Title of Invention	A PHARMACEUTICAL COMPOSITION WITH BIOAVAILABILITY ENHANCERS FOR EXTENDED ANTIBACTERIAL ACTION AND SUSTAINED RELEASE OF CEFADROXIL AND CLAVULANIC ACID IN A BILAYER TABLET
Abstract	The present invention is to provide a pharmaceutical composition that provides Cefadroxil with an enhanced activity in combination with clavulanic acid. In the present invention the Cefadroxil or its hydrates, salts or esters acts as an active ingredient whereas clavulanic acid present as an antibiotic adjuvant as either immediate release or controlled release part which enhances antimicrobial activity.

Title of Invention

A PHARMACEUTICAL COMPOSITION WITH BIOAVAILABILITY ENHANCERS FOR EXTENDED ANTIBACTERIAL ACTION AND SUSTAINED RELEASE OF CEFADROXIL AND CLAVULANIC ACID IN A BILAYER TABLET

Abstract

The present invention is to provide a pharmaceutical composition that provides Cefadroxil with an enhanced activity in combination with clavulanic acid. In the present invention the Cefadroxil or its hydrates, salts or esters acts as an active ingredient whereas clavulanic acid present as an antibiotic adjuvant as either immediate release or controlled release part which enhances antimicrobial activity.

Full Text	Title: FORMULATION OF CEFADROXIL AND CLAVULANIC ACID WITH BIOAVAII-ABILITY ENHANCER FOR ENHANCEMENT OF ANTIMICROBIAL ACTIVITY Field of the invention: The present invention belongs to the field of pharmaceutical technology. More particularly the invention principally relates to a pharmaceutical composition of normal and modified release fixed dose formulations comprising a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient, Clavulanic Acid and complicated in Betacyclodextrin or similar bioavailability enhancer. The invention relates to pharmaceutical composition of normal and modified release fixed dose formulations in which the active material is selected from Cefadroxil, or its pharmaceutically 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 Betacyclodextrin or similar bioavailability enhancer, to enhance the absorption of the fixed dose combination of the antibiotics. Inclusion of Clavulanic Acid enables enhanced antimicrobial activity and potentiation of Cefadroxil. 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 penicillin’s, 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 between second-generation cephalosporins, such as Cofactor 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. United States Patent No. 4,250,166 discloses a long-acting Cephalexin preparation comprising of normal quick-releasing Cephalexin and particulate Cephalexin coated with a copolymer of methylmethacrylate and methacrylic acid which dissolves at a pH from 5. 5 to 6.5 and the potency ratio of the normal Cephalexin to coated cephalexin is between 40: 60 and 25 : 75. United States Patent No. 5,948,440 discloses a controlled release tablet of an active ingredient comprising of cefaclor, cephalexin, or their pharmaceutically acceptable hydrates, salts, or esters as active ingredient, and a mixture of hydrophilic polymers selected from the group consisting of at least one hydroxypropyl methylcellulose and at least one hydroxypropylcellulose. The composition optionally also contains one or more of a water-soluble or water dispersible diluent. The quantities of the hydrophilic polymers and water- soluble or water-dispersible diluents are such that the therapeutically effective active ingredient is released at a rate suitable for twice daily administration of the pharmaceutical composition. U.S Patent Application No. 20040126429 discloses a modified release preparation of the Fixed Dose Combination of Amoxycillin plus Clavulanic Acid with a claim of both immediate and sustained action in the NDDS. Japanese Patent JP 57165392A discloses a long-acting cephalexin tablet comprising cephalexin mixed with 210% w/w oils and fats (e. g. higher fatty acid, higher alcohol, alcohol ester, etc.) and with a vehicle such as microcrystalline cellulose and a lubricant such as magnesium stearate, and the mixture is pressed, formed to granules passing through a 20 mesh sieve, and subjected to the slug-forming process to obtain a high-quality long-acting tablet. The rate of dissolution of cephalexin can be controlled by selecting the kind of oils and fats and the number of the times of slug formation process. There exists a need for a pharmaceutical composition that can provide controlled release of Cefadroxil 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 Cefadroxil, 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 Cefadroxil with an enhanced activity in combination with Clavulanic Acid. Another objective of the present invention is to provide a pharmaceutical composition that provides a more bioavailability preparation with an absorption enhancer such as Betacyclodextrin 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 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 Cefadroxil, or its pharmaceutically acceptable hydrates, salts or esters in a controlled release matrix. The Cefadroxil, or its pharmaceutically acceptable hydrates, salts or esters may be present in an amount from about 500 mg to about 750 mg by weight of the controlled release matrix. Further, the Cefadroxil, or its pharmaceutically acceptable hydrates, salts or esters may be present in an amount from 125 mg to 750 mg in the conventional dosage form. 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 Clavulanic Acid is used in combination with Cefadroxil 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 once a day profile. According to the present invention, the pharmaceutical composition is complexated in Betacydodextrin or any other absorption enhancer that enhances the absorption of the fixed dose combination of the antibiotic. 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. 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.-lantanas enzymes which mediate bacterial resistance to betalactam antibiotics. 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. and Moraxeila spp. 5. The use of davulanate 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 davulanate together with a cephalosporin antibiotic selected from the cephalosporins, Cefadroxil. 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 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. 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 clavulanate. 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-hydroxybenzoates or sorbic acid, and. if desired, conventional flavoring or coloring 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 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 sterilized before filling into a suitable vial or ampoule and sealing. 15. Advantageously, agents such as a local unaesthetic, 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 sterilized 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 clavulanic acid are extremely hygroscopic the solid and non-aqueous 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 prettied. 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. 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. 18. 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 intramuscularly and intravenous administration. 19. 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. 20. 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. 21. 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. 22. 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%. 23. 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 Cefadroxil 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. 24. 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. 25. 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 olavulanate. 26. An example of a unit dosage form of a formulation of this invention comprises 12.5 to 1000 mg of potassium clavulanate and 125 to 1000 mg of Cefadroxil - both in the conventional form as well as modified release form. 27. A further example of this formulation is the addition of an absorption enhancer, such as Betacyclodextrin to enhance the bioavailability 28. An in-vitro study to evaluate the relative Minimum Inhibitory Concentrations of the novel formulation with that of plain Cefadroxil. The results demonstrated a significantly superior antibacterial activity of the novel formulation, including activity against strains resistant to plain Cefadroxil. 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, Cefadroxil is a 1®* line antibiotic like amoxycillin and addition of Clavulanic acid would certainly give a new lease of life for this excellent antibiotic. AMBIT OF THE INVENTION: Therapeutic applications as follows: 1. Cefadroxil is indicated for the treatment of the following infections when caused by susceptible strains of the designated microorganisms. However augmentation with an enzyme inhibitor would widen its application against the Betalactamase producing organisms as well. 2. Respiratory tract infections caused by Streptococcus pneumoniae and Streptococcus progenies 3. Obits media due to Streptococcus pr)eumor)ia, Haemophilus mfluenzae, Staphylococcus aureus, Streptococcus pyogenes, and Moraxeila catarrhalis 4. Skin and skin structure infections caused by Staphylococcus aureus and/or Streptococcus pyogenes 5. Bone infections caused by Staphylococcus aureus and/or Proteus mirabilis 6. Genitourinary tract infections, including acute prostatitis, caused by Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae 7. Ce is indicated for the treatment of patients with infection caused by susceptible strains of the designated organisms in the following diseases. However aumentation with an enzyme inhibitor would widen its application against the Betalactamase producing organisms as well 8. Urinary tract infections caused by £. coli, P. mirabilis, and Klebsiella species. 9. Skin and skin structure infections caused by staphylococci and/or streptococci. 10. Pharyngitis and/or tonsillitis caused by Streptococcus pyogenes (Group A beta-hemolytic streptococci). 11. Bone And Joint Infections caused by Gram +ve organisms. 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. I claim: 1. A Pharmaceutical composition of Cefadroxil and its hydrates, salts or esters containing an enzyme inhibitor such as Clavulanate. besides a bioavailability enhancer such as Betacyclodextrin. The Claim is for improved Antimicrobial activity and stability to hydrolysis by Betalactamases. 2. A Pharmaceutical composition as claimed in claim 1, wherein the clavulanic acid in combination with Cefadroxil is in ratio of 6:1 or 4:1 based on the requirement for enhanced antimicrobial activity. 1. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1, 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. 2. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1, wherein the Cefadroxil or its hydrates, salts or esters are present in an amount between 500 mg to 750 mg by weight in a controlled release form and between 125 mg to 750 mg in the conventional dosage form. 3. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1. wherein the clavulanic acid 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. 4. 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. 5. 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 solely 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. 6. 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 polyvinylpyrrolidone fillers. 7. 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. 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.

Full Text

Title: FORMULATION OF CEFADROXIL AND CLAVULANIC ACID WITH BIOAVAII-ABILITY ENHANCER FOR ENHANCEMENT OF ANTIMICROBIAL ACTIVITY
Field of the invention:
The present invention belongs to the field of pharmaceutical technology. More particularly the invention principally relates to a pharmaceutical composition of normal and modified release fixed dose formulations comprising a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient, Clavulanic Acid and complicated in Betacyclodextrin or similar bioavailability enhancer. The invention relates to pharmaceutical composition of normal and modified release fixed dose formulations in which the active material is selected from Cefadroxil, or its pharmaceutically 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 Betacyclodextrin or similar bioavailability enhancer, to

enhance the absorption of the fixed dose combination of the antibiotics. Inclusion of Clavulanic Acid enables enhanced antimicrobial activity and potentiation of Cefadroxil.
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 penicillin’s, 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 between second-generation

cephalosporins, such as Cofactor 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.
United States Patent No. 4,250,166 discloses a long-acting Cephalexin preparation comprising of normal quick-releasing Cephalexin and particulate Cephalexin coated with a copolymer of methylmethacrylate and methacrylic acid which dissolves at a pH from 5. 5 to 6.5 and the potency ratio of the normal Cephalexin to coated cephalexin is between 40: 60 and 25 : 75.
United States Patent No. 5,948,440 discloses a controlled release tablet of an active ingredient comprising of cefaclor, cephalexin, or their pharmaceutically acceptable hydrates, salts, or esters as active ingredient, and a mixture of hydrophilic polymers selected from the group consisting of at least one hydroxypropyl methylcellulose and at least one hydroxypropylcellulose. The composition optionally also contains one or more of a water-soluble or water dispersible diluent. The quantities of the hydrophilic polymers and water-

soluble or water-dispersible diluents are such that the therapeutically effective active ingredient is released at a rate suitable for twice daily administration of the pharmaceutical composition.
U.S Patent Application No. 20040126429 discloses a modified release preparation of the Fixed Dose Combination of Amoxycillin plus Clavulanic Acid with a claim of both immediate and sustained action in the NDDS.
Japanese Patent JP 57165392A discloses a long-acting cephalexin tablet comprising cephalexin mixed with 210% w/w oils and fats (e. g. higher fatty acid, higher alcohol, alcohol ester, etc.) and with a vehicle such as microcrystalline cellulose and a lubricant such as magnesium stearate, and the mixture is pressed, formed to granules passing through a 20 mesh sieve, and subjected to the slug-forming process to obtain a high-quality long-acting tablet. The rate of dissolution of cephalexin can be controlled by selecting the kind of oils and fats and the number of the times of slug formation process.

There exists a need for a pharmaceutical composition that can provide controlled release of Cefadroxil 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 Cefadroxil, 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 Cefadroxil with an enhanced activity in combination with Clavulanic Acid.

Another objective of the present invention is to provide a pharmaceutical composition that provides a more bioavailability preparation with an absorption enhancer such as Betacyclodextrin
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
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 Cefadroxil, or its pharmaceutically acceptable hydrates, salts or esters in a controlled release matrix. The Cefadroxil, or its pharmaceutically acceptable hydrates, salts or esters may be present in an amount from about 500 mg to about 750 mg by weight of the controlled release matrix.
Further, the Cefadroxil, or its pharmaceutically acceptable hydrates, salts or esters may be present in an amount from 125 mg to 750 mg in the conventional dosage form.
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 Clavulanic Acid is used in combination with Cefadroxil 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 once a day profile.
According to the present invention, the pharmaceutical composition is complexated in Betacydodextrin or any other absorption enhancer that enhances the absorption of the fixed dose combination of the antibiotic.
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. 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.-lantanas enzymes which mediate bacterial resistance to betalactam antibiotics.
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. and Moraxeila spp.

5. The use of davulanate 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 davulanate together with a cephalosporin antibiotic selected from the cephalosporins, Cefadroxil.
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 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.

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 clavulanate. 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-hydroxybenzoates or sorbic

acid, and. if desired, conventional flavoring or coloring 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 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 sterilized before filling into a suitable vial or ampoule and sealing.
15. Advantageously, agents such as a local unaesthetic, 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 sterilized 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 clavulanic acid are extremely hygroscopic the solid and non-aqueous 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 prettied. 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. 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.
18. 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 intramuscularly and intravenous administration.

19. 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.
20. 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.
21. 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.
22. 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%.
23. 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 Cefadroxil 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.
24. 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.
25. 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 olavulanate.
26. An example of a unit dosage form of a formulation of this invention comprises 12.5 to 1000 mg of potassium clavulanate and 125 to 1000 mg of Cefadroxil - both in the conventional form as well as modified release form.
27. A further example of this formulation is the addition of an absorption enhancer, such as Betacyclodextrin to enhance the bioavailability
28. An in-vitro study to evaluate the relative Minimum Inhibitory Concentrations of the novel formulation with that of plain Cefadroxil. The results demonstrated a significantly superior antibacterial activity of the novel formulation, including activity against strains resistant to plain Cefadroxil.

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, Cefadroxil is a 1®* line antibiotic like amoxycillin and addition of Clavulanic acid would certainly give a new lease of life for this excellent antibiotic.
AMBIT OF THE INVENTION:
Therapeutic applications as follows:
1. Cefadroxil is indicated for the treatment of the following infections when caused by susceptible strains of the designated microorganisms. However augmentation with an enzyme inhibitor would widen its application against the Betalactamase producing organisms as well.
2. Respiratory tract infections caused by Streptococcus pneumoniae and Streptococcus progenies

3. Obits media due to Streptococcus pr)eumor)ia, Haemophilus mfluenzae, Staphylococcus aureus, Streptococcus pyogenes, and Moraxeila catarrhalis
4. Skin and skin structure infections caused by Staphylococcus aureus and/or Streptococcus pyogenes
5. Bone infections caused by Staphylococcus aureus and/or Proteus mirabilis
6. Genitourinary tract infections, including acute prostatitis, caused by Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae
7. Ce is indicated for the treatment of patients with infection caused by susceptible strains of the designated organisms in the following diseases. However aumentation with an enzyme inhibitor would widen its application against the Betalactamase producing organisms as well
8. Urinary tract infections caused by £. coli, P. mirabilis, and Klebsiella species.

9. Skin and skin structure infections caused by staphylococci and/or streptococci.
10. Pharyngitis and/or tonsillitis caused by Streptococcus pyogenes (Group A beta-hemolytic streptococci).
11. Bone And Joint Infections caused by Gram +ve organisms.
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.

I claim:
1. A Pharmaceutical composition of Cefadroxil and its hydrates, salts or esters containing an enzyme inhibitor such as Clavulanate. besides a bioavailability enhancer such as Betacyclodextrin. The Claim is for improved Antimicrobial activity and stability to hydrolysis by Betalactamases.
2. A Pharmaceutical composition as claimed in claim 1, wherein the clavulanic acid in combination with Cefadroxil is in ratio of 6:1 or 4:1 based on the requirement for enhanced antimicrobial activity.
1. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1, 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.

2. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1, wherein the Cefadroxil or its hydrates, salts or esters are present in an amount between 500 mg to 750 mg by weight in a controlled release form and between 125 mg to 750 mg in the conventional dosage form.
3. A Pharmaceutical composition to enhance the antimicrobial activity as claimed in claim 1. wherein the clavulanic acid 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.
4. 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.
5. 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 solely 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.
6. 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 polyvinylpyrrolidone fillers.
7. 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.
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.

Documents:

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Patent Number

269450

Indian Patent Application Number

1436/CHE/2005

PG Journal Number

44/2015

Publication Date

30-Oct-2015

Grant Date

23-Oct-2015

Date of Filing

07-Oct-2005

Name of Patentee

SRINIVAS JEGANNATHAN

Applicant Address

NO 10 V K FLATS 1ST CROSS STREET SUNDARAM COLONY TAMBARAM SANATORIUM CHENNAI

Inventors:

#	Inventor's Name	Inventor's Address
1	SRINIVAS JEGANNATHAN	NO 10 V K FLATS 1ST CROSS STREET SUNDARAM COLONY TAMBARAM SANATORIUM CHENNAI

PCT International Classification Number

A61K 9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA