aboutllZSrng,about11501ng,aboutll75 rng,about12001ng,about12251ng,about12501ng,about12751ng,aboutl3001ng,about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, or about 1500 mg.

The dose of the pharmaceutical active and mode of administration of the pharmaceutical composition will depend upon the intended patient or subject and the targeted microorganism, e.g., the target bacterial organism.

As further described below, it is often ageous to mill the pharmaceutical active to a small and uniform le size, y in the micron range, z'.e. micronization. g can be performed using standard techniques well known to one of ordinary skill in the art. In one embodiment, useful particle size ranges for the pharmaceutical active are generally from about 0.01 microns to about 100 microns. In another embodiment, useful particle size ranges for the ceutical active are from about 0.1 microns to about 20 microns. In another embodiment, useful particle size ranges for the ceutical active are from about 0.5 microns to about 5 microns. b. E?ervescent Agent(s) The compositions of the present invention comprise an effervescent agent. A wide variety of effervescent agents can be employed. Without being limited by theory, it is postulated that the effervescent agent can in certain instances help to drive the antimicrobial compound from the stomach into small intestine, and therefore into the blood stratum. Part of the reason for this is that in the highly acid environment of the h, the effervescent agent, which is typically the salt of a basic material or the mixture of a salt of a basic material and an acidic material or its salt, can react with the stomach acid to generate carbon dioxide bubbles, z'.e. effervescence, which in turn can aid in tablet disintegration and nt or absorption of the antimicrobial agent from the stomach into the bloodstream. The net effect is believed to reduce the amount of free antimicrobial compound in the gastrointestinal tract, thus reducing the potential for undesirable gastrointestinal side effects or contributing to the pment of antibiotic resistance.

The effervescent agent lly ses one or more alkaline materials or salts of alkaline als. Nonlimiting examples of effervescent agents include compositions comprising one or more of sodium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, ium carbonate, potassium bicarbonate, potassium hydrogen phosphate, potassium dihydrogen phosphate, potassium hydroxide, magnesium carbonate, magnesium hydroxide, ium oxide, calcium carbonate, calcium oxide.

It is further found that certain acidic materials, or salts f, can be combined with the alkaline material of the effervescent agent. These acidic materials and salts thereof e, citric acid, sodium citrate, potassium citrate, maleic acid, maleic anhydride, sodium malate, potassium malate, tartaric acid, sodium tartrate, potassium tartrate, fumaric acid, sodium fumarate, potassium fumarate, ascorbic acid, sodium ascorbate, potassium ascorbate, and mixtures thereof.

In some embodiments, the invention relates to a pharmaceutical composition wherein said effervescent agent comprises sodium onate, sodium dihydrogen phosphate, and citric acid.

In some embodiments, the invention relates to a pharmaceutical composition wherein said effervescent agent comprises sodium bicarbonate and sodium dihydrogen In some embodiments, the ion relates to a pharmaceutical composition wherein said effervescent agent comprises sodium bicarbonate, sodium dihydrogen phosphate monohydrate (also known as sodium phosphate monobasic monohydrate), and anhydrous citric acid.

In some embodiments, the invention relates to a pharmaceutical composition wherein said effervescent agent comprises sodium bicarbonate and sodium dihydrogen phosphate monohydrate.

In some embodiments, the effervescent agent is present in the pharmaceutical compositions described herein in the amount from about 0.1 to about 1500 mg. In some embodiments, the effervescent agent is t in the pharmaceutical compositions described herein in the amount from about 100 mg to about 750 mg. In some embodiments, the escent agent is present in the pharmaceutical compositions bed herein in the amount from about 250 mg to about 500 mg. In some ments, the effervescent agent is present in the pharmaceutical compositions described herein in the amount from about 0.1 to about 10 mg, from about 10 mg to about 20 mg, from about 20 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 500 mg, from about 500 mg to about 1000 mg or from about 1000 mg to about 1500 mg. In some ments, the escent agent is present in the pharmaceutical compositions described herein in the amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050, mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, and about 1500 mg. 0. Water In one embodiment, the compositions of the t invention comprise from about 0.1 % to about 99.9% water, in ?arther embodiments from about 1% to about 99% water, in yet r ments from about 5% to about 95% water, and in yet further ments from about 10% to about 90% water. In de?ning a composition, the amount of water can be designated as "q.s." or "Q.S.", which means as much as suf?ces, to provide a ?nal composition or volume of 100%. d. Sugars and Sugar Alcohols The compositions of the present invention, when further made into a lyophile, can further comprise a sugar, a sugar alcohol, or mixtures thereof. Without being limited by theory, these sugars and sugar alcohols are believed to aid in the formation of the lyophile during the lyophilization process. Typically, the lyophile is made by drying the ition under appropriate conditions, such as, for e, by freeze drying. Non-limiting examples of sugars e mannose, sucrose, dextrose, and mixtures thereof. Non-limiting examples of sugar alcohols useful herein include sorbitol, ol, xylitol and mixtures thereof.

In one embodiment, the compositions comprise from about 0.1% to about 50% of a sugar or sugar alcohol. e. Polyhydroxy Amine Compound In one embodiment, the compositions of the present invention comprise a polyhydroxy amine compound. The polyhydroxy amine compound is separate from and does not encompass the polyhydroxy compound of the compositions of the present invention. The polyhydroxy amine compound is generally a C3-C8 ht, branched, or cyclic compound having 2 or more hydroxy substituents, and at least one amine (either substituted or unsubstituted) substituent.

In further embodiments the droxy amine compound is meglumine.

Meglumine corresponds to CAS Registry Number 62848 and is also known as ine, USP; l-Deoxy-l-(methylamino)-D-glucitol; yl-D-glucamine; ol, ldeoxy- l ylamino)-, D- (8C1); Sorbitol, l-deoxy- l -methylamino- (6C1); l-Deoxy- l - (methylamino)-D-glucitol; l -Deoxy- l -methylaminosorbitol; D-(-)-N-Methylglucamine; Meglumin; Methylglucamin; Methylglucamine; N-Methyl-D(-)-glucamine; yl-D- glucamine; N-Methylglucamine; N-Methylsorbitylamine; NSC 52907; NSC 7391. It also has the CA Index Name D-Glucitol, l-deoxy-l-(methylamino)- (9C1). A chemical formula for meglumine is as follows: H OH MeNH/\l OH S R/\/ R R OH OH In one embodiment, the polyhydroxy amine compound comprises from about 0.1% to about 50% by weight of the composition. In further embodiments, the polyhydroxy amine nd comprises from about 0.25% to about 20% by weight of the composition.

In yet ?arther embodiments, the polyhydroxy amine compound ses from about 0.5% to about 10% by weight of the composition. In yet further embodiments, the polyhydroxy amine compound comprises from about 1% to about 5% by weight of the composition. 1? Chelating Agents The compositions of the present invention can ?arther comprise a chelating agent.

It is to be understood that this chelating agent is de?ned herein as being separate from and does not include the already described escent agent, which can also have chelating properties. The ing agent is also defined herein as excluding the cyclodextrin, the polyhydroxy amine compound, or any of the other components described herein, even though the cyclodextrin, the polyhydroxy amine compound, or other components described herein can also have chelating properties. An example of a chelating agent useful herein is EDTA, also known as ethylenediaminetetraacetic acid, or a salt thereof. Useful salts include, for example, a sodium salt, a potassium salt, a calcium salt, a ium salt, and mixtures of these salts. An example of a mixture of salts or a mixed salt is the monosodium monocalcium salt of EDTA. It is found that the um salt of EDTA, also known as disodium EDTA, is useful herein. For convenience, the disodium EDTA can ?rst be separately prepared as an aqueous solution for use in formulating the compositions of the present invention.

In one embodiment, the disodium EDTA comprises from about 0.0010% to about 0.10% by weight of the composition. In further embodiments, the um EDTA comprises from about 0.0050% to about 0.050% by weight of the composition. In yet r embodiments, the um EDTA comprises from about 0.010% to about 0.020% by weight of the composition. In other embodiments the disodium EDTA comprises about 0.010% of the composition, or about 0.011% of the composition, or about 0.012% of the composition, or about 0.013% of the composition, or about 0.014% of the composition, or about 0.015% of the ition, or about 0.016% of the composition, or about 0.017% of the ition, or about 0.018% of the composition, or about 0.019% of the composition, or about 0.020% of the composition. These weight percentages of the um EDTA described herein are on the basis of the ethylenediaminetetraacetic acid. g. pHModi?ers andpH ofthe Compositions The compositions of the present invention can ?lrther comprise various als for modifying or adjusting the pH of the ition. Such materials include acids, bases, buffer systems, etc. Non-limiting examples of such pH modi?ers include, for example, hydrochloric acid and sodium hydroxide. Examples of other useful materials include triethanolamine, sodium carbonate, and lysine. Furthermore, the polyhydroxy amine compound, such as described above, can be used as a pH modi?er. More speci?cally, the polyhydroxy amine compound, meglumine, can be used as a pH modi?er. In some ments, the pH modi?er is present in the composition in an amount of 1-5 mg, 5-50 mg, 50-100 mg, 100-200 mg, or 0 mg.

The compositions of the present invention should have a pH so that the composition is suitable for administration to a patient or subject. The compositions have a pH from about pH 7 to about pH 11. In further embodiments, the compositions have a pH from about pH 8 to about pH 10. In further embodiments, the compositions have a pH from about pH 8.5 to about pH 9.5. In further embodiments, the itions have a pH from about pH 8.8 to about pH 9.2. In further embodiments, the compositions have a pH of about h. Additional Components Pharmaceutical itions of the present invention se an effective amount of a quinolone carboxylic acid derivative or a pharmaceutically acceptable salt thereof and an effervescent agent, or one or more additional agents dissolved or dispersed in a pharmaceutically acceptable carrier. The phrases "pharmaceutical or pharmacologically acceptable" refers to molecular entities and compositions that do not e an adverse, ic or other rd reaction when administered to an animal, such as, for example, a human, as appropriate. The preparation of a pharmaceutical composition that contains an effective amount of a quinolone carboxylic acid derivative or a pharmaceutically acceptable salt thereof and an effervescent agent will be known to those of skill in the art in light of the present disclosure, as exempli?ed by Remington 's Pharmaceutical Sciences, 18th ed. Mack Printing Company, 1990, incorporated herein by nce. Moreover, for animal (e.g. , human) stration, it will be understood that preparations should meet sterility, pyrogenicity, general safety and purity standards as required by Food and Drug Administration’s Office of Biological Standards.

The compositions of the present invention can ?arther comprise one or more additional components ed from a wide variety of excipients known in the ceutical formulation art. ing to the desired properties of the tablet or capsule, any number of ingredients can be selected, alone or in combination, based upon their known uses in ing the compositions of the present invention. As used herein, "pharmaceutically able carrier" includes any and all solvents, sion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, ?avoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington 's Pharmaceutical Sciences, 18th ed. Mack Printing Company, 1990, pp. 1289 1329, incorporated herein by reference). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. Such ingredients include, but are not limited to solvents (e.g, ethanol), dispersion media, coatings (e.g., enteric rs), isotonic agents, absorption delaying , salts, drugs, drug stabilizers, gels, plasticizers, binders, excipients, disintegration agents, lubricants, sweetening agents, ?avoring agents, dyes, colorants; waxes, gelatin; preservatives (e.g., antibacterial agents and antifungal agents such as methyl paraben, sodium benzoate, and potassium benzoate); antioxidants (e.g., butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E and vitamin E esters such as tocopherol acetate); surfactants; UV-absorbers, such like materials and combinations thereof. Exemplary cellulose ethers include hydroxyalkyl celluloses and carboxyalkyl celluloses. Exemplary ose ethers include yethyl celluloses, hydroxypropyl celluloses, hydroxypropylmethyl-celluloses, y methylcelluloses, and mixtures thereof.

Any of the excipients can be present in the formulation in an amount of about 0 mg to about 1500 mg. In some ments, an excipient is present in the formulation in an amount of about 0 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 200 mg to about 500 mg, about 500 mg to about 800 mg, about 800 mg to about 1000 mg or about 1000 mg to about 1500 mg.

In some embodiments, microcrystalline ose is present in the formulation in an amount of about 0 mg to about 200 mg or about 200 mg to about 500 mg.

In some embodiments, water is present in the formulation in an amount of about 0 mg to about 500 mg.

In some embodiments, a binder is present in the formulation in an amount of about 0 mg to about 100 mg or about 0 to about 200 mg.

In some embodiments, a disintegrant is present in the formulation in an amount of about 0 mg to about 100 mg or about 0 mg to about 200 mg.

In some embodiments, a film coating is present in a tablet in an amount of about 0 mg to about 20 mg or about 0 mg to about 200 mg.

In some embodiments, a lubricant is present in the formulation in an amount of about 0.1 mg to about 20 mg. In further ments, a lubricant is present in the formulation in an amount of about 0.5 mg to about 10 mg.

In some ments, an c coating is present in a tablet in an amount of about 0 mg to about 20 mg or about 0 mg to about 200 mg.

In some ments, a plasticizer is present in a tablet in an amount of about 1 mg to about 30 mg.

In one embodiment, the itions of the present invention comprise a carrier.

The carrier can be a dextrose solution or saline, at a pharmaceutically acceptable concentration. The composition comprising a carrier can be administered to a patient via an iv. bag. 3. Processing The compositions of the present invention are made using conventional equipment and mixing techniques, such as dry granulation or wet granulation. Examples of techniques used to make the compositions described herein are provided in Remington’s Pharmaceutical Sciences, 17th edition, 1985, Editor: Alfonso R. Gennaro, Mack Publishing Company, Easton, PA 18042, which is incorporated by nce herein. 4. Gastrointestinal bility The compositions of the present invention have improved gastrointestinal tolerability. Also, the compositions of the present invention reduce the potential for gastrointestinal side s. Non-limiting gastrointestinal side effects e diarrhea, ?atulence, nausea, vomiting, abdominal pain, dyspepsia, belching, bloating, gastritis, and general abdominal discomfort. The gastrointestinal tolerability of the compositions of the present invention can be evaluated using various models as described in the Examples below.

. Doses and Methods of Treating, Preventing, or Reducing the Risk of Infections In some embodiments, the itions disclosed herein are useful in treating microbial infections (e.g. bacterial infections).

The itions of the present invention are useful for treating, preventing or reducing the risk of a ial infection, e.g, a skin infection, a skin and skin ure infections such as a complicated skin and skin structure ion (cSSSI), an uncomplicated skin and skin structure ion (uSSSI) and an acute bacterial skin and skin structure infection (ABSSSI), pneumonia and other respiratory tract infections such as a community respiratory-tract infection, a nosocomial (hospital-acquired) pneumonia, a community acquired pneumonia, a hospital acquired community pneumonia and a post-viral pneumonia, an abdominal ion, a y tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, itis, an infection due to surgical or invasive medical procedures, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus (MRSA) infection, a vancomycin- resistant Enterococcz' infection, a linezolid-resistant organism infection, tuberculosis, a one resistant Gram-positive infection, a cipro?oxacin ant methicillin resistant (MRSA) infection, bronchitis, uncomplicated gonorrhea, and a multi-drug resistant (MDR) Gram-negative ion.

The dose of active nd and mode of administration, e.g, ion, intravenous drip, etc. will depend upon the intended patient or subject and the ed microorganism, e.g., the target bacterial organism. Dosing strategies are sed in LS.

Goodman, et al., The Pharmacological Basis ofTherapeutics, 201-26 (5th ed. 1975), the entire contents of which are herein incorporated in its entirety.

Compositions can be formulated in unit dosage form for ease of administration and mity of . Unit dosage form refers to ally discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The speci?cation for the unit dosage forms of the invention are dictated by and ly dependent on the unique characteristics of the active compound and the therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

Compositions of the present ion are made in the form of a dry mixture, an aqueous on, an aqueous suspension, a non-aqueous solution, a non-aqueous suspension, or an emulsion. The pharmaceutical compositions are made in unit dosage forms, which may further be in the form of a tablet or a capsule. The tablet may be a bilayer tablet comprising more than one layer. In one embodiment, the bilayer tablet comprises a ?rst and a second layer. In some embodiments, the ?rst layer comprises the one carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof and the second layer comprises the aluminum compound. In some embodiments, the second layer in the bilayer tablet is a delayed or sustained or controlled release layer, wherein the second layer is released in the gastrointestinal tract ream from the stomach. Alternatively, the quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof and the aluminum compound are administered as separate unit dosage forms. In some embodiments, when the quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof and the um compound are administered as separate unit dosage forms, the quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof is administered first and the aluminum compound is administered second and within two hours of the quinolone carboxylic acid derivative. In yet other embodiments, the quinolone carboxylic acid derivative or a pharmaceutically acceptable salt or ester and the aluminum compound are concurrently administered as te unit dosage forms.

In conjunction with the methods of the present invention, pharmacogenomics (1.6. the study of the relationship between an individual’s genotype and that dual’s response to a foreign compound or drug) can be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation n dose and blood concentration of the cologically active drug. Thus, a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics s in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of ent with the drug.

Generally, an ive amount of dosage of active compound will be in the range of from about 0.1 to about 100 mg/kg of body weight/day. In one embodiment, the amount will be from about 1.0 to about 50 mg/kg of body weight/day. The amount administered will also likely depend on such variables as the overall health status of the t, the relative biological efficacy of the compound delivered, the formulation of the drug, the presence and types of excipients in the formulation, the route of administration, and the infection to be me¢pmwmm¢ormmmmgme?$ofz?w??smbemmmwmdmm?mnmmhmmge administered can be increased beyond the above upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage can be smaller than the optimum.

In some embodiments, the compositions disclosed herein comprise a dose of active compound of from about 0.1 to about 1500 mg per dose. In some embodiments, the compositions disclosed herein comprise a dose of active compound of about 100 mg to about 750 mg per dose. In some embodiments, the compositions disclosed herein comprise a dose of active compound of about 250 mg to about 500 mg per dose. In some embodiments, the compositions disclosed herein comprise a dose of active compound of about 300 mg per dose. In some ments, the itions disclosed herein comprise a dose of active compound of about 400 mg per dose. In some embodiments, the compositions disclosed herein comprise a dose of active compound of about 450 mg per dose. In some embodiments, the compositions disclosed herein comprise a dose of active compound of about 0.1 to about 10 mg per dose, about 10 mg to about 20 mg per dose, about 20 mg to Orngperdose,aboutSOIngtoaboutlOOrngperdose,aboutlOOrngtoaboutZOOrng perdose,about2001ngtoabout500rngperdoggaboutSOOrngtoaboutlOOOrngperdose or about 1000 mg to about 1500 mg per dose. Non-limiting examples of doses, which can be formulated as a unit dose for convenient administration to a patient include: about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050, mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, and about 1500 mg. The ing doses are useful for administering the nds of the present invention according to the methods of the present invention. The foregoing doses are particularly useful for administering the quinolone carboxylic acid derivatives of the present invention, ularly the compound known by the name dela?oxacin and pharmaceutically acceptable salts, esters and prodrugs thereof.

As is understood by one of ordinary skill in the art, generally, when dosages are described for a pharmaceutical active, the dosage is given on the basis of the parent or active . Therefore, if a salt, hydrate, or another form of the parent or active moiety is used, a corresponding adjustment in the weight of the nd is made, although the dose is still referred to on the basis of the parent or active moiety delivered. As a non-limiting example, if the parent or active moiety of st is a monocarboxylic acid having a molecular weight of 250, and if the monosodium salt of the acid is desired to be delivered to be delivered at the same dosage, then an adjustment is made recognizing that the monosodium salt would have a molecular weight of approximately 272 (z'.e. minus 1H or 1.008 atomic mass units and plus 1 Na or 22.99 atomic mass units). Therefore, a 250 mg dosage of the parent or active compound would pond to about 272 mg of the monosodium salt, which would also deliver 250 mg of the parent or active compound. Said another way, about 272 mg of the monosodium salt would be lent to a 250 mg dosage of the parent or active compound.

In one embodiment, compositions of the invention is useful in the manufacture of a medicament for treating, preventing or reducing the risk of infection in a patient in need thereof. In another embodiment, dela?oxacin, or a pharmaceutically acceptable salt thereof, is useful in the manufacture of a medicament for treating, preventing or reducing the risk of infection in a t in need thereof. Such infections can be due to, e.g., a skin infection, a skin and skin structure infections such as a complicated skin and skin structure infection (cSSSI), an uncomplicated skin and skin structure infection (uSSSI) and an acute bacterial skin and skin structure infection (ABSSSI), pneumonia and other respiratory tract infections such as a community respiratory-tract infection, a nosocomial (hospital-acquired) pneumonia, a community acquired pneumonia, a hospital ed community pneumonia and a post- viral pneumonia, an abdominal infection, a urinary tract ion, bacteremia, emia, endocarditis, an ventricular shunt infection, a ar access infection, meningitis, an infection due to surgical or invasive l procedures, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus (MRSA) infection, a vancomycin-resistant Enterococcz' infection, a linezolid-resistant organism infection, tuberculosis, a quinolone resistant Gram-positive ion, a cipro?oxacin resistant methicillin resistant (MRSA) infection, bronchitis, licated gonorrhea, and a multi- drug resistant (MDR) Gram-negative infection.

In some embodiments, the pharmaceutical composition comprises: from about 0.01% to about 80 % by weight of a quinolone carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; and from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the composition.

In some embodiments, the pharmaceutical composition comprises: from about 1% to about 60 % by weight of a quinolone carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; and from about 0.1% to about 50% by weight of an effervescent agent, as ed to the total weight of the composition.

In some embodiments, the pharmaceutical composition comprises: from about % to about 50 % by weight of a quinolone ylic acid derivative, or a pharmaceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; and from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the composition.

In some embodiments the pharmaceutical composition comprising: from about 0.01% to about 80% by weight of a quinolone carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; from about 0.1% to about 50% by weight of ine, as compared to the total weight of the composition; and from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the composition.

In some embodiments the pharmaceutical composition comprising: from about 0.01% to about 80% by weight of a quinolone carboxylic acid derivative, or a ceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; from about 1% to about 40% by weight of meglumine, as compared to the total weight of the composition; and from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the composition.

In some embodiments the pharmaceutical composition comprising: from about 0.01% to about 80% by weight of a quinolone carboxylic acid derivative, or a ceutically acceptable salt thereof, as ed to the total weight of the composition on an acid basis; from about 10% to about 30% by weight of meglumine, as compared to the total weight of the composition; and from about 0.1% to about 50% by weight of an effervescent agent, as compared to the total weight of the composition.

Using dela?oxacin as a non-limiting example, in some ments, an example of a composition useful in the methods of the present ion contains about 300 mg of dela?oxacin, or a pharmaceutically acceptable salt thereof. In ?arther embodiments, an example of a composition useful in the s of the present invention contains about 400 mg of dela?oxacin, or a pharmaceutically acceptable salt thereof. In ?arther embodiments, an example of a composition useful in the methods of the present invention contains about 450 mg of dela?oxacin, or a pharmaceutically acceptable salt thereof. 6. Examples The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations f are possible without departing from the spirit and scope of the ion.

Ingredients are identified by chemical, USP, or CTFA name.

The following formulations are preparing using mixing ques and equipment familiar to one of ordinary skill in the art.

The disclosed formulations are useful for oral administration to a patient for treating, ting, or reducing the risk of a microbial infection, e.g., a skin infection, a skin and skin structure infections such as a complicated skin and skin structure ion (cSSSI), an uncomplicated skin and skin structure infection (uSSSI) and an acute bacterial skin and skin structure infection (ABSSSI), pneumonia and other respiratory tract infections such as a community respiratory-tract infection, a nosocomial (hospital-acquired) pneumonia, a community acquired pneumonia, a hospital acquired ity pneumonia and a post-viral pneumonia, an abdominal ion, a urinary tract infection, bacteremia, septicemia, rditis, an atrio-ventricular shunt infection, a vascular access infection, meningitis, an infection due to surgical or ve medical procedures, a peritoneal infection, a bone infection, a joint infection, a illin-resistant Staphylococcus aureus (MRSA) infection, a vancomycin-resistant Enterococcz' infection, a lid-resistant organism infection, tuberculosis, a quinolone resistant Gram-positive infection, a cipro?oxacin resistant methicillin resistant (MRSA) infection, bronchitis, uncomplicated gonorrhea, and a multi- drug resistant (MDR) Gram-negative infection. More specifically, the disclosed formulations are useful for reducing the risk of or preventing infection due to a surgical or invasive medical procedure to be performed upon the patient, and in such case, the ation can be administered just prior to or up to about 1 hour prior to the surgical or ve medical procedure.

EXAMPLE 1 The following is a sample formulation comprising the combination of dela?oxacin and an effervescent agent. The r tablet of this example was made using standard formulation and tableting techniques. Table 1 provides a Quantitative Composition of 400 mg xacin Bilayer Tablet.

TABLE 1 Drug Layer, Intra-granular (Wet Granulation) _- Dela?oxacin (Megluniine salt)(1) 577.2 41.23 Water, USP (4) (Up to 100.) Magnesium stearate, NF "m Buffering Layer, Extra-granular _- Magnesium stearate, NF 0.086 Total for Bilayer Tablet 1400 (1) Equivalent to 400 mg free acid (based on 69.3% salt conversion). The actual values may vary slightly depending on the purity and e solvent content from the certi?cate of analysis (CoA). (2) The exact amount will be adjusted based on the purity ofAPI. (3) For binder solution (PVP solution) preparation, and granulation. Removed during drying process. (4) Maximum additional water for granulation, removed during drying process.

Table 2 provides a simpli?ed Quantitative Composition of 400 mg Dela?oxacin Bilayer Tablet, showing total s of each ingredient (z'. e. where the ents are not separated by granulation or layer).

TABLE 2 Dela?oxacin (Meglumine 1) 577.2 41 .23 Sodium phosphate monobasic, monohydrate, USP Citric acid, Anhydrous, powder, USP Magnesium te, NF (1) Equivalent to 400 mg free acid (based on 69.3% salt sion). The actual values may vary slightly depending on the purity and residue solvent content from the certi?cate of analysis (CoA). (2) The exact amount will be adjusted based on the purity ofAPI.

The foregoing composition is useful for oral administration to a patient for treating, preventing, or reducing the risk of a microbial infection.

EXAMPLE 2 The following is a sample formulation sing the combination of dela?oxacin and an effervescent agent. The single layer tablet of this example was made using standard formulation and tableting techniques. Table 3 provides a Quantitative Composition of 400 mg Dela?oxacin Single Layer Tablet.

TABLE 3 Dela?oxacin (Meglurnine salt)(1) 577.2 46.18 Water, USP (4) Final Tablet Weight 1250 (1) Equivalent to 400 mg free acid (based on 69.3% salt sion). The actual values may vary slightly depending on the purity and residue t content from the certi?cate of analysis (CoA). (2) The exact amount will be ed based on the purity ofAPI. (3) For binder solution (PVP solution) preparation and granulation. Removed during drying process. (4) Maximum additional water for ation, removed during drying process.

Table 4 provides a simpli?ed Quantitative Composition of 400 mg Dela?oxacin Single Layer , showing total amounts of each ient (1.6. where the components are not separated by granulation).

TABLE 4 Dela?oxacin (Meglumine salt)(1) 577.2 46.18 Sodium phosphate monobasic, monohydrate Citric acid, Anhydrous (1) The amount of dela?oxacin is based on a theoretical potency of 100% as free acid (based on 69.3% salt conversion). The exact amount may vary slightly depending on the purity and residue solvent content from the certi?cate of analysis (CoA). (2) The exact amount will be adjusted based on the purity ofAPI.

The foregoing composition is useful for oral administration to a patient for treating, preventing, or reducing the risk of a microbial infection.

EXAMPLE 3 The following is a sample formulation comprising the combination of dela?oxacin and an effervescent agent. The single layer tablet of this example was made using standard ation and tableting techniques. The 450 mg single layer tablet improves tablet dissolution and reduces overall tablet weight compared to a 400 mg bilayer tablet. Table 5 provides a tative Composition of 450 mg Dela?oxacin Single Layer Tablet.

TABLE 5 Ingredient (450 mg) Dela?oxacin mine salt)(1) 649.4 47.40 rystalline Cellulose, PH 101 121.0 Total extragranular FINAL TABLET 1370 (1) The amount of dela?oxacin is based on a theoretical potency of 100% as free acid (based on 69.3% salt conversion). The exact amount may vary slightly depending on the purity and residue solvent content from the certi?cate of analysis (CoA). (2) The exact amount of microcrystalline cellulose will be adjusted based on the purity of (3) For binder solution preparation, and granulation. Removed during drying process. (4) Target additional water for granulation, ?nal amount depending on granulation end point with upper limit of 100 mg. This water is removed during drying process.

Table 6 provides a simpli?ed Quantitative Composition of 450 mg Dela?oxacin Single Layer Tablet, showing total amounts of each ingredient (lie. where the ents are not separated by granulation).

TABLE 6 xacin (Meglumine salt)(1) 649.4 47.40 Sodium phosphate monobasic, monohydrate Citric acid, Anhydrous (1) The amount of dela?oxacin is based on a theoretical potency of 100% as free acid (based on 69.3% salt conversion). The exact amount may vary slightly depending on the purity and e solvent content from the cate of analysis (CoA). (2) The exact amount of microcrystalline cellulose will be adjusted based on the purity of The foregoing composition is useful for oral administration to a patient for treating, preventing, or reducing the risk of a microbial infection. In ular, this composition was sful at achieving an AUC nearly identical to that of a 300 mg intravenous formulation of dela?oxacin meglumine. Notably, this composition includes an increased drug content as compared with the Bilayer Tablet composition of Example 1, but with reduced tablet weight.

EXAMPLE 4 The results of a dissolution study performed by utilizing USP dissolution tus 2 at a paddle speed of 50 rpm, in 900 mL of SOmM Sodium Phosphate Buffer with mM hexadecyltrimethylammonium bromide (HTAB), pH 6.8 as dissolution medium are shown in The testing temperature was 37.0 :: 0.5 0C. The samples were pulled at 7.5, , 30, 45, 60 minutes and every additional 15 minutes to in?nity at a higher paddle speed of 250 rpm. Samples were ed by HPLC and the amount of drug released were ed and calculated against the label d dose. Speci?cally, compares the dissolution of the 450 mg Dela?oxacin Single Layer Tablet as described in Example 3, a capsule containing 400 mg dela?oxacin meglumine, the 400 mg Dela?oxacin Single Layer Tablet as described in Example 2, and the 400 mg Dela?oxacin Bilayer Tablet as described in Example The compositions disclosed herein exhibited a comparable dissolution pro?le as compared to a formulation of dela?oxacin ine in a e, as shown in Table 7.

Speci?cally, the 400 mg Dela?oxacin Bilayer Tablet disclosed in Example 1 and the 400 mg Dela?oxacin Single Layer Tablet disclosed in Example 2 exhibited satisfactory dissolution pro?le as compared to the dela?oxacin API in a capsule, while the 450 mg xacin Single Layer Tablet disclosed in Example 3 exhibited an improved dissolution pro?le (based on amount dissolved) as compared to the xacin API in a capsule. Importantly, the compositions disclosed herein dissolve much more quickly than traditional tablets, which is the ?rst step for absorption of the API into the intestine.

TABLE 7 Dissolution Pro?le of Dela?oxacin Tablets API in capsule, Bilayer tablets, Single layer Single layer Time (min) 400 mg 400 mg tablets, 400 mg s, 450 mg _ % dissolved (% to label claim) "nun- "mu—n _ Amount Dissolved, mg "nun- "____ Clinical 24.3 17.6 18.0 24.0 exposure (AUC) EXAMPLE 5 Compositions of the present invention were evaluated in a nical animal study. administered to mini-pigs in a preclinical animal study. The test ations were formulated as dosing solutions for oral administration gavage to non-naive male Géttingen mini-pigs, approximately four months old and weighing 10-128 kilograms at the outset of the study. Group Assignments and dose levels are provided in Table 8.

TABLE 8 Dela?oxacin Dela?oxacin Number of . Meglumine Meglumlne Salt Animals Salt Dose Concentration (mg/kg/day) (mg/mL) (mL/kg) (mL/kg) 2. Dela?oxacin meglumine salt 3. Dela?oxacin . meglumine salt tablet/day + effervescence* *Group 3 animals received 1 escence tablet immediately after the test article formulation Animals in Groups 1 and 2 were dosed once daily with vehicle l or dela?oxacin meglumine salt for seven consecutive days. Animals in Group 3 were given dela?oxacin meglumine salt, followed by the effervescent treatment, daily for seven consecutive days. Mortality and clinical observations were evaluated daily and for thirteen days following completion of dosing. The s that received the combination of dela?oxacin ine salt and effervescence (lie. the effervescent agent) showed subtle ements in the severity, incidence, onset and resolution of abnormal fecal consistency.

For example, animals in Group 1 had loose feces during the dosing phase, whereas animals in Group 3 only exhibited soft feces, which is the least severe category of abnormal fecal consistency. There were dual animals in Group 3 that did not exhibit abnormal fecal consistency throughout the study. Following completion of dosing, abnormal fecal consistency resolved somewhat faster in Group 3 than in Group 2. Plasma exposure was consistent across the non-control groups.

EXAMPLE 6 Compositions of the t invention were administered to human ts in a clinical trial. The subjects were administered bilayer tablets, see Example 1, above, containing dela?oxacin meglumine API (400 mg dela?oxacin per capsule on a free acid basis) and the effervescent agent.

The following dosing regimen was followed in this nine (9) day clinical trial. On days 1 and 2, the subjects were administered placebo twice daily (BID). On day 3, the subjects were administered the bilayer tablet. On days 4 through 9, the subjects were administered the bilayer tablet twice daily, twelve hours apart, under fasted conditions.

Various evaluations and assessments were made during the course of the study including drug blood levels for determining pharmacokinetic/pharmacodynamic (PK/PD) parameters, nce of ea (both self-reported and clinical assessment using the standard Bristol stool chart), and adverse event reporting.

In clinical trials, administration of dela?oxacin with an effervescent agent resulted in d side effects, as compared to administration of dela?oxacin in the absence of an escent agent, as shown in Table 9. Speci?cally, Table 9 shows improved properties for a bilayer tablet of dela?oxacin and an effervescent agent (1.6. Regimen C) as compared to compositions of dela?oxacin t an effervescent agent (z'.e. Regimen A, a e containing dela?oxacin meglumine, and Regimen B, a capsule containing dela?oxacin potassium).

The most frequently reported Treatment-Emergent Adverse Events (TEAEs) overall in this trial were classified as intestinal disorders (16.7%), with diarrhea the most commonly reported TEAE (11.7%), followed by abdominal pain (5.0%). The highest percentage of subjects who reported diarrhea received oral dela?oxacin meglumine salt capsules or oral dela?oxacin potassium salt capsules (15.0% each), with ts who received an oral dela?oxacin ine salt bilayer tablet reporting fewer incidences of diarrhea (5.0%). Abdominal pain, the second most commonly reported TEAE, was reported most by ts who received oral dela?oxacin potassium salt capsules (10.0%) followed by ts who ed an oral dela?oxacin meglumine salt bilayer tablet (5.0%).

TABLE 9 GI Adverse Events Reported by Two or More ts (Safety Population) Oral Dela?oxacin 400 mg Meglumine Potassium Meglumine Salt Salt Bilayer Tablet (A1) (C1) Overall Gastrointestinal disorders 5 (25.0%) 3 (15.0%) 2 (10.0%) 10 (16.7%) Diarrhea 3 (150%) 3 (150%) 1 (50%) 7 (117%) Abdominal Pain n 2 (100%) 1 (50%) 3 (50%) Nausea l (5.0%) l (l.7%) AUC(0-inf)(ug*hr/mL)2 ll6__24 178:5 n A: 400-mg dela?oxacin meglumine salt (4 X lOO-mg capsules) Regimen B: 400-mg dela?oxacin potassium salt (4 X 100-mg capsules) Regimen C: 400-mg dela?oxacin meglumine salt bilayer tablet (1 X 400-mg tablet) 2 Reported as a mean value.

Blood samples for the pharmacokinetic (PK) is of dela?oxacin were collected from each subject in all groups. Noncompartmental PK analysis was performed on the plasma tration data using Phoenix® WinNonlin® version 6.1 (Certara, St. Louis, Missouri). AUCs were calculated as mean plus or mius standard ion, rounded to the tenths, using the linear trapezoidal rule. TEAE are reported as frequency and percent of subjects that exhibited the TEAE.

The exposure (tie. AUC) and TEAE data shown in Table 9 further demonstrate the advantages of the compositions disclosed herein. For example, while Regimen C demonstrated about 30% less re as compared to Regimen A, patients receiving n C reported fewer GI side effects than those ing Regimen A. Because the dosage of dela?oxacin meglumine was the same in Regimens A and C, this means a larger percentage of the drug was present in the gut of patients receiving Regimen C as compared to Regimen A. A larger percentage of drug in the gut would be expected to result in a higher rate of TEAEs, but in this case the exact opposite was seen. These data evince the profound effect of the disclosed effervescent formulations at reducing GI adverse events. Additionally, Regimen B demonstrated approximately 35% less exposure than Regimen C, meaning patients receiving Regimen B had less drug in the gut as compared to n C. However, Regimen B actually results in increased side effects as compared to Regimen C. Again, these date show the profound and unexpected effect of the claimed effervescent formulations.

Without g to be bound by theory, the inventors postulate that air bubbles evolving as the compositions disclosed herein dissolve assist the drug es in g through the stomach into the intestine providing for a lower residence time in the patient’s stomach as compared to a tablet lacking an effervescent agent. This decreased residence time in the stomach is postulated to result in the surprisingly reduced GI side effects demonstrated by the compositions sed .

The ing compositions are useful for oral administration to a patient for treating, preventing, or reducing the risk of a microbial infection.

INCORPORATION BY REFERENCE The entire disclosure of each of the patent documents, ing certi?cates of correction, patent ation documents, scienti?c articles, governmental reports, websites, and other references referred to herein is incorporated by reference in its entirety for all purposes.

EQUIVALENTS The invention can be embodied in other specific forms t departing from the spirit or essential characteristics thereof The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein.

Claims (34)

1. A pharmaceutical composition comprising: (a) a one carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof; and (b) an effervescent agent comprising a e of sodium bicarbonate, sodium dihydrogen phosphate and citric acid; wherein said quinolone carboxylic acid derivative corresponds to the following compound (A) F COOH N N HO Cl F or a pharmaceutically acceptable salt or ester thereof.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of said quinolone carboxylic acid derivative is D-glucitol, 1-deoxy(methylamino)-,1- (6-amino-3,5-difluoropyridinyl)chlorofluoro-1,4-dihydro(3-hydroxy azetidinyl)oxoquinolinecarboxylate.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable salt of said quinolone ylic acid derivative is lline D-glucitol, 1-deoxy lamino)-,1-(6-amino-3,5-difluoropyridinyl)chlorofluoro-1,4-dihydro(3- hydroxyazetidinyl)oxoquinolinecarboxylate characterized by an X-ray powder diffraction pattern substantially in accordance with that shown in wherein the pattern is obtained from a copper radiation source (Cu-Ka, 40 kV, 4 mA).

4. The pharmaceutical composition of claim 1, wherein the ceutically able salt of said quinolone carboxylic acid derivative is D-glucitol, 1-deoxy(methylamino)-,1- (6-amino-3,5-difluoropyridinyl)chlorofluoro-1,4-dihydro(3-hydroxy azetidinyl)oxoquinolinecarboxylate, characterized by an X-ray powder diffraction pattern having peaks at about 6.35, 12.70, 19.10, and 20.50 degrees 2?, wherein the pattern is obtained from a copper radiation source (Cu-Ka, 40 kV, 4 mA).

5. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable salt of said quinolone carboxylic acid derivative is D-glucitol, 1-deoxy(methylamino)-, 1- (6-amino-3,5-difluoropyridinyl)chlorofluoro-1,4-dihydro(3-hydroxy azetidinyl)oxoquinolinecarboxylate, characterized by a melting point of about 168- 171 °C.

6. The pharmaceutical composition of claim 3, wherein the pharmaceutically able salt of said quinolone carboxylic acid derivative is D-glucitol, 1-deoxy(methylamino)-, 1- (6-amino-3,5-difluoropyridinyl)chlorofluoro-1,4-dihydro(3-hydroxy azetidinyl)oxoquinolinecarboxylate, terized by the differential scanning calorimetry thermogram shown in

7. The pharmaceutical composition of claim 1, r comprising a polyhydroxyamine compound.

8. The pharmaceutical composition of claim 7, wherein said droxyamine compound is meglumine.

9. The pharmaceutical composition of claim 1, comprising: (a) from about 0.01% to about 80% by weight of the quinolone ylic acid tive, or a pharmaceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; and (b) from about 0.1% to about 50% by weight of the effervescent agent, as compared to the total weight of the composition.

10. The pharmaceutical composition of claim 1, comprising: (a) from about 0.01% to about 80% by weight of the quinolone carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, as ed to the total weight of the composition on an acid basis; (b) from about 0.1% to about 50% by weight of meglumine, as compared to the total weight of the composition; and (c) from about 0.1% to about 50% by weight of the effervescent agent, as compared to the total weight of the composition.

11. The pharmaceutical composition of claim 1, comprising: (a) from about 0.01% to about 50% by weight of the quinolone ylic acid derivative, wherein the quinolone ylic acid derivative is delafloxacin, or a pharmaceutically acceptable salt thereof, as compared to the total weight of the composition on an acid basis; and (b) from about 0.1% to about 50% by weight of the escent agent, as compared to the total weight of the composition.

12. The pharmaceutical composition of claim 1, comprising: (a) from about 0.01% to about 50% by weight of the quinolone carboxylic acid derivative, wherein the quinolone carboxylic acid derivative is delafloxacin, or a pharmaceutically able salt thereof, as compared to the total weight of the composition on an acid basis; (b) from about 0.1% to about 50% by weight of meglumine, as ed to the total weight of the composition; and (c) from about 0.1% to about 50% by weight of the effervescent agent, as compared to the total weight of the composition.

13. The pharmaceutical composition of claim 1, comprising: (a) from about 100 mg to about 750 mg of the quinolone carboxylic acid derivative, wherein the quinolone carboxylic acid tive is delafloxacin, on an acid active basis; and (b) from about 100 mg to about 500 mg of the effervescent agent.

14. The pharmaceutical composition of claim 1, comprising: (a) about 400 mg of a pharmaceutically able salt of said quinolone carboxylic acid derivative, wherein the pharmaceutically acceptable salt of said quinolone ylic acid derivative is delafloxacin meglumine, on an acid active basis; and (b) about 150 mg of the effervescent agent.

15. The pharmaceutical composition of claim 1, comprising: (a) about 400 mg of the quinolone carboxylic acid derivative, wherein the one carboxylic acid derivative is delafloxacin, (b) about 177 mg of meglumine; and (c) about 150 mg of the effervescent agent.

16. The pharmaceutical composition of claim 1, comprising: (a) about 450 mg of the quinolone carboxylic acid derivative, wherein the quinolone carboxylic acid derivative is delafloxacin; and (b) about 150 mg of the effervescent agent.

17. The pharmaceutical composition of claim 1, comprising: (a) about 650 mg of a ceutically acceptable salt of said quinolone carboxylic acid derivative, wherein the pharmaceutically acceptable salt of said quinolone ylic acid derivative is delafloxacin meglumine; and (b) about 150 mg of the effervescent agent.

18. The pharmaceutical ition of any one of claims 1 to 17, wherein said composition has improved intestinal tolerability.

19. The pharmaceutical composition of any one of claims 1 to 17, wherein said composition has reduced potential to cause gastrointestinal side effects.

20. The pharmaceutical composition of claim 18 or 19, wherein said composition has improved gastrointestinal tolerability or has reduced potential to cause gastrointestinal side effects as evaluated in a mini pig model.

21. The pharmaceutical composition of claim 18 or 19, wherein said composition has improved gastrointestinal bility or has d potential to cause gastrointestinal side effects as evaluated in humans.

22. The pharmaceutical composition of any one of claims 1 to 21, which has diminished ial to cause bacterial resistance.

23. The pharmaceutical composition of any one of claims 1 to 22 in the form of a dry mixture, an aqueous solution, an aqueous suspension, a non-aqueous solution, a non-aqueous suspension, or an emulsion.

24. The pharmaceutical composition of any one of claims 1 to 22 which is a unit dosage.

25. The pharmaceutical composition of any one of claims 1 to 22 in the form of a tablet.

26. The pharmaceutical composition of claim 25, wherein the tablet is a single layer

27. The pharmaceutical composition of claim 25, wherein the tablet is a bilayer tablet sing a first layer and a second layer.

28. The pharmaceutical composition of claim 27, wherein a first layer comprises said quinolone carboxylic acid derivative or a pharmaceutically acceptable salt thereof and said second layer comprises said escent agent.

29. The pharmaceutical composition of claim 27 or 28, wherein said second layer is a d release layer, where said second layer is released in the gastrointestinal tract downstream from the stomach.

30. The pharmaceutical composition of any one of claims 1 to 22 in the form of a capsule.

31. Use of a composition of any one of claims 1 to 30 in the manufacture of a medicament for treating, preventing, or reducing the risk of a bacterial infection in a patient in need thereof, wherein the ment is administered in an effective amount.

32. Use of claim 31, wherein the medicament has improved gastrointestinal bility.

33. Use of a claim 31, wherein the medicament has reduced potential to cause gastrointestinal side effects.

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