Title of Invention

SYNERGISTIC ANTIBACTERIAL COMPOSITION OF CEFIXIME AND CLOXACILLIN / DICLOXACILLIN SODIUM OR ANY OTHER OXACILLIN WITH CLAVULANIC ACID

Abstract

A Pharmaceutical composition of Cefixime and its hyd~ates, salts or esters containing betalactam antibiotics which act as an active ingredient in fixed dose combination with Linezolid and Potassium Clavulanate, besides an absorption enhancer such as, Betacyclodextrin in conventional as well as modified release fixed dosage formulation to enhance antimicrobial activity. Further, the composition is made G.I. friendly with the addition of substance for restoration of microflora .

Full Text

Title: Fixed Dose Synergistic Antibacterial Formulation of Cefixime and Dicloxacillin sodium and Clavulanic Acid. Field of invention: The present invention belongs to the field of pharmaceutical technology and relates to a pharmaceutical composition of normal and modified release fixed dose formulations comprising a betalactam antibiotic or their pharmaceutical^ acceptable hydrates, salts or esters as the active ingredient, Clavulanic Acid. More particularly the invention relates to pharmaceutical composition of normal and modified release fixed dose formulations in which the active material is selected from Cefixime Trihydrate and Dicloxacillin, or its pharmaceutical^ acceptable hydrates, salts or esters. The composition comprises Clavulanic Acid as an antibiotic adjuvant at either immediate release or controlled release part. Further optionally, the composition contains Prebiotic, such as Isomaltooligosaccharides to overcome the dysbiosis likely to be caused by the fixed dose combination of the antibiotics. Inclusion of Clavulanic Acid enables enhanced antimicrobial activity and potentiation of Cefixime. Further, Dicloxacillin is added to provide the much-needed coverage of Gram +ve organisms, which is a therapy gap for Cefixime. The Fixed Dose Combination of Cefixime, Dicloxacillin sodium and Clavulanic Acid is a Novel Drug Delivery System, comprising an immediate release form and a sustained release form. The composition thus contains Cefixime Trihydrate, Dicloxacillin Sodium, Clavulanic Acid and Probiotics, such as Isomaltooligosaccharides. Background of 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 Clavulanic Acid 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 Clavulanic Acid has been found to substantially enhance the antibacterial activity even among second generation cephalosporins, such as Cefaclor and Cefprozil (U.S. Patent Application No. 20030109503 of GSK). Most drugs used to treat microbial infections are given more than once during a dosage regimen. The objectives during antimicrobial therapy are to maximize blood concentration; preferably several fold higher than the minimum inhibitory concentration (MIC) for the particular agent, but to minimize both the risk of toxicity to the patient and of promoting microbial resistance. Although oral administration will be the preferred route, in the case of antibiotics this route is frequently unattractive because of their low or variable oral bioavailability. While many compounds are known to be useful as pharmacologically active substances, some of them have relatively short biological half-life and need to be administered several times a day in order to achieve desired therapeutic effect. However, a decrease in the frequency of administration will not only reduce the burden on the patient but will also increase compliance and thus provide greater therapeutic effect. It can be achieved by controlling the release of active ingredients or by reducing the elimination of the active ingredient from the body, so that the effective level is maintained in the blood for a prolonged period of time. This has been primarily achieved by development of new drug delivery systems utilizing diverse techniques and principles. Amongst these, known in the art is one such delivery system, which employs hydrophilic polymers to produce, sustained or modified release pharmaceutical compositions. For modified release solid dosage forms comprising a drug dispersed uniformly in hydrophilic polymers, release of the drug is controlled primarily by diffusion of the drug, or by surface erosion of the hydrophilic polymers into the surrounding medium, or by a combination of the two processes. Control of the rate of release can produce constant blood levels of the active ingredient that may result in reducing the frequency of administration, thereby improving patient compliance to the dosage regimen. The relevant prior art methods, which teach adaptation of diverse delivery systems for sustained release of the active, are as follows. US Patent Application No. 20020136764 discloses an antibiotic product, in particular a betalactam such as cephalosporin (in particular cefuroxime and/or cefpodoxime) or a penicillin (in particular axmoxicillin or dicloxacillin) is comprised of at least three dosages forms, each of which has a different release profile, with the C.sub.max for the antibiotic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a C.sub.max at different times. US Patent Application No. 20030096007 discloses an antibiotic composition that is a mixture of antibiotic compositions or dosage forms wherein said composition contains a first composition or dosage form comprising a first antibiotic and a pharmaceutically acceptable carrier; a second composition or dosage form comprising the first antibiotic and a pharmaceutically acceptable carrier; a third composition or dosage form comprising a second antibiotic different from the first antibiotic and a pharmaceutically acceptable carrier; and a fourth composition or dosage form comprising the second antibiotic and a pharmaceutically acceptable carrier; wherein the second and third compositions each have a release profile that provides a maximum serum concentration of the first antibiotic released from the second composition and a maximum serum concentration for the second antibiotic released from the third composition at a time after the first antibiotic released from the first composition reaches a maximum serum concentration, and wherein the fourth composition has a release profile that provides for a maximum serum concentration of the second antibiotic released from the fourth composition at a time after the antibiotics released from the second and third compositions reach a maximum serum concentration. The first antibiotic is one of Amoxicillin or dicloxacillin and the second antibiotic is the other of Amoxicillin or dicloxacillin. U.S Patent Application No. 20050181051 highlights a synergistic antibacterial formulation and a method of making the same is disclosed. The composition contains Cefixime Trihydrate, Cloxacillin Sodium and Lactobacillus sporogenes spores. Japanese PCT Application No. WO 99/52530 discusses antibacterial agents, cephem antibiotics, in particular, cefixime or cefdinir that are administered as a blend of the active ingredients or as individual preparations thereof. There exists a need for a pharmaceutical composition that can provide controlled release of Cefixime, Clavulanic Acid and Dicloxacillin such that it provides an immediate action and is also maintained in the blood at therapeutically effective level for 24 hr resulting in once-daily administration of the composition thereby improving patient compliance to the dosage regimen. The present invention gives the advantage of administering the drug in a manner. Since the antibiotics are high dosing/high frequency, extended release drug delivery systems have not been very successful in reducing the frequency of dosing. Thus the object of the present invention is to provide an immediate as well as long acting pharmaceutical composition of a betalactam antibiotic such as Cefixime + Clavulanic Acid + Dicloxacillin, or its pharmaceutically acceptable hydrates, salts or esters in a modified release matrix formulation. Objectives: The objective of the present invention is to provide a pharmaceutical composition that provides Cefixime and Dicloxacillin with an enhanced activity in combination with Clavulanic Acid. A further objective of the present invention is to provide a pharmaceutical composition that provides a conventional dosage form of the Fixed Dose Combination Yet another objective of the present invention is to provide a pharmaceutical composition that provides a modified release dosage form of the Fixed Dose Combination to enhance patient compliance The final objective of the present formulation is to provide a pharmaceutical composition that provides a G.I Friendly Antibiotic Formulation with the addition of Probiotics, such as Isomaltooligosaccharides Summary: The composition of this invention is in the form of a matrix tablet comprising the active ingredient, w-hydrophilic polymers, water-soluble and/or water dispersible diluents, pharmaceutically acceptable tablet excipients, and antibiotic adjuvant if any, for controlling the release of active ingredients. According to the present invention, the active ingredient is a betalactam antibiotic such as Cefixime, or its pharmaceutically acceptable hydrates, salts or esters in a controlled release matrix. The Dicloxacillin, or its pharmaceutically acceptable hydrates, salts or esters may be present in an amount from about 500 mg to about 1000 mg by weight of the controlled release matrix. Further, the Dicloxacillin, or its pharmaceutically acceptable hydrates, salts or esters may be present in an amount from 125 mg to 500 mg in the conventional dosage form. According to the present invention the Clavulanic Acid is used in combination with Cefixime + Dicloxacillin in a ratio of 6:1 or 4:1 based on the requirement for enhanced antimicrobial activity. It is an antibiotic adjuvant for reducing the elimination rate and increasing the half-life of the therapeutically active ingredient. Inclusion of Clavulanic Acid allows reduction in the amount of active incorporated in the hydrophilic polymer matrix but still provides the desired dosage convenience. Preparation of ingredients - 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: • This invention relates to pharmaceutical formulations, in particular to novel formulations for the treatment of bacterial infections. • Clavulanic acid in the form of its derivatives (hereinafter termed "clavulanate"), 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. • 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 • 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. and Moraxella spp. • The use of clavulanate 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 clavulanate together with a cephalosporin antibiotic selected from the cephalosporins, Cefixime. • The betalactam antibiotics referred to herein may be in the form of the free acids or pharmaceutical^ acceptable salts or in-vivo hydrolysable esters. • The davulanate 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. • 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 davulanate. 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. • 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. • 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. • 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. • The Immediate Release Component - The immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the antibiotic. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components. • The Delayed Release Component - The components in this composition are the same immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule. • 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; non-aqueous 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. Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride. For parenteral administration, fluid unit dosage forms are prepared utilizing clavulanate 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. » 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. Since salts of clavulanic acid 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. In view of the extreme moisture sensitivity of clavulanate, aqueous suspensions or solutions insofar as they contain clavulanate must be provided as dry solids for reconstitution with water shortly before administration. 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. 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. The clavulanate may suitably be administered to the patient at a daily dosage of from 0.3 to 15 mg/kg, preferably from 0.7 to 10 mg/kg, for example from 0.7 to 7 mg/kg, of body weight. For an adult human (of approximately 70 kg body weight), from 25 to 1000 mg, preferably from 50 to 500 mg, of clavulanate expressed as its free acid equivalent may be administered daily, suitably in from 1 to 6, preferably from 2 to 4, separate doses. Higher or lower dosages may, however, be used in accordance with clinical practice. When the formulations according to the invention are presented in unit dosage form, each unit dose may suitably comprise from 12.5 to 1000 mg, preferably from 12.5 to 250 mg, of clavulanate. Each unit dose may, for example, be 12.5, 25, 37.5, 50, 62.5, 75, 87.5, 100, 125, 150, 200, or 250 mg of clavulanate. The ratio of the amount of the clavulanate used according to the invention to the amount of any antibacterial agent present may vary within a wide range. In a pharmaceutical or medicament formulation of this invention the said ratio may, for example, be from 1:1 to 1:30; more particularly, it may, for example, be from 1:1 to 1:12, for example 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight, suitably within a variance of +-.10%. Suitable unit dosages and maximum daily dosages of any antibacterial agent used in combination with clavulanate in this invention may for example be determined according to the unit dosages and maximum daily dosages of the agent used conventionally. For example amoxycillin is generally provided in unit dosages of 125 to 1000 mg, administered from 2 to 4 times daily to a typical daily dosage of 125 to 3000 mg per day. For example Cloxacillin is generally provided in unit dosages of 125 and 1000 mg, and may be dosed up to a maximum daily dosage of 4000 mg per day. A preferred combination of this invention is clavulanate with amoxycillin, in a ratio clavulanate:amoxycillin in the range 1:1 to 1:12, for example together in a formulation. An example of a suitable formulation according to the invention for oral administration is one comprising from 125 to 3000 mg, preferably from 500 to 1000 mg, of amoxycillin trihydrate, in admixture or conjunction with from 12.5 to 250 mg, preferably from 25 to 125 mg, of potassium clavulanate per unit dose. A further example of a suitable formulation according to this invention for parenteral administration is one comprising from 125 to 3000 mg of sodium amoxycillin, in admixture or conjunction with from 12.5 to 250 mg, preferably from 25 to 125 mg, of potassium clavulanate. An example of a unit dosage form of a formulation of this invention comprises 12.5 to 1000 mg of potassium clavulanate and 100 to 400 mg of Cefixime -both in the conventional form as well as modified release form. • An in-vitro study to evaluate the relative Minimum Inhibitory Concentrations of the novel formulation with that of plain Dicloxacillin, besides comparing the MIC Values with Linezolid and Vancomycin for coverage of S.aureus and Broad Spectrum Antibiotics like Co-Amoxiclav and Piperacillin + Tazobactum for spectrum coverage. The results demonstrated a significantly superior antibacterial activity of the novel formulation, including activity against strains resistant to plain Cefixime. 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 Clavulanic acid. Besides, bacterial resistance to Cefixime is on the rise and addition of Clavulanic acid would certainly give a new lease of life for this excellent broad spectrum antibiotic to have a wide spectrum of activity and scope to use as a 1st Line Antibiotic. Further, addition of Dicloxacillin provides the much-needed Gram +ve coverage, which is a therapy gap of Cefixime. 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. I claim: 1. A Pharmaceutical composition of Cefixime and its hydrates, salts or esters containing betalactam antibiotics which act as an active ingredient in fixed dose combination with Cloxacillin and Potassium Clavulanate, besides an absorption enhancer such as, Betacyclodextrin in conventional as well as modified release fixed dosage formulation to enhance antimicrobial activity. Further, the composition is made G.I. friendly with the addition of substance for restoration of microflora 2. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1, wherein the Potassium Clavulanate in combination with Cefixime is in ratio of 1.25:1 or 1.25:2. Whereas the Potassium Clavulanate and active ingredient is in a ratio of 1.25:0.5 to 1.25:4. 3. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1, wherein the combination of Cefixime and Potassium Clavulanate with Linezolid is developed in both normal and modified orally administered conventional dosage forms 4. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 3, wherein the composition is in the form of a matrix tablet comprising active ingredients, W-hydrophilic polymers, Water-soluble and or Water dispersible diluents and excipients and antibiotic adjuvant. 5. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 3 and 5, wherein the Cefixime and/ or its hydrates, salts or esters are present in an amount between 100 mg to 400 mg by weight in a controlled/modified release pattern and between 50 mg to 400 mg in the conventional dosage form. 6. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1, wherein the clavulanic acid and active ingredients such as the Cefixime and Cloxacillin, 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 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 1% up to about 98% of the formulation and usually they will form up to about 80%of the formulation. 8. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1, wherein formulations may contain 0.1-90% by weight, preferably from 10-60% by weight of the active ingredients, depending on the method of administration.A Pharmaceutical composition that contains Cefixime, Potassium Clavulanate and Cloxacillin as active ingredients, provides a superior antimicrobial property with extended spectrum of activity, covering a wide variety of both Gram +ve and Gram -ve aerobic and anaerobic organisms

Documents:

1733-che-2005 amended claims 22-07-2011.pdf

1733-che-2005 amended pages of specification 22-07-2011.pdf

1733-che-2005 form-1 22-07-2011.pdf

1733-CHE-2005 FORM-13 22-07-2011.pdf

1733-CHE-2005 AMENDED PAGES OF SPECIFICATION 22-10-2012.pdf

1733-CHE-2005 AMENDED CLAIMS 22-10-2012.pdf

1733-che-2005 correspondence others 22-07-2011.pdf

1733-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 22-10-2012.pdf

1733-CHE-2005 FORM-13 22-10-2012.pdf

1733-CHE-2005 AMENDED CLAIMS 04-03-2013.pdf

1733-CHE-2005 AMENDED CLAIMS 27-01-2011.pdf

1733-CHE-2005 AMENDED PAGES OF SPECIFICATION 04-03-2013.pdf

1733-CHE-2005 AMENDED PAGES OF SPECIFICATION 27-01-2011.pdf

1733-CHE-2005 CORRESPONDENCE OTHERS 04-03-2013.pdf

1733-CHE-2005 CORRESPONDENCE OTHERS 27-01-2011.pdf

1733-CHE-2005 OTHER PATENT DOCUMENT 04-03-2013.pdf

1733-CHE-2005 CORRESPONDENCE OTHERS 15-01-2013.pdf

1733-che-2005-claims.pdf

1733-che-2005-correspondnece-others.pdf

1733-che-2005-description(complete).pdf

1733-che-2005-form 1.pdf

1733-che-2005-form 26.pdf

1733-che-2005-form 3.pdf

1733-che-2005-form 5.pdf