Antibacterial composition

Abstract

Disclosed herein are pharmaceutical compositions comprising cefepime, or a pharmaceutically acceptable salt thereof, tazobactam, or a pharmaceutically acceptable salt thereof, and arginine, or a pharmaceutically acceptable salt thereof, and their use in the treatment, control or prevention of bacterial infections.

Description

[0001] This invention patent application is a divisional application of the invention patent application with international application number PCT / IB2017 / 051871, international application date March 31, 2017, application number 201780002387.6 entering the Chinese national phase, and name “Antibacterial Composition”.

[0002] Related patent applications

[0003] This application claims the benefit of Indian Patent Application No. 201621011250 filed on March 31, 2016, the disclosure of which is incorporated herein by reference in its entirety as if fully set forth herein. Field of the Invention

[0004] The present invention relates to antimicrobial compositions and methods for treating, controlling or preventing bacterial infections. Background Art

[0005] Infections caused by bacteria remain an area of ​​serious concern worldwide. One of the key difficulties in treating, controlling or preventing bacterial infections is the ability of bacteria to develop resistance to one or more antimicrobial agents over time. Representative examples of these bacteria that have developed resistance to typical antimicrobial agents include: penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococci, and methicillin-resistant Staphylococcus aureus. The problem of emerging resistance in bacteria is often solved by switching to new antimicrobial agents. However, the development of new antimicrobial agents can be expensive and may not always be a permanent solution as bacteria tend to develop resistance to the new antimicrobial agents after a short period of time. In general, bacteria are often effective in developing resistance to antimicrobial agents because they are able to reproduce very rapidly and pass on resistance genes during replication. Bacteria develop resistance to existing antimicrobial agents through a variety of mechanisms, including the production of β-lactamases, mutations in penicillin-binding proteins (PBPs), the production of efflux pumps, and decreased expression of outer membrane proteins or porins. For example, in response to continued exposure to multiple β-lactam antimicrobials, bacteria have developed several types of β-lactamases that hydrolyze penicillins, cephalosporins, monobactams, and carbapenems.

[0006] There is an urgent need to develop new methods for treating bacterial infections, especially infections caused by bacteria that are resistant to one or more existing antibacterial agents. PCT International Patent Application PCT / IB2011 / 053398 discloses a composition comprising at least one antibacterial agent and tazobactam. For example, a composition comprising cefepime and tazobactam has a synergistic antibacterial effect against a variety of bacteria. However, when the combination of cefepime and tazobactam is administered intravenously, it causes venous inflammation (this effect is also called phlebitis). Now, the inventors have surprisingly found that if a specific amount of arginine or a pharmaceutically acceptable salt thereof is added to the composition before administration, and the pH of the composition is carefully maintained within a certain range during administration, a composition comprising cefepime and tazobactam can be used without causing phlebitis. Summary of the invention

[0007] Therefore, a pharmaceutical composition suitable for parenteral administration is provided, the 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 should be sufficient to maintain the pH of the composition within the range of 4.5-8 before parenteral administration.

[0008] In another aspect, provided is a use of the pharmaceutical composition of the present invention in the preparation of a medicament for treating, controlling or preventing bacterial infection.

[0009] In another general aspect, provided is a method for treating, controlling or preventing a bacterial infection in a subject, the method comprising parenterally administering a pharmaceutical composition of the present invention.

[0010] In another general aspect, there is provided 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 preparation of a medicament for treating, controlling or preventing bacterial infection.

[0011] In another general aspect, provided is a method for treating or preventing a bacterial infection in a subject, 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.

[0012] The following description sets forth in detail one or more embodiments of the present invention. Other features, objectives and advantages of the present invention will become more apparent from the following description (including the claims). DETAILED DESCRIPTION OF THE INVENTION

[0014] Reference will now be made to exemplary embodiments, which are described herein using specific language. However, it should be understood that these embodiments are not intended to limit the scope of the present invention. Any substitution and further improvement of the features of the present invention described herein, as well as any other application of the principles of the present invention described herein, that any person of ordinary skill in the relevant art can think of based on this specification, are considered to be within the scope of the present invention. It must be noted that the singular forms of "one", "a kind of" and "said" used in this specification and the appended claims include plural referents unless the context clearly indicates otherwise. All patents, patent applications and references cited in this specification are incorporated herein by reference in their entirety.

[0015] Now, the inventors have surprisingly found that bacterial infections can be treated 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 described herein also minimize or eliminate the problems associated with phlebitis.

[0016] The term "pharmaceutically acceptable salt" as used herein refers to one or more salts of a given compound that have the desired pharmacological activity of the free compound and do not produce adverse effects biologically or otherwise. Generally, "pharmaceutically acceptable salts" refer to and include salts that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. (J Pharmaceutical Sciences, 66: 1-19 (1977)) describe in detail a variety of pharmaceutically acceptable salts, which are incorporated herein by reference.

[0017] As used herein, the terms "infection" or "bacterial infection" refer to and include the presence of bacteria in or on a subject, which may benefit the subject if its growth is inhibited. Thus, the term "infection" refers to the presence of bacteria as well as the undesirable normal flora. The term "infection" includes infections caused by bacteria.

[0018] As used herein, the terms "treat, treating or treatment" refer to administering an agent, including a pharmaceutical composition or one or more active ingredients, for preventive and / or therapeutic purposes. The term "preventive treatment" refers to treating a subject that is not yet infected, but the subject is susceptible to infection or otherwise at risk of infection (preventing bacterial infection). The term "therapeutic treatment" refers to administering treatment to an already infected subject. As used herein, the terms "treat, treating or treatment" also refer to administering a composition as described herein or one or more active ingredients, with or without additional active or inert ingredients, for the following purposes: (i) reducing or eliminating a bacterial infection or one or more symptoms of a bacterial infection, or (ii) retarding the development 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 manifestations of adverse symptoms of a bacterial infection.

[0019] The term "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" as used herein refers to an amount having a therapeutic effect or an amount required 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 the active ingredient or pharmaceutical composition required to produce the desired therapeutic effect, which can be determined by clinical trial results, model animal infection studies and / or in vitro studies (such as in agar or fermentation medium). The pharmaceutically effective amount depends on a number of factors, including but not limited to the microorganisms involved (such as bacteria), the characteristics of the subject (such as height, weight, sex, age and medication history), the severity of the infection and the specific type of antimicrobial agent or active ingredient used. For preventive treatment, a therapeutically or preventively effective amount is an amount that is effective in preventing microbial (such as bacterial) infection. The amount of the active ingredient and / or pharmaceutical composition according to the present invention should be effective to provide the desired therapeutic effect or result.

[0020] The term "administration" or "administering" includes delivering a composition or one or more active ingredients to a subject, including, for example, by any suitable method for delivering the composition or active ingredient to the site of infection. The method of administration may vary depending on a number of factors, for example, the nature of the components or active and / or inert ingredients of the pharmaceutical composition, the site of possible or actual infection, the microorganisms involved, the severity of the infection, the age and physical condition of the subject, etc. Some non-limiting examples of ways to administer a composition or active ingredient to a subject according to the present invention include Oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, rectal, vaginal, gene gun, skin patch, eye drops, ear drops or mouthwash. In the case of a pharmaceutical composition comprising more than one ingredient (active or inert), one way to administer such a composition is by mixing the ingredients (e.g., in the form of a suitable unit dosage form such as tablets, capsules, solutions, powders, etc.) and then administering the dosage form. Alternatively, the ingredients may also be administered separately (simultaneously or sequentially), as long as the ingredients achieve a beneficial therapeutic level to achieve the desired therapeutic effect.

[0021] The term "parenteral administration" refers to and includes a route of administration that does not directly involve the gastrointestinal tract. Typically, non-limiting examples of parenteral routes of administration include intravenous (injection into a vein), intraarterial (injection into an artery), bone marrow infusion (injection into the bone marrow), intramuscular, intracerebral, intrathecal, and subcutaneous administration. In general, parenteral administration is performed by injecting or administering the composition or active ingredient directly into a subject without directly involving the gastrointestinal tract.

[0022] The term "growth" used herein refers to the growth of one or more microorganisms and includes the propagation or expansion of microorganisms (such as bacteria). The term "growth" also includes the maintenance of ongoing metabolic processes of microorganisms (such as bacteria), including processes that keep microorganisms alive.

[0023] As used herein, the term "efficacy" refers to the ability of a therapeutic agent or composition or one or more active ingredients to produce a desired biological effect in a subject. For example, the term "antimicrobial efficacy" of a composition or antimicrobial agent refers to the ability of the composition or antimicrobial agent to treat or prevent microbial (e.g., bacterial) infection in a subject.

[0024] As used herein, the term "synergy" or "synergy" refers to the interaction of two or more agents such that their combined effect is greater than the individual effects.

[0025] As used herein, the term "antimicrobial agent" refers to any substance, compound, or combination of substances or compounds that can: (i) inhibit, reduce, or prevent the growth of bacteria; (ii) inhibit or reduce the ability of bacteria to establish an infection in a subject; or (iii) inhibit or reduce the ability of bacteria to multiply or remain infectious in the environment. The term "antimicrobial agent" also refers to a compound that can reduce the infectivity or toxicity of bacteria.

[0026] As used herein, the term "β-lactam antibacterial agent" refers to a compound that has antibacterial properties and contains a β-lactam nucleus in its molecular structure.

[0027] The term "β-lactamase" as used herein refers to any enzyme or protein or any other substance that decomposes the β-lactam ring. The term "β-lactamase" includes enzymes produced by bacteria and has the ability to partially or completely hydrolyze the β-lactam ring in a β-lactam compound.

[0028] As used herein, the term "β-lactamase inhibitor" refers to a compound that is capable of partially or completely inhibiting the activity of one or more β-lactamases.

[0029] The term "pharmaceutically inert ingredient" or "inert ingredient", "carrier" or "excipient" refers to a compound or substance used to facilitate administration of a 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, among others. Typically, non-limiting examples of liquid carriers include sterile water, saline, buffers, nonionic surfactants, and edible oils such as oil, peanut oil, and sesame oil, among others. 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 of Merck & Company, Rahway, NJ, USA. Considerations for the introduction of various components into pharmaceutical compositions are described, for example, in Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th edition, edited by Gilman et al. (1990), Pergamon Press, which is incorporated herein by reference in its entirety.

[0030] The term "subject" as used herein refers to a vertebrate or invertebrate, including mammals. The term "subject" includes humans, animals, birds, fish, or amphibians. Typical non-limiting examples of "subjects" include humans, cats, dogs, horses, sheep, cows, pigs, lambs, rats, mice, and guinea pigs.

[0031] Those skilled in the art will appreciate that the compounds described herein may generally exist or be used in various pharmaceutically acceptable forms, including pharmaceutically acceptable salts, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or other pharmaceutically acceptable derivatives thereof. Therefore, reference to the compounds is intended to include pharmaceutically acceptable salts, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or other pharmaceutically acceptable derivatives thereof. For example, the terms "cefepime", "tazobactam" or "arginine" include pharmaceutically acceptable salts, prodrugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or other pharmaceutically acceptable derivatives thereof.

[0032] 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 ingredient." The term "pharmaceutical composition" or "composition" as used herein refers to and includes the composition according to the present invention.

[0033] In a general aspect, a pharmaceutical composition suitable for parenteral administration is provided, the 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 should be sufficient to maintain the pH of the composition in the range of 4.5-8 before parenteral administration.

[0034] In some embodiments, tazobactam is present as tazobactam sodium. In some other embodiments, cefepime is present as cefepime hydrochloride. In some embodiments, arginine is present as arginine hydrochloride.

[0035] In some embodiments, the pH of the composition is in the range of about 6-8 prior to parenteral administration.

[0036] In some other embodiments, the pH of the composition is in the range of about 6.5-7.5 prior to parenteral administration.

[0037] In some embodiments, the content of cefepime or a pharmaceutically acceptable salt thereof in the composition is about 0.01 grams to about 10 grams.

[0038] In some other embodiments, the content of tazobactam or a pharmaceutically acceptable salt thereof in the composition is about 0.01 grams to about 10 grams.

[0039] 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:

[0040] (i) about 0.50 g of cefepime or a pharmaceutically acceptable salt thereof, and about 0.50 g of tazobactam or a pharmaceutically acceptable salt thereof;

[0041] (ii) about 0.75 g of cefepime or a pharmaceutically acceptable salt thereof, and about 0.75 g of tazobactam or a pharmaceutically acceptable salt thereof;

[0042] (iii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, and about 1 gram of tazobactam or a pharmaceutically acceptable salt thereof;

[0043] (iv) about 1.5 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

[0044] (v) about 2 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 2 grams of tazobactam or a pharmaceutically acceptable salt thereof;

[0045] (vi) about 2.5 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 2.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

[0046] (vii) about 2 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 1 gram of tazobactam or a pharmaceutically acceptable salt thereof;

[0047] (viii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, and about 0.5 gram of tazobactam or a pharmaceutically acceptable salt thereof;

[0048] (ix) about 3 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 3 grams of tazobactam or a pharmaceutically acceptable salt thereof; or

[0049] (x) about 3 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the composition of the present invention consists of cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof as the only active ingredients.

[0051] In some other embodiments, the content of arginine or a pharmaceutically acceptable salt thereof in the composition according to the present invention is about 0.50 g to about 0.90 g per gram of cefepime or a pharmaceutically acceptable salt thereof.

[0052] In some other embodiments, the content of arginine or a pharmaceutically acceptable salt thereof in the composition according to the present invention is about 0.70 g to about 0.80 g per gram of cefepime or a pharmaceutically acceptable salt thereof.

[0053] 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 of the present invention in any of the following amounts:

[0054] (i) about 0.50 g of cefepime or a pharmaceutically acceptable salt thereof, about 0.50 g of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.35 g to about 0.40 g of arginine or a pharmaceutically acceptable salt thereof;

[0055] (ii) about 0.75 g of cefepime or a pharmaceutically acceptable salt thereof, about 0.75 g of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.525 g to about 0.60 g of arginine or a pharmaceutically acceptable salt thereof;

[0056] (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 about 0.80 grams of arginine or a pharmaceutically acceptable salt thereof;

[0057] (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 about 1.2 grams of arginine or a pharmaceutically acceptable salt thereof;

[0058] (v) about 2 grams of cefepime or a pharmaceutically acceptable salt thereof, about 2 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 1.4 grams to about 1.6 grams of arginine or a pharmaceutically acceptable salt thereof;

[0059] (vi) about 2.5 grams of cefepime or a pharmaceutically acceptable salt thereof, about 2.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 1.75 grams to about 2 grams of arginine or a pharmaceutically acceptable salt thereof;

[0060] (vii) about 2 grams of cefepime or a pharmaceutically acceptable salt thereof, about 1 gram of tazobactam or a pharmaceutically acceptable salt thereof, and about 1.4 grams to about 1.6 grams of arginine or a pharmaceutically acceptable salt thereof;

[0061] (viii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, about 0.5 gram of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.70 gram to about 0.80 gram of arginine or a pharmaceutically acceptable salt thereof;

[0062] (ix) about 3 grams of cefepime or a pharmaceutically acceptable salt thereof, about 3 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 2.1 grams to about 2.4 grams of arginine or a pharmaceutically acceptable salt thereof; or

[0063] (x) about 3 grams of cefepime or a pharmaceutically acceptable salt thereof, about 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 2.1 grams to about 2.4 grams of arginine or a pharmaceutically acceptable salt thereof.

[0064] The pharmaceutical composition according to the present invention may contain 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, talcum, cellulose, cross-linked sodium carboxymethyl cellulose, glucose, gelatin, sucrose, magnesium carbonate, wetting agents, emulsifiers, solubilizers, buffers, lubricants, stabilizers, binders, etc.

[0065] In some embodiments, the composition according to the present invention further comprises 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, magnesium aluminum 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, disodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, anhydrous aluminum hydroxide gel, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium hydroxide, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium lactate, magnesium metasilicate, magnesium oxide, magnesium phthalate, magnesium phosphate, 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, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, tromethamine, trishydroxymethylaminomethane, amino acids 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 optically active isomers thereof, or racemic mixtures thereof, acid salts of amino acids, alkali salts of amino acids or mixtures thereof.

[0066] Pharmaceutical compositions of the present invention can be formulated into various dosage forms, including solid, semisolid, aerosol and liquid dosage forms. Typical non-limiting examples of dosage forms include tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs, injection preparations, etc. If necessary, the compositions of the present invention can also be prepared and packaged as bulk form or unit dosage form.

[0067] The composition of the present invention can also be formulated as 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 a mixture. Alternatively, the composition of the present invention can also be formulated as 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 are in separate vials or dosage forms; any two active ingredients are in one vial or dosage form, and the third active ingredient is in a separate vial or dosage form).

[0068] In some embodiments, the pharmaceutical composition according to the present invention is in the form of a powder or a solution. In some other embodiments, the pharmaceutical composition according to the present invention is in the form of a powder or a solution, which can be reconstituted by adding a compatible reconstitution diluent prior to administration.

[0069] In some embodiments, the pharmaceutical compositions according to the present invention are in the form of a powder, which can be reconstituted by the addition of a compatible reconstitution diluent prior to parenteral administration.

[0070] In some embodiments, the pharmaceutical composition according to the present invention is in the form of a solution ready for parenteral administration.

[0071] In some embodiments, the pharmaceutical composition according to the present invention is in the form of a solution, which can be further diluted by the addition of a compatible reconstitution diluent prior to parenteral administration.

[0072] In some embodiments, the pharmaceutical composition according to the present invention is in the form of a powder, which is contained in a bottle or bag as a unit dose prior to parenteral administration. In some other embodiments, the pharmaceutical composition according to the present invention is in the form of a solution, which is contained in a bottle or bag as a unit dose prior to parenteral administration.

[0073] In some other embodiments, the pharmaceutical composition according to the present invention is in the form of a frozen composition that can be diluted with a compatible reconstitution diluent prior to administration.

[0074] A variety of reconstitution diluents can be used. Typical non-limiting examples of reconstitution diluents include water for injection, 0.9% sodium chloride solution, 5% dextrose solution, physiological saline solution, and the like.

[0075] In another general aspect, methods of treating, controlling or preventing bacterial infections using compositions according to the invention are provided. In some embodiments, methods for treating, controlling or preventing bacterial infections in subjects are provided, comprising administering an effective amount of a composition of the invention to the subject. In some other embodiments, methods for treating, controlling or preventing bacterial infections in subjects are provided, comprising administering a pharmaceutical composition of the invention parenterally.

[0076] In some embodiments, the pharmaceutical composition according to the present invention is used to treat, control or prevent bacterial infection. In some embodiments, the composition according to the present invention is used to prepare a medicament for treating, controlling or preventing bacterial infection.

[0077] 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 to prepare a medicament for treating, controlling or preventing bacterial infection.

[0078] In some embodiments, provided is a method for treating, controlling, or preventing a bacterial infection in a subject, 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.

[0079] In some embodiments, a method for 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 a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, in the methods according to the present invention, cefepime or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.01 grams to about 10 grams.

[0081] In some other embodiments, in the methods according to the present invention, tazobactam or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.01 grams to about 10 grams.

[0082] In some other embodiments, a method for treating, controlling or preventing a bacterial infection in a subject is provided, the method comprising parenteral administration of a solution having a pH in the range of 4-8; the solution comprising cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof; the arginine or a pharmaceutically acceptable salt thereof is present in an amount sufficient to maintain the pH of the composition in the range of 4.5-8 prior to parenteral administration.

[0083] In some embodiments, a method for treating, controlling or preventing a bacterial infection is provided, the method comprising parenteral administration of a solution comprising cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof, the pH of the solution being in the range of 4.5 to 8. In some other embodiments, the pH of the solution is in the range of about 6.5 to 7.5.

[0084] 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:

[0085] (i) about 0.50 g of cefepime or a pharmaceutically acceptable salt thereof, and about 0.50 g of tazobactam or a pharmaceutically acceptable salt thereof;

[0086] (ii) about 0.75 g of cefepime or a pharmaceutically acceptable salt thereof, and about 0.75 g of tazobactam or a pharmaceutically acceptable salt thereof;

[0087] (iii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, and about 1 gram of tazobactam or a pharmaceutically acceptable salt thereof;

[0088] (iv) about 1.5 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

[0089] (v) about 2 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 2 grams of tazobactam or a pharmaceutically acceptable salt thereof;

[0090] (vi) about 2.5 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 2.5 grams of tazobactam or a pharmaceutically acceptable salt thereof;

[0091] (vii) about 2 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 1 gram of tazobactam or a pharmaceutically acceptable salt thereof;

[0092] (viii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, and about 0.5 gram of tazobactam or a pharmaceutically acceptable salt thereof;

[0093] (ix) about 3 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 3 grams of tazobactam or a pharmaceutically acceptable salt thereof; or

[0094] (x) about 3 grams of cefepime or a pharmaceutically acceptable salt thereof, and about 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof.

[0095] 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:

[0096] (i) about 0.50 g of cefepime or a pharmaceutically acceptable salt thereof, about 0.50 g of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.35 g to about 0.40 g of arginine or a pharmaceutically acceptable salt thereof;

[0097] (ii) about 0.75 g of cefepime or a pharmaceutically acceptable salt thereof, about 0.75 g of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.525 g to about 0.60 g of arginine or a pharmaceutically acceptable salt thereof;

[0098] (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 about 0.80 grams of arginine or a pharmaceutically acceptable salt thereof;

[0099] (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 about 1.2 grams of arginine or a pharmaceutically acceptable salt thereof;

[0100] (v) about 2 grams of cefepime or a pharmaceutically acceptable salt thereof, about 2 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 1.4 grams to about 1.6 grams of arginine or a pharmaceutically acceptable salt thereof;

[0101] (vi) about 2.5 grams of cefepime or a pharmaceutically acceptable salt thereof, about 2.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 1.75 grams to about 2 grams of arginine or a pharmaceutically acceptable salt thereof;

[0102] (vii) about 2 grams of cefepime or a pharmaceutically acceptable salt thereof, about 1 gram of tazobactam or a pharmaceutically acceptable salt thereof, and about 1.4 grams to about 1.6 grams of arginine or a pharmaceutically acceptable salt thereof;

[0103] (viii) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, about 0.5 gram of tazobactam or a pharmaceutically acceptable salt thereof, and about 0.70 gram to about 0.80 gram of arginine or a pharmaceutically acceptable salt thereof;

[0104] (ix) about 3 grams of cefepime or a pharmaceutically acceptable salt thereof, about 3 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 2.1 grams to about 2.4 grams of arginine or a pharmaceutically acceptable salt thereof; or

[0105] (x) about 3 grams of cefepime or a pharmaceutically acceptable salt thereof, about 1.5 grams of tazobactam or a pharmaceutically acceptable salt thereof, and about 2.1 grams to about 2.4 grams of arginine or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, according to the method of the present invention, the composition of the present invention is administered by any suitable method, which is used to deliver the composition or its components to the position required. In the method using the active ingredient for administration, the active ingredient can also be administered by any suitable method. The method of administration can depend on multiple factors, for example, the property of the active ingredient or composition, the position of possible or actual infection, the microorganism involved, the severity of infection, the age and physical condition of the object, etc. Some non-limiting examples according to the method of administration of the present invention include intravenous, intraperitoneal, intramuscular, parenteral, intratracheal, rectal, etc.

[0107] The composition according to the present invention comprises 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. It will be appreciated by those skilled in the art that these active ingredients can be formulated into various dosage forms, wherein the active ingredients can exist together (as a mixture) or as separate components. When the active ingredients in the composition are formulated as a mixture, such a composition can be delivered by administering such a mixture. For compositions or dosage forms in which the active ingredients are not present in the form of a mixture but in the form of separate components, the composition / dosage form can be administered in several ways. In one possible manner, the active ingredients can be mixed in a desired proportion and then the mixture is administered as desired. Alternatively, the active ingredients can be administered separately in appropriate amounts to achieve the same or equivalent therapeutic level or effect as that achieved by administering an equivalent mixture. If desired, one or more inert ingredients or inactive ingredients can also be used during formulation and / or administration.

[0108] In some embodiments, in the method according to the present invention, cefepime or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially. In some embodiments, the composition or active ingredient according to the present invention is packaged in the form of a kit. The composition or active ingredient can be packaged in one or more containers, such as bottles, vials, syringes, boxes, bags, etc. The kit may also include instructions for use of its contents.

[0109] Depending on specific requirements or desired therapeutic effects, the compositions or active ingredients of the present invention can be administered at different time intervals. In some embodiments, the compositions or active ingredients of the present invention are administered once, twice, three times or four times a day. In some other embodiments, the compositions or active ingredients of the present invention are administered every 4 hours, 6 hours, 8 hours, 12 hours or 24 hours.

[0110] In another general aspect, the composition or active ingredient of the present invention is used for prophylactic treatment of a subject, comprising administering a prophylactically effective amount of the composition or active ingredient of the present invention to a subject at risk of bacterial infection.

[0111] In general, the compositions or active ingredients of the present invention are effective against infections caused by various bacteria, including bacteria that are resistant 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 present invention include infections caused by bacteria of the genus Escherichia, Staphylococcus, Streptococcus, Haemophilus, Klebsiella, Moraxella, Enterobacter, Proteus, Serratia, Pseudomonas, Acinetobacter, Citrobacter, Stenotrophomonas, Bacteroides, Prevotella, Fusobacterium, Clostridium.

[0112] In general, the compositions or active ingredients according to the present invention can be used to treat, control or prevent serious infections, including, for example, skin and soft tissue infections, febrile neutropenia, urinary tract infections, intra-abdominal infections, respiratory tract infections, pneumonia (nosocomial), bacteremia, meningitis, diabetic foot infections, bone and joint infections, surgical site infections, Shigella dysentery, etc.

[0113] It is obvious to those skilled in the art that various substitutions and modifications can be made to the compositions and / or methods disclosed herein without departing from the scope and spirit of the invention. For example, those skilled in the art will appreciate that the invention can be implemented in various different ways described within the general description. Example

[0114] The following examples illustrate the most well-known embodiments of the present invention. However, it should be understood that the following are merely examples or illustrations of the application of the principles of the present invention. As long as they do not depart from the spirit and scope of the present invention, those skilled in the art may make many modifications and substitutions to the compositions, methods and systems. The appended claims are intended to cover these modifications and arrangements. Therefore, although the present invention has been specifically described above, the following examples provide additional details of the embodiments of the present invention that are currently considered to be the most feasible and preferred.

[0115] Example 1

[0116] The antimicrobial activity of the combination of cefepime and tazobactam against various bacterial strains, including those known to produce one or more β-lactamases, was studied in a quantitative drug diffusion assay in accordance with CLSI recommendations (Clinical and Laboratory Standards Institute, CLSI, Performance Standards for Antimicrobial Susceptibility Testing, 20th Edition Instructional Supplement, M 100-S20, Vol. 30, No. 1, 2010).

[0117] In a typical study, an overnight bacterial culture after appropriate dilution was inoculated into molten, cooled agar medium and poured into plates. Antimicrobial agents containing 6 mm diameter disks were placed on the agar surface. Inhibition zones were observed after incubation at 35 ± 2 ° C in ambient air for 16-18 hours. The overall procedure was performed in accordance with CLSI recommendations and the results are shown in Table 1. These tests are routinely used to determine the possibility of using a given antimicrobial agent or combination to treat a specific infection. In general, zone inhibition values ​​in the sensitive (S) range indicate that the strain is sensitive to the antimicrobial agent or combination. It is generally believed that if the zone inhibition value is in the resistant (R) range, the antimicrobial agent or combination under consideration will not be able to effectively treat the infection. CLSI-based susceptibility evaluations of these combinations (which guide treatment decisions in hospitals / community agencies) show that the combination of cefepime and tazobactam can convert the susceptibility spectrum of ESBL strains from "resistant" to "sensitive", indicating that the cefepime-tazobactam combination of the present invention has favorable clinical utility.

[0118]

[0119] Example 2

[0120] A 12-day repeated dose study was conducted to study the effect of arginine on the tolerance of intravenous administration of a composition comprising cefepime and tazobactam. Three groups of rats were used in this study, each group including 5 male Wistar rats (160-180 grams). The first group of rats (Group I) was given cefepime for injection (400 mg / kg dose). The second group of rats (Group II) was given a combination of cefepime and tazobactam sodium for injection (the doses of cefepime and tazobactam were each 400 mg / kg of water for injection). The third group of rats (Group III) was given a combination of cefepime and tazobactam sodium for injection and additional arginine (in 5 ml of water for injection, the doses of cefepime and tazobactam were each 400 mg / kg, containing 4 mg / ml arginine). In a typical process, a new vial was opened every day, the required amount of arginine diluent was added, and the pH value was recorded. Additionally, dilutions were made with 0.9% saline to reach a final concentration of 100 mg / mL, and the pH was recorded. In each case, dose failures due to phlebitis were counted, and the results are shown in Table 2. In the case of rats, failed dosing attempts due to loss of tail vein integrity were counted.

[0121] As can be seen from the results of Table 2, for administration of Cefepime for injection at a pH in the range of about 4.1-4.2, the percentage of failed administration attempts was about 13.1%. For administration of a solution containing Cefepime for injection and Tazobactam Sodium (pH in the range of about 3.8-4.1), the percentage of failed administration attempts was even higher (about 15.1%). Surprisingly, when the same composition containing Cefepime for injection and Tazobactam Sodium was administered but arginine was added and the pH of the solution was adjusted to a range of about 6 to about 7.4 before administration, the percentage of failed administration attempts dropped significantly to about 3.1%. This study confirmed that the frequency of failed administration attempts was reduced (less phlebitis) after adding arginine to the composition and adjusting the pH operating range.

[0122] Example 3

[0123] Several compositions containing the disclosed amounts of active ingredients were prepared in powder and solution form. Some compositions were also prepared in solution form with a pH within the disclosed range.

[0124]

Claims

1. A pharmaceutical composition suitable for parenteral administration, the composition comprising the following ingredients: (a) 2 grams of cefepime or a pharmaceutically acceptable salt thereof, (b) 2 grams of tazobactam or a pharmaceutically acceptable salt thereof, and (c) arginine or a pharmaceutically acceptable salt thereof; wherein: The pH of the composition is maintained in the range of 6-8 prior to parenteral administration.

2. The pharmaceutical composition according to claim 1, characterized in that The compositions are in the form of powders which can be reconstituted prior to parenteral administration by the addition of a compatible reconstitution diluent.

3. The pharmaceutical composition according to claim 1, characterized in that The composition is in the form of a solution ready for parenteral administration.

4. The pharmaceutical composition according to claim 1, characterized in that The composition is in the form of a solution which can be further diluted by the addition of a compatible reconstitution diluent prior to parenteral administration.

5. The pharmaceutical composition according to claim 1, characterized in that The composition is in the form of a powder and is a unit dose contained in a bottle or bag prior to parenteral administration.

6. The pharmaceutical composition according to claim 1, characterized in that The composition is in the form of a solution and is a unit dose contained in a bottle or bag prior to parenteral administration.

7. The pharmaceutical composition according to claim 1, characterized in that 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 as a mixture or as separate components.

8. The pharmaceutical composition of any one of claims 1 to 7, for use in a method for treating, controlling or preventing bacterial infection.

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