RU2813568C2 - Antibacterial compositions - Google Patents

Abstract

FIELD: infectology.

SUBSTANCE: intended for antibacterial therapy. An antibacterial pharmaceutical composition suitable for intravenous administration contains: (a) 2 grams of cefepime or a pharmaceutically acceptable salt thereof, (b) 2 grams of tazobactam or a pharmaceutically acceptable salt thereof, and (c) 1.4 grams to 1.6 grams of arginine, or its pharmaceutically acceptable salt, where the pH of the composition is in the range from 6 to 8 before intravenous administration.

EFFECT: providing a therapeutic synergistic antibacterial composition that can be administered without causing phlebitis.

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Description

RELATED PATENT APPLICATIONS

This application claims priority to Indian Patent Application No. 201621011250, filed March 31, 2016, the disclosure of which is incorporated by reference in its entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The invention relates to antibacterial compositions and methods for treating, controlling or preventing bacterial infections.

BACKGROUND OF THE INVENTION

Infections caused by bacteria continue to be a major concern worldwide. One of the key problems in the treatment, control or prevention of bacterial infections is the ability of bacteria to develop resistance to one or more antibacterial agents over time. Representative examples of such bacteria that have developed resistance to typical antibacterial agents include: penicillin-resistant Streptococcus pneumoniae , vancomycin-resistant Enterococci , and methicillin-resistant Staphylococcus aureus . The problem of emerging bacterial drug resistance is often solved by switching to new antibacterial agents. However, developing new antibacterial agents can be expensive and not always a permanent solution, as bacteria often develop resistance to new antibacterial agents over time. In general, bacteria are often effective in developing antibacterial resistance due to their ability to reproduce very quickly and pass on the resistance genes that they replicate. Bacteria develop resistance to existing antibacterial agents through various mechanisms, including the production of beta-lactamases, mutations in penicillin-binding proteins (PBPs), production of efflux pumps, and decreased expression of outer membrane proteins or porins. For example, in response to prolonged exposure to various beta-lactam antibacterial agents, bacteria have developed several types of beta-lactamases that are capable of hydrolyzing antibacterial agents belonging to the penicillins, cephalosporins, monobactams, and even carbapenems.

There is an urgent need to develop new treatments for bacterial infections, and in particular infections caused by bacteria with acquired resistance to one or more existing antibacterial agents. A composition comprising at least one antibacterial agent and tazobactam is disclosed in international PCT patent application No. PCT/IB2011/053398. For example, a composition comprising cefepime and tazobactam exhibited a synergistic antibacterial effect against a wide range of bacteria. However, the combination of cefepime and tazobactam, when administered intravenously, caused inflammation of the veins (an effect also known as phlebitis). Applicants have now unexpectedly discovered that it is possible to use a composition comprising cefepime and tazobactam without causing phlebitis if a certain amount of arginine or a pharmaceutically acceptable salt thereof is added to the composition prior to administration and the pH of the composition is carefully maintained within a certain range during administration.

SUMMARY OF THE INVENTION

Thus, a pharmaceutical composition suitable for parenteral administration is provided, said composition comprising: (a) cefepime or a pharmaceutically acceptable salt thereof, (b) tazobactam or a pharmaceutically acceptable salt thereof, and (c) arginine or a pharmaceutically acceptable salt thereof; the amount of arginine or a pharmaceutically acceptable salt thereof in the composition is sufficient to maintain the pH of the composition in the range of 4.5 to 8 before parenteral administration.

Another general aspect concerns the use of the pharmaceutical compositions of the invention 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 or preventing a bacterial infection in a subject, said method comprising parenteral administration of a pharmaceutical composition of the invention.

Another general aspect concerns the use of: (a) cefepime or a pharmaceutically acceptable salt thereof, (b) tazobactam or a pharmaceutically acceptable salt thereof, and (c) arginine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment, control or prevention of a bacterial infection.

In another general aspect, there is provided a method of treating or preventing a bacterial infection in a subject, said method comprising administering to said subject: (a) cefepime or a pharmaceutically acceptable salt thereof, (b) tazobactam or a pharmaceutically acceptable salt thereof, and (c) arginine or a pharmaceutically acceptable salt thereof. .

Details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will become apparent from the following description, including the claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made to illustrative embodiments, and specific language will be used herein to describe the same. However, it should be understood that no limitation on the scope of the invention is intended herein. It is within the scope of the invention to consider changes and further modifications to the features of the invention illustrated herein and to additional applications of the principles of the invention as illustrated herein that may occur to one of ordinary skill in the art having knowledge of this specification. It should be noted that, as used in this specification and the accompanying claims, the singular forms include the plural forms unless the content clearly dictates otherwise. All references, including patents, patent applications and literature, cited in the specification are expressly incorporated herein by reference in their entirety.

The Applicant has surprisingly discovered that it is possible to treat bacterial infections using cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof. The compositions and methods disclosed herein also minimize or eliminate problems associated with phlebitis.

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

The term "infection" or "bacterial infection" implies and includes the presence of bacteria in or on a subject which, if their growth were suppressed, would benefit that subject. As such, the term "infection" in addition to referring to the presence of bacteria also refers to natural microflora that is undesirable. The term "infection" includes infections caused by bacteria.

The term “treat,” “treat,” or “cure” means the administration of a medicament, including a pharmaceutical composition, or one or more active ingredients, for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to the treatment of a subject who is not yet infected but is susceptible to infection or is otherwise at risk of infection (prevention of bacterial infection). The term “therapeutic treatment” means administering a course of treatment to a subject already suffering from an infection. The terms “treat,” “treating,” or “treating,” as used herein, also mean the administration of compositions or one or more of the active ingredients contemplated herein, with or without additional active or inert ingredients, for the purpose of: (i) reducing or eliminating either a bacterial infection or one or more symptoms of a bacterial infection, or (ii) inhibiting the progression of a bacterial infection, or one or more symptoms of a bacterial infection, or (iii) reducing the severity of a bacterial infection, or one or more symptoms of a bacterial infection, or (iv) suppressing the clinical manifestations of a bacterial infection, or (v) suppressing the manifestation of adverse symptoms of a bacterial infection.

The term "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" as used herein refers to an amount that produces a therapeutic effect or is the amount necessary to produce a therapeutic effect in a subject. For example, a therapeutically or pharmaceutically effective amount of an active ingredient or pharmaceutical composition is the amount of active ingredient or pharmaceutical composition required to obtain the desired therapeutic effect, as assessed by clinical trials, animal model infection studies, and/or in vitro studies (eg, agar or broth).The pharmaceutically effective amount depends on a number of factors, including, but not limited to, the microorganism (eg, bacteria), characteristics of the subject (eg, height, weight, gender, age, and medical history), severity of infection, and the specific type of antibacterial agent or active ingredient used. For prophylactic treatment, a therapeutically or prophylactically effective amount is that amount that would be effective in preventing microbial (eg, bacterial) infection. The active ingredients and/or pharmaceutical compositions of the invention are used in amounts that are effective in providing the desired therapeutic effect or result.

The term "administration" or "administering" includes delivery of the composition or one or more active ingredients to a subject, including, for example, delivery by any suitable means that serves to deliver the composition or active ingredients to the site of infection. The route of administration may vary depending on various factors, such as, for example, the components of the pharmaceutical composition or the nature of the pharmaceutically active and/or inert ingredients, the microorganism involved, the severity of the infection, the age and physical condition of the subject, and the like. Some non-limiting examples of routes for administering a composition or active ingredients of the invention to a subject include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, transdermal patch, eye drops, ear drops, or mouthwash. In the case of a pharmaceutical composition comprising more than one ingredient (active or inert), one route of administration of such composition is by mixing the ingredients (for example, in a suitable unit dosage form such as tablet, capsule, solution, powder and the like) and then administration of the dosage form. Alternatively, the ingredients may also be administered separately (simultaneously or sequentially) until the ingredients reach appropriate therapeutic levels that provide the desired therapeutic effect.

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

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

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

The term "synergistic" or "synergism" as used herein refers to the interaction of two or more agents such that their combined effect is greater than the individual effects.

The term “antibacterial agent” as used herein refers to any substance, compound or combination of substances, or combination of compounds capable of: (i) inhibiting, reducing or preventing the growth of bacteria; (ii) inhibiting or reducing the ability of bacteria to cause infection in a subject; or (iii) inhibiting or reducing the ability of bacteria to reproduce or remain infectious in the environment. The term “antibacterial agent” also refers to a compound capable of reducing the infectivity or virulence of bacteria.

The term “beta-lactam antibacterial agent”, as used herein, refers to compounds with antibacterial properties and containing beta-lactam nuclei in their molecular structure.

The term "beta-lactamase" as used herein refers to any enzyme or protein or any other substance that cleaves the beta-lactam ring. The term "beta-lactamase" includes enzymes produced by bacteria that have the ability to hydrolyze the beta-lactam ring in the beta-lactam compound, either partially or completely.

The term “beta-lactamase inhibitor” as used herein refers to a compound capable of inhibiting the activity of one or more beta-lactamase enzymes, either partially or completely.

The term “pharmaceutically inert ingredient” or “inert ingredient”, “carrier” or “excipient” refers to a compound or material used to facilitate administration of the compound, including, for example, increasing the solubility of the compound. Typical non-limiting examples of solid carriers include starch, lactose, dicalcium phosphate, sucrose and kaolin, etc. Typical non-limiting examples of liquid carriers include sterile water, saline, buffers, non-ionic surfactants and edible oils such as peanut and sesame oils, etc. In addition, various excipients 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.). Recommendations for the inclusion of 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., incorporated herein by reference in its entirety.

The term "subject" as used herein refers to vertebrates or invertebrates, including mammals. The term "subject" includes humans, animals, birds, fish or amphibians. Typical non-limiting examples of “subject” include humans, cats, dogs, horses, sheep, cows, pigs, lambs, rats, mice and guinea pigs.

Those skilled in the art will appreciate that the compounds described herein may generally exist or be used in various pharmaceutically acceptable forms, including the form of pharmaceutically acceptable salts, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers thereof. , adducts or other similar pharmaceutically acceptable derivatives. Thus, reference to a compound includes its pharmaceutically acceptable salts, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or other pharmaceutically acceptable derivatives. For example, the terms cefepime, tazobactam or arginine include their pharmaceutically acceptable salts, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or other similar pharmaceutically acceptable derivatives.

Cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof are each individually referred to as an "active ingredient" and are collectively referred to as the "active ingredients". The terms “pharmaceutical compositions” or “composition” as used herein mean and include the compositions of the invention.

In one general aspect, pharmaceutical compositions suitable for parenteral administration are provided, said compositions comprising: (a) cefepime or a pharmaceutically acceptable salt thereof, (b) tazobactam or a pharmaceutically acceptable salt thereof, and (c) arginine or a pharmaceutically acceptable salt thereof; the amount of arginine or a pharmaceutically acceptable salt thereof in the composition is sufficient to maintain the pH of the composition in the range of 4.5 to 8 before parenteral administration.

In some embodiments, tazobactam is present as tazobactam sodium. In some other embodiments, cefepime is present as cefepime hydrochloride. In some embodiments, the arginine is present in the form of arginine hydrochloride.

In some embodiments, the pH of the composition is in the range of 6 to 8, prior to parenteral administration.

In some other embodiments, the pH of the composition is in the range of 6.5 to 7.5, prior to parenteral administration.

In certain embodiments, cefepime or a pharmaceutically acceptable salt thereof is present in the composition in an amount of from about 0.01 grams to about 10 grams.

In some other embodiments, tazobactam or a pharmaceutically acceptable salt thereof is present in the composition in an amount of from about 0.01 grams to about 10 grams.

In some embodiments, cefepime or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof are present in the composition in any of the following amounts:

(i) approximately 0.50 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 0.50 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(ii) approximately 0.75 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 0.75 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(iii) approximately 1 gram of cefepime or a pharmaceutically acceptable salt thereof and approximately 1 gram of tazobactam or a pharmaceutically acceptable salt thereof;

(iv) approximately 1.5 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(v) approximately 2 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 2 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(vi) approximately 2.5 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 2.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(vii) approximately 2 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 1 gram of tazobactam or a pharmaceutically acceptable salt thereof;

(viii) approximately 1 gram of cefepime or a pharmaceutically acceptable salt thereof and approximately 0.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(ix) approximately 3 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 3 grams of tazobactam or a pharmaceutically acceptable salt thereof; or

(x) about 3 grams of cefepime or a pharmaceutically acceptable salt thereof and about and about 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof.

In some embodiments, the compositions of the invention consist of cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof as single active ingredients.

In certain embodiments, arginine or a pharmaceutically acceptable salt thereof is present in the compositions of the invention in an amount of from about 0.50 grams to 0.90 grams per gram of cefepime or a pharmaceutically acceptable salt thereof.

In some other embodiments, arginine or a pharmaceutically acceptable salt thereof is present in the compositions of the invention in an amount that is from about 0.70 grams to 0.80 grams per gram of cefepime or a pharmaceutically acceptable salt thereof.

In some embodiments, cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof are present in the composition in any of the following amounts:

(i) about 0.50 grams of cefepime or a pharmaceutically acceptable salt thereof, about 0.50 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.35 grams to 0.40 grams of arginine or a pharmaceutically acceptable salt thereof;

(ii) about 0.75 grams of cefepime or a pharmaceutically acceptable salt thereof, about 0.75 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.525 grams to 0.60 grams of arginine or a pharmaceutically acceptable salt thereof;

(iii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, about 1 gram of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.70 grams to 0.80 grams of arginine or a pharmaceutically acceptable salt thereof;

(iv) about 1.5 grams of cefepime or a pharmaceutically acceptable salt thereof, about 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 1.05 grams to 1.2 grams of arginine or a pharmaceutically acceptable salt thereof;

(v) approximately 2 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 2 grams of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 1.4 grams to 1.6 grams of arginine or a pharmaceutically acceptable salt thereof;

(vi) approximately 2.5 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 2.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 1.75 grams to 2 grams of arginine or a pharmaceutically acceptable salt thereof;

(vii) approximately 2 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 1 gram of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 1.4 grams to 1.6 grams of arginine or a pharmaceutically acceptable salt thereof;

(viii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, about 0.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.70 grams to 0.80 grams of arginine or a pharmaceutically acceptable salt thereof;

(ix) approximately 3 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 3 grams of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 2.1 grams to 2.4 grams of arginine or a pharmaceutically acceptable salt thereof; or

(x) approximately 3 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 2.1 grams to 2.4 grams of arginine or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions of the invention may include one or more pharmaceutically acceptable carriers or excipients or inert ingredients. Typical, non-limiting examples of such carriers or excipients or inert ingredients include mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate, humectants, emulsifiers, solubilizing agents, buffering agents, lubricants, stabilizing agents, binders and the like.

In some embodiments, the composition of the invention further contains one or more buffering agents. Typical non-limiting examples of buffering agents include aluminum hydroxide, aluminum hydroxide/magnesium carbonate coprecipitate, aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum glycinate, aluminum magnesium hydroxide, aluminum phosphate, calcium acetate, calcium carbonate, calcium formate, calcium bicarbonate, calcium borate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium chloride, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, calcium propionate, dibasic sodium phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, diacidic sodium phosphate, sodium hydrogen succinate, aluminum hydroxide dry gel, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium hydroxide, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, phosphate magnesium, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, hydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, tripolyphosphate sodium, synthetic hydrotalcide, potassium pyrophosphate, sodium pyrophosphate, tripotassium phosphate, trisodium phosphate, trometamol, trihydroxymethylaminomethane, amino acid such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine , phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or its optically active isomers, or racemic mixtures thereof, an acid salt of an amino acid, an alkaline salt of an amino acid or mixtures thereof.

The pharmaceutical compositions of the invention can be formulated into a variety of dosage forms, including solid, semi-solid, aerosol and liquid dosage forms. Typical, non-limiting examples of dosage forms include tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs, injectables and the like. If desired, the compositions of the invention may also be prepared and presented in bulk form or in unit dosage forms.

The composition may also be formulated into a unit dosage form in which the active ingredients (cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof) are present in the mixture. Alternatively, the composition may also be formulated into a unit dosage form in which cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof are present as separate components (e.g., all three active ingredients in separate vials or dosage forms; any two active ingredients in one vial or dosage form, and the third active ingredient in a separate vial or dosage form).

In some embodiments, the pharmaceutical compositions of the invention are present in the form of a powder or solution. In some other embodiments, the pharmaceutical compositions of the invention are present in the form of a powder or solution that can be reconstituted by adding a compatible reconstitution diluent prior to administration.

In certain embodiments, the pharmaceutical compositions of the invention are provided in powder form, which can be reconstituted prior to parenteral administration by adding a compatible reconstitution diluent.

In some embodiments, the pharmaceutical compositions of the invention are presented in the form of a ready-to-use solution for parenteral administration.

In some embodiments, the pharmaceutical compositions of the invention are presented in the form of a solution, which can be further reconstituted prior to parenteral administration by adding a compatible diluent for reconstitution.

In certain embodiments, the pharmaceutical compositions of the invention are presented before parenteral administration in the form of a single dose powder contained in a vial or sachet. In some other embodiments, the pharmaceutical compositions of the invention are presented prior to parenteral administration in the form of a single dose solution contained in a vial or sachet.

In some other embodiments, the pharmaceutical compositions of the invention are in the form of a lyophilized composition that can be reconstituted before parenteral administration with a compatible reconstitution diluent.

A wide range of reconstitution diluents can be used. A typical non-limiting example of a reconstitution diluent includes water for injection, 0.9% sodium chloride solution, 5% dextrose solution, physiological saline solution, and the like.

In another general aspect, methods are provided for treating, controlling or preventing bacterial infection using the compositions of the invention. In some embodiments, a method of treating, controlling, or preventing a bacterial infection in a subject is provided, the method comprising administering to the subject an effective amount of a composition of the invention. In some other embodiments, a method of treating, controlling, or preventing a bacterial infection in a subject is provided, the method comprising parenteral administration of a pharmaceutical composition of the invention.

In some embodiments, the compositions of the invention are used to treat, control, or prevent a bacterial infection. In certain 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 some other embodiments, cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof are used in the manufacture of a medicament for the treatment, control or prevention of a bacterial infection.

In some embodiments, a method of treating, controlling, or preventing a bacterial infection in a subject is provided, the method comprising administering to the subject: (a) cefepime or a pharmaceutically acceptable salt thereof, (b) tazobactam or a pharmaceutically acceptable salt thereof, and (c) arginine or a pharmaceutically acceptable salt thereof. acceptable salt.

In some embodiments, a method of treating, controlling, or preventing a bacterial infection in a subject is provided, the method comprising parenterally administering to the subject: (a) cefepime or a pharmaceutically acceptable salt thereof, (b) tazobactam or a pharmaceutically acceptable salt thereof, and (c) arginine or pharmaceutically acceptable salt.

In certain embodiments, in the methods of the invention, cefepime or a pharmaceutically acceptable salt thereof is administered in an amount that is from about 0.01 grams to about 10 grams.

In some other embodiments, in the methods of the invention, tazobactam or a pharmaceutically acceptable salt thereof is administered in an amount that is from about 0.01 grams to about 10 grams.

In some other embodiments, methods are provided for treating, controlling, or preventing a bacterial infection in a subject, the methods comprising parenteral administration of a solution having a pH in the range of 4 to 8; said solution comprises cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof; said arginine or a pharmaceutically acceptable salt thereof is present in an amount sufficient to maintain the pH of the composition in the range of 4.5 to 8 before parenteral administration.

In certain embodiments, methods are provided for treating, controlling, or preventing a bacterial infection, said methods comprising parenterally administering a solution containing cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof, said solution having a pH ranging from 4.5 to 8. In some other embodiments, the solution has a pH in the range of about 6.5 to 7.5.

In some embodiments, cefepime or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof are administered in any of the following amounts:

(i) approximately 0.50 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 0.50 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(ii) approximately 0.75 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 0.75 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(iii) approximately 1 gram of cefepime or a pharmaceutically acceptable salt thereof and approximately 1 gram of tazobactam or a pharmaceutically acceptable salt thereof;

(iv) approximately 1.5 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(v) approximately 2 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 2 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(vi) approximately 2.5 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 2.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(vii) approximately 2 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 1 gram of tazobactam or a pharmaceutically acceptable salt thereof;

(viii) approximately 1 gram of cefepime or a pharmaceutically acceptable salt thereof and approximately 0.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

(ix) approximately 3 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 3 grams of tazobactam or a pharmaceutically acceptable salt thereof; or

(x) approximately 3 grams of cefepime or a pharmaceutically acceptable salt thereof and approximately 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof.

In some other embodiments, cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof are administered in any of the following amounts:

(i) about 0.50 grams of cefepime or a pharmaceutically acceptable salt thereof, about 0.50 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.35 grams to 0.40 grams of arginine or a pharmaceutically acceptable salt thereof;

(ii) about 0.75 grams of cefepime or a pharmaceutically acceptable salt thereof, about 0.75 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.525 grams to 0.60 grams of arginine or a pharmaceutically acceptable salt thereof;

(iii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, about 1 gram of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.70 grams to 0.80 grams of arginine or a pharmaceutically acceptable salt thereof;

(iv) about 1.5 grams of cefepime or a pharmaceutically acceptable salt thereof, about 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 1.05 grams to 1.2 grams of arginine or a pharmaceutically acceptable salt thereof;

(v) approximately 2 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 2 grams of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 1.4 grams to 1.6 grams of arginine or a pharmaceutically acceptable salt thereof;

(vi) approximately 2.5 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 2.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 1.75 grams to 2 grams of arginine or a pharmaceutically acceptable salt thereof;

(vii) approximately 2 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 1 gram of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 1.4 grams to 1.6 grams of arginine or a pharmaceutically acceptable salt thereof;

(viii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, about 0.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.70 grams to 0.80 grams of arginine or a pharmaceutically acceptable salt thereof;

(ix) approximately 3 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 3 grams of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 2.1 grams to 2.4 grams of arginine or a pharmaceutically acceptable salt thereof; or

(x) approximately 3 grams of cefepime or a pharmaceutically acceptable salt thereof, approximately 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and approximately 2.1 grams to 2.4 grams of arginine or a pharmaceutically acceptable salt thereof.

In other embodiments, in the methods of the invention, the compositions of the invention are administered by any suitable method that serves to deliver the composition or components thereof to the desired site. In the case of methods using administration of active ingredients, the active ingredients may also be administered by any appropriate method. The route of administration may vary depending on various factors, such as, for example, the nature of the active ingredients or composition, the site of potential or actual infection, the microorganism involved, the severity of the infection, the age and physical condition of the subject, and so on. Some non-limiting examples of the methods of administration of the invention include intravenous, intraperitoneal, intramuscular, parenteral, intratracheal, intrarectal and the like.

The compositions of the invention include three active ingredients: cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof. Those skilled in the art will appreciate that these active ingredients may be formulated into various dosage forms in which the active ingredients may be present either together (in a mixture) or as separate components. When the active ingredients in a composition are formulated as a mixture, said composition can be delivered by administering such a mixture. A composition or dosage form in which the active ingredients are not included in the form of a mixture, but are included in the form of separate components, such a composition/dosage form can be administered in several ways. In one possible method, the active ingredients are mixed in predetermined proportions, and the mixture is then administered as needed. Alternatively, the active ingredients may be administered separately in appropriate amounts to achieve the same or equivalent therapeutic level or effect that would be achieved by administering an equivalent mixture. If desired, one or more inert ingredients or inactive ingredients may also be used during formulation and/or administration.

In certain embodiments, in the methods of the invention, cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt are administered simultaneously or sequentially. In some embodiments, the compositions or active ingredients of the invention are packaged in kit form. The compositions or active ingredients may be packaged in one or more containers, such as a vial, vial, syringes, boxes, sachets, and the like. The kit may also include instructions for using the contents.

The compositions or active ingredients of the invention may be administered at various time intervals depending on the specific need or desired therapeutic effect. In some embodiments, the compositions or active ingredients of the invention are administered one, two, three, or four times per day. In some other embodiments, the compositions or active ingredients of the invention are administered every 4 hours, 6 hours, 8 hours, 12 hours, or 24 hours.

In another general aspect, the compositions or active ingredients of the invention are used for the prophylactic treatment of a subject, comprising administering to the subject at risk of a disease caused by bacteria a prophylactically effective amount of the composition or active ingredients of the invention.

In general, the compositions or active ingredients of the invention are effective against infections caused by a wide range of bacteria, including those that exhibit resistance to one or more known antibacterial agents or compositions. Some non-limiting examples of infections that can be treated, controlled or prevented using the compositions and methods of the invention include infections caused by bacteria belonging to the genus Escherichia, Staphylococcus, Streptococcus, Haemophilus, Klebsiella, Moraxella, Enterobacter, Proteus, Serratia, Pseudomonas, Acinetobacter , Citrobacter, Stenotrophomonas, Bacteroides, Prevotella, Fusobacterium, Clostridium .

In general, the compositions or active ingredients of the invention are useful for the treatment, control or prevention of a number of infections, including, for example, skin and soft tissue infections, febrile neutropenia, urinary tract infections, abdominal infections, respiratory tract infections, pneumonia (nosocomial), bacteremia , meningitis, diabetic foot syndrome, bone and joint infections, surgical site infections, Shigella dysentery and the like.

It will be apparent to one skilled in the art that various substitutions and modifications in the compositions and/or methods disclosed herein can be made without departing from the spirit and scope of the invention. For example, those skilled in the art will appreciate that the invention may be practiced in a variety of ways as disclosed in the general description.

EXAMPLES

The following examples illustrate the most currently known embodiments of the invention. However, it should be understood that the following is merely an example or illustration of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods and schemes may be developed by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and designs. Thus, although the details of the present invention have been disclosed above, the following examples provide further detail regarding which embodiments of the invention are currently considered to be most practically relevant and preferred.

Example 1

The antibacterial activity of cefepime in combination with tazobactam against various strains of bacteria, including those bacteria known to produce one or more beta-lactamases, was examined by a quantitative drug diffusion assay performed in accordance with CLSI (Clinical and Laboratory Standards Institute (CLSI) guidelines ), functional characteristics for antimicrobial susceptibility testing, 20th Information Supplement, M 100 - S20, Vol. 30, No. 1, 2010).

In a typical study, overnight bacterial cultures, after appropriate dilution, are inoculated onto molten, cooled agar culture media and deep plated. Discs with a diameter of 6 mm containing antibacterial agents are placed on the top surface of the agar. Observation based on the delay zone is carried out 16-18 hours after incubation at a temperature of 35 ± 2°C in ambient air. The general procedure is carried out in accordance with the CLSI recommendations, and the results are presented in Table 1. These tests are used in routine practice in determining whether a particular infection can be treated with a given antibacterial agent or composition. In general, the values of the zones of inhibition within the sensitivity range (S) indicate that the strain is sensitive to that antibacterial agent or composition. In general, it is expected that an antibacterial agent or combination in question will not be effective in treating an infection if the values of the inhibition zones are in the resistance range (R). The CLSI sensitivity assessment of these combinations (which determines hospital/outpatient treatment decisions) shows that the combination of cefepime and tazobactam can change the susceptibility profile of ESBL strains from 'resistant' to 'susceptible', suggesting a high clinical value of the combination cefepime-tazobactam according to the invention.

Table 1. Antibacterial activity of cefepime alone and in combination with tazobactam Ser. Bacterial strain Suppression area (mm) Cefepime as such Cefepime in combination with tazobactam (10 mcg)* 1. E. coli M-138 Zero (R) 23 (S) 2. E. coli B-89 8 (R) 20 (S) 3. E. coli B-123 8 (R) 20 (S) 4. E. coli M50 7.5(R) 24 (S) 5. E. coli 7MP 16 (I) 20.5 (S) 6. E. coli S-112 17 (I) 20.5 (S) (R): Resistant; (I): Intermediate; (S): Sensitive (Interpretation according to CLSI, 2010 guidelines)
* in case of possible treatment, the combination of Cefepime (0.5 g) + Tazobactam (0.5 g)

Example 2

To study the effect of arginine on the tolerability of intravenous formulations containing cefepime and tazobactam, a twelve-day multiple-dose study was conducted. Three groups of rats are used in this study, each consisting of 5 male Wistar rats (160-180 g). The first group of rats (group I) was administered cefepime for injection (at a dose of 400 mg/kg). A second group of rats (group II) was administered a combination of cefepime injection and tazobactam sodium (each of cefepime and tazobactam at a dose of 400 mg/kg in water for injection). A third group of rats (group III) was administered a combination of cefepime injection and tazobactam sodium with additional arginine (each of cefepime and tazobactam at a dose of 400 mg/kg in 5 ml water for injection containing 4 mg/ml arginine). A typical procedure is to open a new vial daily, add the required amount of arginine diluent, and record the pH. Next, dilute with 0.9% saline to obtain a final concentration of 100 mg/ml and record the pH. Dose failure due to phlebitis is included in each case and the results are presented in Table 2. Dosing failure due to loss of tail vein integrity in rats is included.

As can be seen from the results shown in Table 2, the dosing failure rate is approximately 13.1% when cefepime injection is administered at a pH in the range of approximately 4.1 to 4.2. The dosing failure rate is even higher (about 15.1%) when a solution containing cefepime injection and tazobactam sodium (pH ranging from 3.8 to 4.1) is administered. Surprisingly, the dosing failure rate is significantly reduced to approximately 3.1% when the same composition containing injection cefepime and tazobactam sodium is administered with the addition of arginine and the pH of the solution is adjusted prior to administration to a value ranging from approximately 6 to 7.4. The study confirms a lower rate of dosing failures after adding arginine to the formulation, as well as adjusting the operating pH range (fewer phlebitis).

Example 3

Some compositions containing the active ingredients in the disclosed amounts are prepared in the form of powders and solutions. Individual compositions are also prepared in the form of solutions with a pH within the stated range.

Table 2 . Effect of arginine on the tolerability of intravenous compositions containing cefepime and tazobactam Group of rats pH of the solution before administration Dosing day Number of failed dosing attempts (%) 1 2 3 4 5 6 7 8 9 10 eleven 12 Group(I) (cefepime for injection 4.0-4.2 0 0 0 1 1 2 3 3 3 4 4 4 25 (13.1) Group(II) (cefepime for injection + tazobactam sodium 3.8-4.1 0 0 0 1 0 1 4 4 2 5 6 6 29 (15.1) Group(III) (cefepime injection+tazobactam sodium+added arginine 6.0-7.4 0 0 1 1 1 0 0 1 0 1 0 1 6 (3.1)

Claims (8)

1. An antibacterial pharmaceutical composition suitable for intravenous administration, said composition comprising: (a) 2 grams of cefepime or a pharmaceutically acceptable salt thereof, (b) 2 grams of tazobactam or a pharmaceutically acceptable salt thereof, and (c) from 1.4 grams to 1. 6 grams of arginine or a pharmaceutically acceptable salt thereof, where the pH of the composition is in the range of 6 to 8 before intravenous administration. 2. Antibacterial pharmaceutical composition according to claim 1, where the pH of the composition is in the range from 6.5 to 7.5. 3. An antibacterial pharmaceutical composition according to claim 1 or 2, wherein said composition is in the form of a powder that can be reconstituted by adding a compatible reconstitution diluent before intravenous administration. 4. Antibacterial pharmaceutical composition according to claim 1 or 2, where the said composition is presented in the form of a ready-to-use solution for intravenous administration. 5. Antibacterial pharmaceutical composition according to claim 1 or 2, said composition is presented in the form of a solution, which can further be further diluted by adding a compatible diluent for reconstitution before intravenous administration. 6. Antibacterial pharmaceutical composition according to claim 1 or 2, where the composition is presented in the form of a powder and in the form of a unit dose contained in a vessel or bag before intravenous administration. 7. Antibacterial pharmaceutical composition according to claim 1 or 2, where the composition is presented in the form of a solution and in the form of a unit dose contained in a vessel or bag before intravenous administration. 8. Antibacterial pharmaceutical composition according to any one of paragraphs. 1-7 for use in a method of treating, controlling or preventing a bacterial infection.