RU2796503C2 - Antibacterial compositions - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention can be used to treat, control or prevent a bacterial infection. The antibacterial pharmaceutical composition is presented in the form of a 100 ml solution with a pH in the range of 9 to 10.5 and an osmolarity in the range of 250 to about 350 mosmol/l which contains the following: (a) 1,186.7 mg of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, L- arginine salt, (b) 1,333 mg of L-arginine or a pharmaceutically acceptable salt thereof, and (c) 580 mg of sodium chloride.

EFFECT: increased stability of the composition.

8 cl, 3 tbl, 1 ex

Description

RELATED PATENT APPLICATIONS

The present application claims the priority and benefit of Indian Provisional Patent Application No. 201721013400 filed April 14, 2017; the contents of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions and their use in the treatment, control or prevention of bacterial infections.

STATE OF THE ART TO which THE INVENTION RELATES

Infections caused by bacteria continue to be a significant concern around the world. The emergence of bacterial resistance to known antibacterial agents is becoming a major problem in the treatment of bacterial infections. One of the ways to treat bacterial infections, and in particular those caused by resistant bacteria, is the development of new antibacterial agents that can overcome bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154) reviewed approaches to the development of new antibiotics. However, the development of new antibacterial agents is a difficult task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have described problems in identifying antibacterial agents. Several antibacterial agents and/or compositions are described in the art. However, there remains a need for potent antimicrobial agents and/or compositions for use in the treatment, control and/or prevention of bacterial infections.

SUMMARY OF THE INVENTION

Thus, pharmaceutical compositions and their use for the treatment, control or prevention of a bacterial infection in an individual are contemplated.

In one general aspect, a pharmaceutical composition is provided in the form of a solution, said solution containing S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo -1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, L-arginine salt, said solution having a pH in the range of about 8 to about 11.

In another general aspect, the use of a composition of the invention in a method for treating, controlling or preventing a bacterial infection is contemplated.

In another general aspect, a method is provided for treating, controlling or preventing a bacterial infection in an individual, said method comprising administering to said individual a composition of the invention.

A detailed description of one or more embodiments of the invention are given in the description below. Other features, objects and advantages of the invention will become apparent from the description below, including the claims.

DETAILED DESCRIPTION OF THE INVENTION

The following are illustrative embodiments and certain language is used to describe them. However, it should be understood that they are not intended to limit the scope of the invention. Changes and other modifications of the features of the invention illustrated in the present description, and additional applications of the principles of the invention, as illustrated in the present description, which are clear to a person skilled in the art and the authors of the invention, should be considered included in the scope of the invention. It should be noted that, as used in the present description and the appended claims, the singular formula includes the plural unless the context clearly indicates otherwise. All references, including patents, patent applications and literature, cited in the description, are incorporated herein by reference in their entirety.

The term "pharmaceutically acceptable salt" as used herein refers to one or more salts of a given compound which have the desired pharmacological activity of the free compound and which are not biologically or otherwise undesirable. In general, "pharmaceutically acceptable salts" refers to and includes salts that are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, and the like, and have an acceptable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, in S. M. Berge, et al. (J. Pharmaceutical Sciences, 66: 1-19 (1977)), incorporated herein by reference in its entirety, various pharmaceutically acceptable salts are described in detail.

The term "infection" or "bacterial infection" as used herein refers to and includes the presence of bacteria in or on an individual whose growth inhibition would result in a benefit to the individual. As such, the term "infection", in addition to referring to the presence of bacteria, also refers to the normal flora, which is not desirable. The term "infection" includes an infection caused by bacteria.

The term "treating", "treating", or "treatment" as used herein refers to the administration of a drug, including a pharmaceutical composition, or one or more pharmaceutically active ingredients for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to the treatment of an individual who is not yet infected, but who is predisposed or at risk of infection (prevention of bacterial infection). The term "therapeutic treatment" refers to the administration of treatment to an individual already suffering from an infection. The terms "treating", "treating", or "treatment" as used herein also refer to administering the compositions, or one or more pharmaceutically active ingredients, described herein, with or without additional pharmaceutically active or inert ingredients, for: (i) reducing or eliminating either the bacterial infection or one or more symptoms of the bacterial infection, or (ii) slowing the progression of the bacterial infection or one or more symptoms of the bacterial infection, or (iii) reducing the severity of the bacterial infection or one or more symptoms of the bacterial infection, or (iv) suppression of the clinical manifestations of the bacterial infection or (v) suppression of the manifestation of adverse symptoms of the bacterial infection.

The term "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" as used herein refers to an amount that has a therapeutic effect or is the amount required to achieve a therapeutic effect in an individual. For example, a therapeutically or pharmaceutically effective amount of an antibacterial agent or pharmaceutical composition is the amount of an antibacterial agent or pharmaceutical composition required to achieve the desired therapeutic effect as determined by the results of clinical trials, infection model animal studies, and/or in vitro studies (e.g., in an environment with agar or broth). The pharmaceutically effective amount depends on several factors, including, but not limited to, the microorganism involved (e.g., bacteria), characteristics of the individual (e.g., height, weight, sex, age, and medical history), the severity of the infection, and the particular type of antibacterial agent used. For prophylactic treatment, a therapeutically or prophylactically effective amount is an amount that can be effective in preventing a microbial (eg, bacterial) infection. The compounds and/or pharmaceutical compositions of the invention are used in amounts that are effective to provide the desired therapeutic effect or result.

The term "administering" or "administering administration" includes delivery of the composition or one or more pharmaceutically active ingredients to an individual, including, for example, any suitable methods that deliver the composition or its active ingredients or other pharmaceutically active ingredients to the site of infection. The method may vary depending on various factors, such as the components of the pharmaceutical composition or the nature of the pharmaceutically active or inert ingredients, the area of potential or actual infection, the microorganism involved, the severity of the infection, the age and physical condition of the individual, and the like. Some non-limiting examples of routes of administration of a composition or pharmaceutically active ingredient to an individual of the invention include oral, intravenous, topical, respiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, rectal, vaginal, gene gun , via a dermal patch, via eye drops, via ear drops, or via mouthwash. In the case of a pharmaceutical composition containing more than one ingredient (active or inert), one way of administering such a composition is by mixing the ingredients (for example, in the form of a suitable unit dosage form such as a tablet, capsule, solution, powder, etc.), and then administering the dosage form. Alternatively, the ingredients can also be administered separately (simultaneously or one after the other) provided that these ingredients reach useful therapeutic levels such that the composition as a whole provides a synergistic and/or desired effect.

The term "growth" as used herein refers to the growth of one or more microorganisms and includes the increase in number or expansion of a population of microorganisms (eg bacteria). The term "growth" also includes the maintenance of ongoing metabolic processes in a microorganism (eg, bacteria), including processes that keep the microorganism alive.

The term "effectiveness" as used herein refers to the ability of a method of treatment, or composition, or one or more pharmaceutically active ingredients to provide the desired biological effect in an individual. For example, the term "antibacterial efficacy" of a composition or antibacterial agent refers to the ability of a composition or antibacterial agent to treat or prevent a microbial (eg, bacterial) infection in an individual.

The term "synergistic" or "synergy" as used herein refers to the interaction of two or more agents in which their combined effect exceeds their individual effects.

The term "pharmaceutically inert ingredient", "inactive ingredient", "carrier", or "excipient" refers to a compound or material used to facilitate the administration of a compound, including, for example, to increase the solubility of the compound. Typical non-limiting examples of solid carriers include starch, lactose, dicalcium phosphate, sucrose, and kaolin, and the like. Typical non-limiting examples of liquid carriers include sterile water, saline, buffers, non-ionic surfactants, and edible oils such as peanut oil and sesame oil, and the like. In addition, various adjuvants commonly used in the art may be included. These and other such compounds are described in the literature, for example, in the Merck Index (Merck & Company, Rahway, N.J.). Factors to consider when including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press., which is incorporated herein by reference in its entirety.

The term "individual", as used in the framework of the invention, refers to a vertebrate or invertebrate animal, including a mammal. The term "individual" includes a human, animal, bird, fish, or amphibian. Typical non-limiting examples of "individual" include humans, cats, dogs, horses, sheep, cows, pigs, rams, rats, mice, and guinea pigs.

The term "parenteral administration" refers to and includes a route of administration that does not directly involve the gastrointestinal tract. Typical non-limiting examples of the parenteral route of administration include intravenous (into a vein), intra-arterial (into an artery), intraosseous infusion (into the bone marrow), intramuscular, intracerebral, intrathecal, subcutaneous administration. Typically, parenteral administration is by injection or infusion of the composition or active ingredient(s) directly into the individual without direct involvement of the gastrointestinal tract.

In one general aspect, a pharmaceutical composition is provided in the form of a solution, said solution containing S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo -1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, L-arginine salt, said solution having a pH in the range of about 8 to about 11. In some embodiments, the solution has a pH in the range of about 9 up to about 10.5.

The compositions of the invention are in the form of a solution and can be prepared, for example, by dissolving S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo- 1H,5H-benzo[i,j]quinolysine-2-carboxylic acid, L-arginine salt, in a pharmaceutically acceptable liquid diluent. Alternatively, compositions of the invention may also be prepared by dissolving any other compound capable of providing S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo- 1H,5H-benzo[i,j]quinolysine-2-carboxylic acid, L-arginine salt, when dissolved in a pharmaceutically acceptable diluent. A typical non-limiting example of such other compounds includes various forms of hydrates of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H- benzo[i,j]quinolysine-2-carboxylic acid, L-arginine salts, including the tetrahydrate form. Typical non-limiting examples of such a liquid diluent include water, sodium chloride solution, dextrose solution, saline solution, and the like. In some embodiments, the composition of the invention is prepared by dissolving S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo [i,j]quinolysine-2-carboxylic acid, L-arginine salt, in water. In some other embodiments, the composition of the invention is prepared by dissolving S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H tetrahydrate -benzo[i,j]quinolizine-2-carboxylic acid, L-arginine salt, in water.

In the form of a solution The -2-carboxylic acid salt of L-arginine may be present as is or in dissociated form. Both of these and any other forms are within the scope of the invention.

The compositions of the invention are in the form of a solution adapted to maintain a pH in the range of about 8 to about 11. In some embodiments, the solution has a pH in the range of about 9 to about 10.5. Typically, the pH is maintained at the desired level by adding a suitable pH adjusting agent to the composition. In some embodiments, the pH is maintained at the desired level by adding a buffer. In some embodiments, the pH is maintained at the desired level by adding a sufficient amount of L-arginine or a pharmaceutically acceptable salt thereof to the composition.

The amount of active and inactive ingredients in the composition according to the invention may vary depending on specific requirements. However, all such active and inactive ingredients in the composition of the invention are present in therapeutically effective amounts such that the composition as a whole is therapeutically effective.

In some embodiments, S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolysine-2-carboxylic acid, a salt of L-arginine, is present in the composition in the range of about 200 mg to about 2000 mg.

In some other embodiments, S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j ]quinolizine-2-carboxylic acid, a salt of L-arginine, is present in the composition in the range of about 400 mg to about 1500 mg.

In another general aspect, pharmaceutical compositions are provided in the form of a solution, said solution having a pH in the range of from about 8 to about 11; and said solution contains: (a) S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ i,j]quinolysine-2-carboxylic acid, L-arginine salt, (b) L-arginine or a pharmaceutically acceptable salt thereof, and (c) sodium chloride.

In some embodiments, pharmaceutical compositions are provided in the form of a solution, said solution having a pH ranging from about 9 to about 10.5; and the solution contains: (a) S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i ,j]quinolysine-2-carboxylic acid, L-arginine salt, (b) L-arginine or a pharmaceutically acceptable salt thereof, and (c) sodium chloride.

In some embodiments, the implementation of the pharmaceutical compositions according to the invention contain L-arginine or its pharmaceutically acceptable salt. In some embodiments, L-arginine, or a pharmaceutically acceptable salt thereof, is present in the composition in the range of from about 200 mg to about 2000 mg. In some other embodiments, L-arginine, or a pharmaceutically acceptable salt thereof, is present in the composition in the range of from about 400 mg to about 1500 mg.

In some embodiments, the implementation of the pharmaceutical compositions according to the invention contain sodium chloride. In some other embodiments, sodium chloride is present in the composition in the range of about 200 mg to about 2000 mg. In some other embodiments, sodium chloride is present in the composition in the range of from about 400 mg to about 1500 mg.

In some embodiments, pharmaceutical compositions are provided in the form of a 100 ml solution, said solution having a pH ranging from about 8 to about 11; and said solution contains: (a) about 200 to about 2000 mg S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo -1H,5H-benzo[i,j]quinolysine-2-carboxylic acid salt of L-arginine, (b) about 200 to about 2000 mg of L-arginine or a pharmaceutically acceptable salt thereof, and (c) from about 200 to about approximately 2000 mg sodium chloride.

In some embodiments, pharmaceutical compositions are provided in the form of a 100 ml solution, said solution having a pH ranging from about 9 to about 10.5; and said solution contains: (a) about 200 to about 2000 mg S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo -1H,5H-benzo[i,j]quinolysine-2-carboxylic acid salt of L-arginine, (b) about 200 to about 2000 mg of L-arginine or a pharmaceutically acceptable salt thereof, and (c) from about 200 to about approximately 2000 mg sodium chloride.

In some embodiments, the compositions of the invention contain from about 2 mg/ml to about 20 mg/ml S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5- methyl 1-oxo-1H,5H-benzo[i,j]quinolysine-2-carboxylic acid, L-arginine salt. In some other embodiments, the implementation of the compositions according to the invention contain from about 2 mg/ml to about 20 mg/ml of L-arginine or its pharmaceutically acceptable salt. In some other embodiments, the implementation of the compositions according to the invention contain from about 2 mg/ml to about 20 mg/ml of sodium chloride.

In some embodiments, the implementation of the compositions according to the invention have an osmolarity in the range from about 250 to about 350 mosmol/l.

The osmolarity can be adjusted to the desired level by adding a suitable substance capable of modifying the osmolarity. In some embodiments, the implementation of the osmolarity to maintain the desired range by adding sodium chloride.

Pharmaceutical compositions of the invention may include one or more pharmaceutically acceptable carriers or excipients, and the like. Typical non-limiting examples of such carriers or excipients include mannitol, lactose, glucose, sucrose, emulsifiers, solubilizers, pH buffers, stabilizers, and the like.

The compositions of the invention are stable over a wide range of storage conditions. In some embodiments, the implementation of the total content of impurities in the compositions according to the invention is less than 5% wt./mass. In some embodiments, the implementation of the total content of impurities in the compositions is less than 5% wt./mass. after storage at a temperature of approximately 40±2°C and a relative humidity of approximately 75±5% for 3 months. In some embodiments, the implementation of the total impurity content in the compositions according to the invention is less than 5% after storage at a temperature of approximately 25±2°C and a relative humidity of approximately 60±5% for 24 months.

In some embodiments, the compositions of the invention comprise one or more of the following:

This section is intentionally left blank.

(i) less than 0.25% wt./mass. 9-fluoro-8-hydroxy-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(ii) less than 3% wt./mass. 9-fluoro-6,7-dihydro-8-amino-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(iii) less than 0.25% wt./mass. 8-fluoro-9-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(iv) less than 0.25% wt./mass. 8-(4-hydroxy-1-piperidinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(v) less than 0.25% wt./mass. 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; or

(vi) less than 0.5% wt./mass. R-(+)-9-fluoro-8-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizin- 2-carboxylic acid.

In some other embodiments, the compositions of the invention contain one or more of the following after storage at a temperature of approximately 40±2°C and a relative humidity of approximately 75±5% for 3 months:

(i) less than 0.25% wt./mass. 9-fluoro-8-hydroxy-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(ii) less than 3% wt./mass. 9-fluoro-6,7-dihydro-8-amino-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(iii) less than 0.25% wt./mass. 8-fluoro-9-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(iv) less than 0.25% wt./mass. 8-(4-hydroxy-1-piperidinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(v) less than 0.25% wt./mass. 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; or

(vi) less than 0.5% wt./mass. R-(+)-9-fluoro-8-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizin- 2-carboxylic acid.

In some other embodiments, the compositions of the invention comprise one or more of the following after storage at a temperature of about 25±2°C and a relative humidity of about 60±5% for 24 months:

(i) less than 0.25% wt./mass. 9-fluoro-8-hydroxy-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(ii) less than 3% wt./mass. 9-fluoro-6,7-dihydro-8-amino-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(iii) less than 0.25% wt./mass. 8-fluoro-9-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(iv) less than 0.25% wt./mass. 8-(4-hydroxy-1-piperidinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid;

(v) less than 0.25% wt./mass. 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; or

(vi) less than 0.5% wt./mass. of R-(+)-9-fluoro-8-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolysine -2-carboxylic acid.

In some embodiments, the pharmaceutical compositions of the invention are in the form of a solution, which can be reconstituted by adding a compatible diluent for reconstitution prior to administration. In some embodiments, the pharmaceutical compositions of the invention are in the form of a ready-to-administer solution for parenteral administration. In some embodiments, the pharmaceutical compositions of the invention are present in the form of a unit dose solution contained in a bottle, vial, or sachet prior to parenteral administration. In some other embodiments, the pharmaceutical compositions of the invention are in the form of a frozen composition that can be diluted with a compatible diluent for reconstitution prior to administration. You can use a wide variety of diluents for recovery. A typical non-limiting example of a reconstitution diluent includes water for injection, 0.9% sodium chloride solution, 5% dextrose solution, normal saline, and the like.

In another general aspect, the compositions of the invention are useful in the treatment, control or prevention of a bacterial infection. In some embodiments, the compositions of the invention are used in the manufacture of a medicament for the treatment, control, or prevention of a bacterial infection.

In another general aspect, a method is provided for treating, controlling and/or preventing a bacterial infection in an individual, said method comprising administering to said individual a composition of the invention. In some embodiments, the composition is administered parenterally.

A person skilled in the art will be well aware that various substitutions and modifications can be made to the invention described in the present description without deviating from the scope and essence of the invention. For example, those skilled in the art will appreciate that the invention may be practiced using various compounds within the scope of the foregoing general descriptions.

EXAMPLES

The following examples illustrate embodiments of the invention that are currently best known. However, it should be understood that the following are only illustrative and typical examples of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods and systems can be established by experts in this field without deviating from the essence and scope of the present invention. The appended claims cover such modifications and permutations. Thus, although the present invention is described in detail in the present description, the following examples provide additional details of the most practical and currently preferred embodiments of the invention.

Example 1

The following is a summary of the various ingredients used in the following example:

Connection A :

S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizin-2- carboxylic acid, L-arginine salt.

Compound B :

9-fluoro-8-hydroxy-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.

Compound C :

9-fluoro-6,7-dihydro-8-amino-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.

Compound D :

8-fluoro-9-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.

Compound E :

8-(4-hydroxy-1-piperidinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.

Connection F :

8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid.

Connection G :

R-(+)-9-fluoro-8-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizin- 2-carboxylic acid.

A wide variety of compositions have been made containing various ingredients (active as well as inactive ingredients). The amounts of such ingredients (active as well as inactive) in these compositions were within the indicated ranges as described. The pH and osmolarity of these compositions varied over a wide range, including the ranges described herein. Details of several examples are given in Table 1 below:

Table 1 Ingredients Composition 1 Composition 2 Connection A 1186.7 mg 890 mg L-arginine 1333 mg 1000 mg Sodium chloride 580 mg 670 mg Nitrogen q.s. for blowing q.s. for blowing Water for injections q.s. up to 100 ml q.s. up to 100 ml

Basically, L-arginine, Compound A, and sodium chloride were sequentially added to an appropriate amount of water (Water for Injection having a dissolved oxygen content of less than 2 ppm). The entire solution was filtered using a 1.2 µm PP filter and 0.2 µm PES filters. The filtered solution was bottled and sterilized. The stability of the obtained compositions was determined under appropriate conditions and the results are shown in Table 2 (for composition 1) and Table 3 (for composition 2).

table 2 Position Test Quantities Initial After storage at 40±2°C and relative humidity 75±5% for 3 months After storage at 25±2°C and 60±5% relative humidity for 24 months 1. Compound A analysis 98.7 100.4 100.1 2. NaCl analysis 100.7 100.7 99.3 3. Related substances according to HPLC 4. Compound B 0.000 0.000 0.000 5. Compound C 0.138 0.381 0.809 6. Compound D 0.000 0.000 0.000 7. Compound E 0.019 0.053 0.023 8. Connection F 0.000 0.000 0.000 9. Connection G 0.000 0.000 0.000 10. Total impurity content 0.157 0.503 0.935 eleven. composition pH 9.67 9.50 9.73 12. Osmolarity (mosmol/l) 291 291 296

Table 3 Position Test Quantities Initial After storage at 40±2°C and relative humidity 75±5% for 3 months After storage at 25±2°C and 60±5% relative humidity for 24 months 1. composition pH 9.42 9.65 9.58 2. Compound A analysis 102.8 101.5 102.7 3. NaCl analysis 100.98 102.1 100.0 4. Related substances (according to HPLC) 5. Compound B 0.000 0.000 0.005 6. Compound C 0.131 0.508 0.608 7. Compound D 0.000 0.000 0.000 8. Compound E 0.049 0.049 0.057 9. Connection F 0.000 0.000 0.000 10. Connection G 0.000 0.000 0.000 eleven. Total impurity content 0.180 0.624 0.777

Claims (27)

1. Antibacterial pharmaceutical composition in the form of a solution with a volume of 100 ml, and the specified solution has a pH in the range from 9 to 10.5 and the specified solution has an osmolarity in the range from about 250 to about 350 mosmol/l; and said solution contains: (a) 1186.7 mg S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H, 5H-benzo[i,j]quinolysine-2-carboxylic acid, L-arginine salt, (b) 1333 mg L-arginine or a pharmaceutically acceptable salt thereof, and (c) 580 mg sodium chloride. 2. The composition according to p. 1, where the total content of impurities in the specified composition is less than 5% wt./mass. 3. The composition according to claim 1, where the total content of impurities in the specified composition is less than 5% wt./mass. after storage at a temperature of approximately 40±2°C and a relative humidity of approximately 75±5% for 3 months. 4. The composition according to p. 1, where the total content of impurities in the specified composition is less than 5% wt./mass. after storage at a temperature of approximately 25±2°C and a relative humidity of approximately 60±5% for 24 months. 5. The composition of claim. 1, where the specified composition contains one or more of the following: (i) less than 0.25% wt./mass. 9-fluoro-8-hydroxy-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (ii) less than 3% wt./mass. 9-fluoro-6,7-dihydro-8-amino-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (iii) less than 0.25% wt./mass. 8-fluoro-9-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (iv) less than 0.25% wt./mass. 8-(4-hydroxy-1-piperidinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (v) less than 0.25% wt./mass. 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; or (vi) less than 0.5% wt./mass. R-(+)-9-fluoro-8-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizin- 2-carboxylic acid. 6. The composition of claim 1, wherein said composition contains one or more of the following after storage at a temperature of approximately 40±2°C and a relative humidity of approximately 75±5% for 3 months: (i) less than 0.25% wt./mass. 9-fluoro-8-hydroxy-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (ii) less than 3% wt./mass. 9-fluoro-6,7-dihydro-8-amino-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (iii) less than 0.25% wt./mass. 8-fluoro-9-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (iv) less than 0.25% wt./mass. 8-(4-hydroxy-1-piperidinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (v) less than 0.25% wt./mass. 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; or (vi) less than 0.5% wt./mass. R-(+)-9-fluoro-8-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizin- 2-carboxylic acid. 7. The composition of claim 1, wherein said composition contains one or more of the following after storage at a temperature of approximately 25±2°C and a relative humidity of approximately 60±5% for 24 months: (i) less than 0.25% wt./mass. 9-fluoro-8-hydroxy-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (ii) less than 3% wt./mass. 9-fluoro-6,7-dihydro-8-amino-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (iii) less than 0.25% wt./mass. 8-fluoro-9-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (iv) less than 0.25% wt./mass. 8-(4-hydroxy-1-piperidinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; (v) less than 0.25% wt./mass. 8,9-difluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid; or (vi) less than 0.5% wt./mass. R-(+)-9-fluoro-8-(4-hydroxy-piperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizin- 2-carboxylic acid. 8. The composition according to any one of paragraphs. 1-7 for use in a method for treating, controlling or preventing a bacterial infection. 9. A composition for use according to claim 8, wherein the composition is administered parenterally.