WO2007086011A1

WO2007086011A1 - Formulation comprising cefepime, tazobactam and linezolid

Info

Publication number: WO2007086011A1
Application number: PCT/IB2007/050243
Authority: WO
Inventors: Jegannathan Srinivas
Original assignee: Jegannathan Srinivas
Priority date: 2006-01-25
Filing date: 2007-01-24
Publication date: 2007-08-02

Abstract

The present invention is to provide a pharmaceutical composition of Cefepime and Tazobactum in fixed dose combination with Linezolid in Injectable dosage form. Tazobactum in the composition acts as Enzyme Inhibitor that enhances the antibacterial activity of Cefepime by inhibiting Betalactamases such as, Group 1 Cephalosporinases, Group 2br TEM-Betalactamases and Group 3 Metallo-Betalactamases. The active ingredients are basically Betalactam antibiotics, selected from Cefepime and combined with Tazobactum. Besides, the composition containing Cefepime and Tazobactum is combined with yet another drug, Linezolid, an Oxazolidinone, a new class of antibacterial, with exceptionally good activity against MRSA, VRSA, E.faecalis and Bacteroides. The present invention is envisaged to have a useful role in Critical conditions as an empiric therapy.

Description

FORMULATION COMPRISING CEFEPIME, TAZOBACTAM AND LINEZOLID

Field of the invention:

The present invention belongs to the field of pharmaceutical technology. More particularly the invention principally relates to a pharmaceutical composition in Injectable dosage form, comprising Cefepime its or pharmaceutically acceptable hydrates, salts or esters as the active ingredient, Tazobactum and further fortified with Linezolid, an Oxazolidinone.

Background of the invention:

Majority of the Gram +ve and Gram -ve bacteria develop resistance to Betalactam Antibiotics by producing enzymes known as Betalactamases, which hydrolyze Betalactam antibiotics such as penicillins, cephalosporins and carbapenems. These enzymes catalyze the hydrolysis of the Betalactam ring to effectively destroy the antibiotic's activity. Enzyme Inhibitors such as Tazobactum have been proved to be extremely useful in overcoming the bacterial resistance by inhibiting the betalactamase enzyme. However, the enzyme inhibitors have a limited or nil action against the bacteria that produce Extended Spectrum Betalactamases (ESBL) such as Pseudomonas spp. Nevertheless, combining

Tazobactum has been found to substantially enhance the antibacterial activity even between second-generation cephalosporins, such as Cefaclor and Cefprozil (U.S. Patent Application No. 20030109503 of GSK).

A similar preparation has been cited in U.S Patent No. 6,554,991 - an oxazolidinone compound, sulbactam, and ampicillin active agents, demonstrating activity against resistant strains of bacteria.

Cefepime has an excellent activity against a wide range of Gram +ve and Gram -ve organisms. However, E.faecalis and Bacteroides are resistant to Cefepime. The Fixed Dose Combination with Linezolid provides this additional spectrum to make the composition suitable for empiric therapy, especially in critical conditions

Cefepime has minimal activity against MRSA. However, improved activity against MRSA can be demonstrated when combined with Vancomycin, Quinupristin-Dalfopristin and

Linezolid (Allen et al, 2002, Vanthitha et al, 2005). It was demonstrated that improved kill rate with Cefepime was attained in combination with Linezolid against the MRSA Strain, R2484

Although the higher generation Cephalosporins exhibit greater stability to hydrolysis by Betalactamases, ESBLs do pose a major threat to almost to all the Cephalosporins, including Cefepime. The addition of Tazobactum provides inhibitory action against a wide ranging Betalactamases that includes Group I Cephalosporinases, Group 2br TEM Betalactamases and Group 3 metallo-Betalactamases

Objectives:

The objective of the present invention is to provide a pharmaceutical composition that provides Cefepime with an enhanced activity in combination with Tazobactum.

Another objective of the present invention is to provide a pharmaceutical composition that provides additional spectrum of activity with the addition of Linezolid, an Oxazolidinone, a new class of antibacterial with excellent activity against MRSA/VRSA and some anerobes

Summary:

The composition of this invention is in the Injectable dosage form comprising the active ingredients in fixed dose combination in specific ratios, with Arginine and Sodium citrate, etc., as inactive ingredients

Further, the Cefepime, or its pharmaceutically acceptable hydrates, salts or esters may be present in an amount from 500 mg to 2000 mg. Examples of other cephalosporin antibiotics that may be used include all other I Generation Cephalosporins and, pharmaceutically acceptable hydrates, salts or esters thereof.

According to the present invention the Tazobactum is used in combination with Cefepime in a ratio of 1 :2, 1 :4 or 1 :8 based on the requirement for enhanced antimicrobial activity. Tazobactum exhibits inhibitory action against Group 1 Cephalosporinases, Group 2br TEM Betalactamases and Group 3 Metallo Betalactamases

Detailed Description of the invention with reference to the Methods:

The pharmaceutical composition of the present invention may be prepared by procedures well known to formulation chemists. The method of manufacturing can affect the release characteristics of the composition. The method is as follows:

1. This invention relates to pharmaceutical formulations, in particular to novel formulations for the treatment of bacterial infections.

2. Tazobactum in the form of its derivatives, particularly its salts, are consequently used in formulations in combination with antibiotics to suppress the activity of beta. -lactamase enzymes which mediate bacterial resistance to betalactam antibiotics. Tazobactum exhibits inhibitory action against Group 1 Cephalosporinases, Group 2br TEM Betalactamases and Group 3 Metallo Betalactamases

3. The above uses, formulation and methods are particularly suitable in respect of penicillin-resistant microorganisms, e.g. which are believed to have a penicillin-binding-protein mediated resistance mechanism.

4. This type of microorganisms includes penicillin- resistant organisms such as Streptococcus spp., e.g. S. pneumoniae, Haemophilus spp., e.g. H. influenzae, Staphylococcus spp., E.coli, Proteus spp. Ps. Aeruginosa and Moraxella spp.

5. The use of Tazobactum together with betalactam antibiotics is believed to be novel per se, and therefore in a further aspect of this invention there is provided a pharmaceutical formulation comprising in combination Tazobactum together with a cephalosporin antibiotic selected from the cephalosporins, Cefepime.

6. The betalactam antibiotics referred to herein may be in the form of the free acids or pharmaceutically acceptable salts or in-vivo hydrolysable esters. 7. The Tazobactum and any other antibacterial agent such as the penicillin or cephalosporin antibiotics, as used in this invention, whether in the form of the free acids, salts, esters or derivatives thereof are preferably each in a substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, preferably at least 85% especially at least 98% pure on a weight basis.

8. The formulation may be formulated for administration by any route, such as oral, topical or parenteral. The route of choice may for example be determined by the route of choice for the antibacterial agent used in combination with the Tazobactum. The formulation may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

9. The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. 10. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present at from about 1 % up to about 98% of the formulation. More usually they will form up to about

80% of the formulation.

11. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. Such tablets may also include an effervescent couple of generally known type, e.g a solid carboxylic acid and an alkali metal carbonate or bicarbonate. Such tablets may also include a chewable base such as mannitol, sorbitol or lactose, optionally together with an effervescent couple. Such tablets and solid dosage forms may be made by any of the generally known methods for such dosage forms, and may be coated according to methods well known in normal pharmaceutical practice. 12. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; nonaqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

13. Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

14. For parenteral administration, fluid unit dosage forms are prepared utilizing Tazobactum and any antibacterial agent and a sterile vehicle, water being preferred. These active compounds, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the active compounds can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

15. Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the formulation can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the ingredients of the suspension are suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The formulation can be sterilised by exposure of its dry constituents to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the formulation to facilitate uniform distribution of the active compounds.

16. Since salts of Tazobactum are extremely hygroscopic the solid and non-aquous liquid formulations of this invention must be prepared in dry conditions, typically at a relative humidity of 30% or less. All constituents of formulations of this invention should be predried. Aqueous solution and suspension formulations of this invention can only be provided in the form of dry solids for make up into aqueous solution or suspension shortly prior to use, for example 5 days in the case of oral suspensions. It may also be necessary to maintain such suspensions at low temperatures, e.g >5. degree. C.

17. A formulation according to the invention may be in unit dosage form, for example unit dosage form for oral or parenteral administration, which latter will primarily include administration by injection or infusion, especially intramuscular and intravenous administration.

18. The above-mentioned formulations may contain 0.1- 90% by weight, preferably from 10-60% by weight of the active materials, depending on the method of administration.

19. The Tazobactum may suitably be administered to the patient at a daily dosage ranging from 125 to 250 mg, preferably from 50 to 500 mg, of clavulanate expressed as its free acid equivalent may be administered daily, suitably in from 1 :8, preferably from 2:1 , separate doses. Higher or lower dosages may, however, be used in accordance with clinical practice. 20. Suitable unit dosages and maximum daily dosages of any antibacterial agent used in combination with Tazobactum in this invention may for example be determined according to the unit dosages and maximum daily dosages of the agent used conventionally. For example Cefepime is generally provided in unit dosages of 500 and 2000 mg, and may be dosed up to a maximum daily dosage of 12000 mg per day.

21. A preferred combination of this invention is Tazobactum with Cefepime, in a ratio Tazobactum:Cefepime in the range 1 :4 to 1 :8, for example together in a formulation.

22. An in-vitro study to evaluate the relative Minimum Inhibitory Concentrations of the novel formulation with that of plain Cefepime. The results demonstrated a significantly superior antibacterial activity of the novel formulation, including activity against strains resistant to plain Cefepime. The results also demonstrated additional spectrum coverage against MRSA, E.faecalis, Bacteroides, etc

Several good antibiotics, especially betalactam antibiotics become ineffective or obsolete due to the resistance to antibiotics by betalactamase producing organisms. This problem can be overcome to a large extent by the addition of an effective enzyme inhibitor like Tazobactum. Besides, Cefepime is preferred as an Empiric therapy in Critical conditions and hence addition of Tazobactum and Linezolid would certainly give a new lease of life for this excellent antibiotic.

DISCLOSURE OF INVENTION:

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth.

Claims

I claim:

1. A Pharmaceutical composition of Cefepime and its sodium, salts or esters containing betalactam antibiotic, which acts as an active ingredient, in fixed dose combination with Linezolid, a new class of antibiotic, oxazolidinones, with an excellent activity against MRSA & VRSA. Besides, Cefepime is combined with an enzyme inhibitor, such as, Tazobactum to enhance antimicrobial activity.

2. A Pharmaceutical composition as claimed in claim 1 , wherein the Tazobactum in combination with Cefepime to be in the ratio of 1 :2, 1 :4 or 1 :8 based on the requirement for enhanced antimicrobial activity.

3. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1 , wherein the composition in the parenteral dosage form to contain Cefepime, Linezolid and Tazobactum as active ingredients. The Composition to contain Arginine, Sodium citrate, etc., as inactive ingredients

4. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1 , wherein the

Cefepime or its hydrates, salts or esters are present in an amount between 500 mg to 2000 mg.

5. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1 , wherein the Linezolid and its salts or esters are present in an amount ranging from 200 to 600 mg

6. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1 , wherein the Tazobactum and antibacterial agent such as the penicillin or cephalosporin antibiotics, whether in the form of the free acids, salts, esters or derivatives thereof are preferable at least 60% pure, more suitably at least 75% pure, preferably at least 85% especially at least 98% pure on a weight basis.

7. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1 , wherein the topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

8. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1 , wherein the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present at from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

9. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1 , wherein the formulations may be in unit dose presentation form of tablets and capsules for oral administration and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone fillers.

10. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1 , wherein the formulations may be in Oral liquid preparations form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.