Title of Invention	A PHARMACEUTICAL COMPOSITION FOR CONTROLLED RELEASE OF A BETA-LACTAM ANTIBIOTIC
Abstract	An improved stable pharmaceutical composition for controlled release of an active ingredient comprises a betalactam antibiotic such as cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters as active ingredient, a calcium salt and a mixture of hydrophilic polymers selected from the group consisting of at least one sodium alginate and one xanthan gum and with or without hydroxypropyl methylcellulose said composition optionally containing probenecid. The composition may also contain one or more of a water and water soluble and/or water dispersible diluents are such that the therapeutically effective active ingredient is released at a rate suitable for once or twice daily administration of the pharmaceutical composition.

Title of Invention

A PHARMACEUTICAL COMPOSITION FOR CONTROLLED RELEASE OF A BETA-LACTAM ANTIBIOTIC

Abstract

An improved stable pharmaceutical composition for controlled release of an active ingredient comprises a betalactam antibiotic such as cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters as active ingredient, a calcium salt and a mixture of hydrophilic polymers selected from the group consisting of at least one sodium alginate and one xanthan gum and with or without hydroxypropyl methylcellulose said composition optionally containing probenecid. The composition may also contain one or more of a water and water soluble and/or water dispersible diluents are such that the therapeutically effective active ingredient is released at a rate suitable for once or twice daily administration of the pharmaceutical composition.

Full Text	FORM2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See section 10; rule 13) 1. Title of the invention. - A PHARMACEUTICAL COMPOSITION FOR CONTROLLED RELEASE OF A BETA-LACTAM ANTIBIOTIC 2. Applicant /?-■ (a) LUPIN LIMITED (b) 159, C.S.T. Road, Kalina, Santacruz (East), Mumbai - 400 098, State of Maharashtra, India (c) An Indian company The following specification particularly describes the nature of this invention and the manner in which it is to be performed FIELD OF THE INVENTION This invention relates to an improved stabilized pharmaceutical composition of modified release tablets comprising a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient, which would provide for controlled release of said actives \ and will also be capable of maintaining its dissolution characteristics upon storage, at ambient and accelerated conditions. The stabilized composition of the invention is also adapted to withstand the peristaltic pressure in the stomach and intestine, maintain the integrity of the composition and thereby avoid problems of dose dumping. Advantageously, the composition of the invention can be selectively provided to favour desired release of the therapeutically effective active ingredient such as at a rate suitable for once or twice daily administration of the pharmaceutical composition. The composition optionally contains probenecid as an antibiotic adjuvant. BACKGROUND OF THE INVENTION United States Patent No. US 6,267,986 Bl teaches preparation of a controlled release pseudoephdrine composition in combination with an antihistamine comprising two discrete zones. The first discrete zone comprises pseudoephdrine, one or more hydrophilic polymers, a salt of a polyuronic acid and a pharmaceutically acceptable salt of a group II metal ion and the second discrete zone comprises an antihistamine. United States Patent No. US 5,419,917 discloses a controlled release hydrogel formulation for substantially zero-order release rate of drug from the hydrogel which is based on the use of an effective amount of a pharmaceutically acceptable ionizable compound. The hydrogel forming agent are being selected from the group consisting of hydroxypropyl methylcellulose, sodium alginate and xanthan and the ionizable compound being selected from the group consisting of alkali metal chlorides, organic acids, alkali metal sulfates and alkali metal alkyl sulfates, dihydrogen sodium phosphate and monohydrogen sodium phosphate. A sustained release cephalexin tablet containing xanthan gum and sodium alginate as matrix formers was evaluated in human volunteers using in-vitrolin-vivo correlations. The optimized 2 formulation containing 5 % xanthan gum and 8 % sodium alginate, decided on the basis of response surface analysis and computer simulation of cephalexin plasma levels versus time curves was used for clinical trials and was found to prolong the cephalexin blood levels up to 8 hours in humans. However, the relative bioavailability of cephalexin was reduced by about 30 % and very little absorption was seen after six to eight hours, rendering the formulation not very useful for once daily regimen (see Dhopeshwarkar V;, O"Keeffe J. C, Zatz J. L., Deeter R. and Horton M., Drug Develp. Ind. Phar., 20, 1851, 1994). Our PCT Application No. PCT/TN00/00112 relates to a pharmaceutical composition of modified release tablets comprising a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient, and a mixture of hydrophilic polymers selected from the group consisting of at least one sodium alginate and at least one xanthan gum as controlled release matrix, and optionally probenecid. Inclusion of probenecid allows reduction in the amount of active incorporated in the polymeric matrix but can still provide desired once daily profile. The resulting modified release matrix formulation not containing probenecid may be administered in a once or twice daily regimen and the resulting modified release matrix formulation containing probenecid may be administered in a once daily regimen. However, it was observed that tablets become soft and irregular after about 6 hours ofin-vitro dissolution studies, the integrity of the tablet and its shape is not maintained at a later stage after hydration. This soft irregular mass of the composition may not withstand the peristaltic pressure in the stomach and intestine, which could possibly lead to dose dumping in later stage. Further, it was observed that the release of the active ingredient was faster from the samples stored for stability study under ambient and accelerated conditions, when compared to initial stage in-vitro dissolution data, which may render the composition ideally not suited for use as a controlled release composition haying desired release profile. OBJECTS OF THE INVENTION The basic object of the present invention is to provide an improved stable composition of a betalactam antibiotic such as cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters in a modified release matrix formulation, which would avoid the 3 above discussed problems associated with stability of the composition and integrity of the composition and consequential dose dumping. A further object of the present invention is to provide an improved stable composition of a betalactam antibiotic such as cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters in a modified release matrix formulation, optionally containing probenecid such that the composition maintains its dissolution characteristics upon storage, at ambient and accelerated conditions. Another object of the present invention is to provide an improved stable composition of a betalactam antibiotic such as cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters in a modified release matrix formulation, optionally containing probenecid such that the integrity and shape of the composition is maintained even at the later stage of hydration. SUMMARY OF THE INVENTION Thus according to one aspect of the present invention there is provided a stable improved pharmaceutical composition for controlled release of an active ingredient comprising a controlled release matrix comprising i)a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient in amounts of 30 % to 90 % by weight, ii)a mix of hydrophilic polymers in amount of 1 % to 25 % selected from the group consisting of at least one sodium alginate in amounts of 0.1 % to 20 %, and at least one xanthan gum in amounts of 0.1 % to 20 % and Hi) a calcium salt in an amount of 8 % to 20 % by weight of sodium alginate. In accordance with a preferred aspect the composition of the invention, in particular the hydrophilic polymers used therein incorporate along witn the said sodium alginate and said xanthan gum optionally at least one hydroxypropyl methylcellulose, preferably in amount of 0.1 % to 20 % by weight of the controlled release matrix. It is found that the above selective controlled release formulation of the invention avoids the shortcoming of integrity of the matrix composition comprising at least one sodium alginate and at least one xanthan gum and also takes care of the desired controlled release profile of 4 the active. By inclusion of a hydroxypropyl methyicellulose in to the matrix, the integrity of the tablet is improved and its shape is maintained at a later stage after hydration so that it withstands the peristaltic pressure in the stomach and intestine thereby obviating the possibility of dose dumping. Advantageously, the selective use of a calcium salt such as calcium sulphate in the defined range as disclosed above is also found to be advantageous in use with sodium alginate as a polymer niatrix material for controlled release formulation. This is because calcium alginate when used as such in sustained release preparation forms a water insoluble gel, which has reduced diffusivity and erosion of gel layer. But addition of the selective calcium salt in dry state in the polymer matrix containing sodium alginate acts as a matrix stabilizing agent by in situ formation of a localized calcium alginate gel, as after ingestion of the composition, the solvent front passes up to the core of the composition resulting in formation of gel layer in a manner such that a gel layer contains combination of sodium and calcium alginate, which would erode faster in comparison to a gel layer containing only calcium alginate leading to desired release profile of the active from the composition. Importantly, the above composition of the invention attends to the problems of stability of the tablets after storage at ambient and accelerated conditions, by selective incorporation of a calcium salt such as calcium sulphate in a defined range as matrix stabilising agent. In accordance with a preferred aspect, the invention proposes the use of a hydroxypropyl methyicellulose into the matrix, which forms a strong gel structure. These hydrophilic polymers when used in appropriate concentrations, form the integrated matrix which provides the desired release profile, when the delivery system travels through the GIT, having varying physiological condition. Surprisingly, the polymers in appropriate combinations are not only effective compared to other commonly used polymers, but works at low concentrations. The combination of these polymers compliment each other such that, it overcomes the deficiencies associated with their use, when used alone. The composition of the invention can optionally also contain one or more water soluble and/or water dispersible diluents, wherein the quantities of the. hydrophilic polymers and water soluble and/or water dispersible diluents are such that the therapeutically effective 5 active ingredient is released at a rate suitable for once or twice daily administration of the pharmaceutical composition. Inclusion of probenecid allows reduction in the amount of active incorporated in the hydrophihc polymer matrix but still provides the desired once a day profile. The preferred betalactam antibiotic is selected from cephalexin, cefaclor or their pharmaceutical^ acceptable hydrates, salts or esters. The modified release matrix formulation not containing probenecid prepared according to present invention may be administered once or twice daily. For Example, the effective therapeutic dose of the active that can be administered by compositions of present invention include 375 mg to 500 mg active twice daily or 750 mg to 1500 mg active once daily. The modified release matrix formulation containing probenecid prepared according to present invention may be administered once daily. For example, the effective therapeutic dose of the active that can be administered by compositions of present invention include 500 mg to 1000 mg active and 500 mg to 1000 mg probenecid once daily. It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. DETAILED DESCRIPTION OF THE INVENTION The composition of this invention is in the form of a. matrix tablet comprising the active ingredient, hydrophilic polymers, a calcium salt, 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 cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters in a controlled release matrix. The cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters may be present in an amount from about 30 % to about 90 % by weight of the controlled release matrix. 6 Further, the cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters may be present in an amount from 100 mg to 2000 mg. Examples of other cephalosporin antibiotics which may be used include cefuroxime, cefamandole, cefoxitin, cephalothin, moxalactam, cephapirin, ceffizoxime, cefonicid and, pharmaceutically acceptable hydrates, salts or esters thereof. Examples of other betalactam antibiotics, which may be used, are amoxicillin, ampicillin, and cloxacillin. Examples of the calcium salts useful in the present invention are calcium sulphate, calcium citrate, disodium. calcium edetate, calcium lactate, calcium ascorbate, calcium gluconate, calcium chloride. The preferred calcium salt is calcium sulphate. Xanthan gum when used as a matrix forming agent in sustained release tablets, releases the drug slightly faster in acidic media, due to more rapid initial surface erosion than at higher pH. After hydration of the gum the drug release is essentially pH independent but the release of drug decrease exponentially. Alginic acid is insoluble in aqueous media. However, as the pH is raised above 3, the alginic acid is partly converted to a soluble salt. Complete neutralization occurs around pH 4, where the alginic acid is completely converted to its corresponding salt. Sodium, potassium, magnesium and ammonium salts are examples of water-soluble alginate salts. Neutralization by calcium, barium and other multivalent alkali materials will produce insoluble alginate salts. Thus when sodium alignate is used along with xanthan gum to form a controlled release matrix, it reduces the initial bursting effi ;t and in later stages acts as a channeling agent to increase the release rate of the active. It is known in the art that in gastric fluid the hydrated sodium alginate is converted into a porous, insoluble alginic acid skin. Once passed into the higher pH of the intestinal tract, the alginic acid skin is converted to a soluble viscous layer. 7 to about 1000 cPs); xanthan gum may be characterized as low viscosity (about 600 to about 1500 cPs), medium viscosity (about 1550 to about 1850 cPs) and high viscosity (greater than about 1900 cPs); and hydroxypropyl methylcellulose may be characterized by their viscosity in a 2 % w/w aqueous solution as low viscosity (less than 1000 cps), medium viscocity (about 1000 cps to about 10,000 cps) and high viscosity (greater then about 10,000 cps). The different viscosity grade polymers may be used in the present invention, but in order to utilize minimum possible concentrations of the polymer to achieve the desired profiles, without compromising on the integrity of the matrix, medium or high viscosity grade polymers are preferred. In a preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters and about 1 % to about 25 % by weight of hydrophilic polymers comprising of sodium alginate in an amount from about 0.1 % to about 20 % by weight, xanthan gum in an amount from about 0.1 % to about 20 % by weight, and hydroxypropyl methylcellulose in an amount from about 0.1 % to about 20 % by weight of controlled release matrix; and calcium sulphate in an amount from about 8 % to about 20 % by weight of sodium alginate. " In a more preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters and about 1 % to about 20 % by weight of hydrophilic polymers comprising of a medium or high viscosity grade sodium alginate in an amount from about 0.1 % to about 15 % by weight, a medium or high viscosity grade xanthan gum in an amount from about 0.1 % to about 15 % by weight, and a medium or high viscosity grade hydroxypropyl methylcellulosv in an amount from about 0.1 % to about 15 % by weight of controlled release matrix; and calcium sulphate in an amount from about 8 % to about 16 % by weight of sodium alginate. In one more preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their 9 to about 1000 cPs); xanthan gum may be characterized as low viscosity (about 600 to about 1500 cPs), medium viscosity (about 1550 to about 1850 cPs) and high viscosity (greater than about 1900 cPs); and hydroxypropyl methylcellulose may be characterized by their viscosity in a 2 % w/w aqueous solution as low viscosity (less than 1000 cps), medium viscocity (about 1000 cps to about 10,000 cps) and high viscosity (greater then about 10,000 cps). The different viscosity grade polymers may be used in the present invention, but in order to utilize minimum possible concentrations of the polymer to achieve the desired profiles, without compromising on the integrity of the matrix, medium or high viscosity grade polymers are preferred. In a preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters and about 1 % to about 25 % by weight of hydrophilic polymers comprising of sodium alginate in an amount from about 0.1 % to about 20 % by weight, xanthan gum in an amount from about 0.1 % to about 20 % by weight, and hydroxypropyl methylcellulose in an amount from about 0.1 % to about 20 % by weight of controlled release matrix; and calcium sulphate in an amount from about 8 % to about 20 % by weight of sodium alginate. In a more preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters and about 1 % to about 20 % by weight of hydrophilic polymers comprising of a medium or high viscosity grade sodium alginate in an amount from about 0.1 % to about 15 % by weight, a medium or high viscosity grade xanthan gum in an amount from about 0.1 % to about 15 % by weight, and a medium or high viscosity grade hydroxypropyl methylcellulose in an amount from about 0.1 % to about 15 % by weight of controlled release matrix; and calcium sulphate in an amount from about 8 % to about 16 % by weight of sodium alginate. In one more preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their 9 stearic acid, magnesium stearate, colloidal silicon dioxide, calcium stearate, zinc stearate, hydrogenated vegetable oil and the like. Preferably the lubricant is magnesium stearate. The immediate release probenecid part of the present invention contains a disintegrating agent at concentration in the range of about 2 % to about 9 % by weight of immediate release part. Preferably the disintegrating agent is sodium starch glycolate. 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. All the hydrophilic polymers are uniformly pre-blended with calcium sulphate, followed by the active ingredient; one or more water soluble or water dispersible diluents are either mixed together with lubricants and the blend is directly compressed into tablets or are granulated by compaction followed by sieving and the granules obtained are compressed into tablets. The active ingredient can be given as controlled release tablets for once or twice a day administration or as controlled release tablet along with separate probenecid tablets as a combipack to be administered simultaneously or coupled with probenecid into a single monolithic or bilayered tablets for once a day administration. The fines incorporated in the blend of active granules form about 12 % to about 30 % by weight of controlled release part, preferably from about 12 % to about 20 %. For the purpose of this patent application, fines denote the particles having size less than 250 microns. The above-mentioned process has the advantage over its granulation by aqueous or non¬aqueous vehicle used conventionally. The active ingredient such as cephalexin or cefaclor, which are sensitive to moisture and heat, can be effectively processed without any difficulty. The polymers used in the composition of present invention, xanthan gum and sodium alginate also are unstable above 60° C and 70° C respectively. As the process is devoid of use of any solvents the potential problem of limiting the residual organic solvent is eliminated. The controlled release matrix formulation of the present invention is not a mere admixture but has properties different from the sum total of the properties of its ingredients. 11 The probenecid part of the composition is prepared by mixing probenecid and one or more water soluble or water dispersible diluents together with lubricants and the blend is granulated by compaction followed by sieving and the granules obtained are lubricated and compressed into a tablet. The fines incorporated in the blend form about 10 % to about 30 % by weight of immediate release part, preferably from about 10 % to about 20 %. The modified release matrix formulation not containing probenecid prepared according to present invention may be administered once or twice daily. For example, the effective therapeutic dose of the active that can be administered by compositions of present invention include 375 mg to 750 mg active twice daily or 750 mg to 1500 mg active once daily. The modified release matrix formulation containing probenecid prepared according to present invention may be administered once daily. The effective therapeutic dose of the active that can be administered by compositions of present invention include 500 mg to 1000 mg active and 500 mg to 1000 mg probenecid once daily. The present invention is illustrated hereunder in greater detail in relation to non-limiting exemplary embodiments as per the following examples: EXAMPLES In the examples given below medium viscosity grade xanthan gum manufactured by Jungbunzlauer, Austria; sodium alginate (Keltone HVCR) manufactured by ISP Alginates; and hydroxypropyl methylcellulose of medium viscocity grade (Methocel K4M™), high viscosity grade (Methocel K15M™) manufactured by Dow Chemicals, USA has been employed. The dissolution results are given in respective tables for each example. Effect of calcium sulphate (as a matrix stabilizing agent) on in-vitro dissolution of tablets on storage at accelerated condition - 12 A) Tablet containing hydroxypropyl methylcellulose Ingredients Tablet with Calcium Sulphate Tablet without Calcium Sulphate Weight (mg/tablet) % w/w Weight (mg/tablet) % w/w Cephalexin 797.82 73.87 797.87 73.87 Sodium Alginate 43.20 4.00 86.40 8.00 Xanthan Gum 54.00 5.00 43.20 ; 4.00 Hydrxypropyl Methylcellulose (MethocelK15M) 54.00 5.00 32.40 3.00 Calcium Sulphate 5.10 0.47 - - Lactose Monohydrate 109.63 10.15 103.93 9.62 Magnesium Stearate 16.20 1.50 16.20 1.50 Total 1080 100 1080 100 Time (in hour) % Cephalexin released (Tablet with calcium sulphate) % Cephalexin released (Tablet without calcium sulphate) Initial lMa 3Mb Initial lMa 3M" 1 22.5 22.6 21.6 22.0 224 22.9 2 35.7 34.3 33.5 37.1 36.8 37.3 3 45.0 42.3 41.3 44.5 44.7 45.0 4 44.4 43.7 43.5 45.6 50.4 52.1 6 48.5 48.5 49.1 48.6 68.0 73.6 8 58.1 58.2 58.9 56.8 89.0 94.1 10 69.4 69.9 69.8 67.2 99.9 12 79.1 82.5 78.0 83.3 14 86.8 91.1 85.2 98.9 aSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 1 month, bSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 3 months. B) Tablet not containing hydroxypropyl methylcellulose Ingredients Tablet with Calcium Sulphate Tablet without Calcium Sulphate Weight (mg/tablet) % w/w Weight (mg/tablet) % w/w Cephalexin 797.87 73.87 800.86 74.14 Sodium Alginate 64.80 7.00 86.40 8.00 Xanthan Gum 75.60 6.00 75.60 7.00 Calcium Sulphate 9.07 0.84 - - Lactose Monohydrate 116.46 10.78 100.94 9.35 Magnesium Stearate 16.20 1.50 16.20 1.50 Total 1080 100 1080 100 13 Time (in hour) % Cephalexin released (Tablet with calcium sulphate) % Cephalexin released (Tablet without calcium sulphate) Initial lMa 3Mb Initial lMa 3Mb 1 24.7 23.4 22.2 20.7 21.6 13.0 2 39.0 36.8 34.9 33.0 37.4 37.1 3 48.0 45.1 45.9 43.1 46.3 51.4 4 48.3 48.7 48.1 43.3 53.7 55.0 6 55.0 55.3 57.8 51.1 69.4 76.5 8 66.7 65.7 70.5 65.0 92.2 95.3 10 82.9 75.4 84.5 81.8 12 87.4 84.7 88.0 96.4 14 100.0 98.1 92.8 100.4 aSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 1 month; bSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 3 months. It would be evident from the above, that incorporation of a calcium salt such as calcium sulphate as a matrix stabilizing agent advantageously favours maintaining the stability of the composition as a control release formulation, and can maintain its dissolution characteristics after storage at accelerated conditions. Additionally, the use of a hydroxypropyl methylcellulose in addition to a xanthan gum and a sodium alginate, though provides composition, which maintains its physical integrity/shape in the later stages of hydration, it does not provide a composition, which can maintain its dissolution characteristics after storage of samples at accelerated conditions. In accordance the further aspect of the invention the following illustrations demonstrate the selectivity in the use of calcium sulphate within the range of the 8 % -20 % by weight of sodium alginate in the controlled release formulation of the invention. Concentration of calcium sulphate C) Calcium sulphate at concentration of 5 % by weight of sodium alginate Ingredients Weight (mg/tabiet) % w/w Cephalexin 797.87 73.87 Sodium Alginate 43.20 4.00 Xanthan Gum 54.00 5.00 14 Hydroxypropyl Methylcellulose (Methocel K15M) 54.00 5.00 Calcium Sulphate 2.16 0.20 Lactose MonohydrateO 112.57 10.42 Magnesium Stearate 16.20 1.50 Weight 1080 100 Time (hour) % Cephalexin released Initial 1M" 1 22.1 24.1 2 34.2 36.3 3 41.3 47.6 4 42.6 47.7 6 46.6 57.4 8 55.0 72.2 10 65.9 86.4 12 72.7 108.9 14 80.1 Samples stored at accelerated conditions of 40° C, 75 % relative humidity for 1 month. The above results demonstrate by way of an increase in the dissolution rate of sample stored at accelerated condition, that concentration of calcium salt has not been adequate for maintaining dissolution characteristics after storage at accelerated conditions. D) Calcium sulphate at concentration of 12 % by weight of sodium alginate Ingredients Weight (mg/unit) % w/w Cephalexin 797.87 73.87 Sodium Alginate 43.20 4.00 Xanthan Gum 54.00 5.00 Hydroxypropyl Methylcellulose (Methocel K15M) 54.00 5.00 Calcium Sulphate 5.10 0.47 Lactose Monohydrate 109.63 10.15 Magnesium Stearate 16.20 1.50 Weight 1080 100 Time (hour) % Cephalexin released Initial lMa 1 22.5 22.6 2 35.7 34.3 3 45.0 42.3 4 44.4 43.7 15 6 48.5 48.5 8 58.1 58.2 10 69.4 69.9 12 79.1 82.5 14 86.8 91.1 aSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 1 month. The dissolution characteristics of sample after storage at accelerated conditions can be maintained by incorporating appropriate concentration of a calcium salt by weight of sodium alginate. E) Calcium sulphate at concentration of 25 % by weight of sodium alginate Ingredients Weight (mg/tablet) % w/w Cephalexin 797.87 73.87 Sodium Alginate 43.20 4.00 Xanthan Gum 54.00 5.00 Hydroxypropyl Methylcellulose (MethocelK15M) 54.00 5.00 Calcium Sulphate 10.80 1.00 Lactose Monohydrate 103.93 " 9.62 Magnesium Stearate 16.20 1.50 Weight 1080 100 Time (hour) % Cephalexin released Initial 1 21.3 2 33.0 3 " 40.0 4 42.1 6 43.5 8 47.7 10 53.9 12 59.7 14 66.1 The above results reveal that the initial release is retarded when higher concentration of calcium salt is used which is again not acceptable. The above illustrations clearly reveal that only when calcium salt is used in amounts within the range of 8 % - 20 % by -"■/eight of sodium alginate, the desired release profile and stability 16 of the compositions can be maintained which is lost when the amount of calcium salt used is beyond the above selected range. Tablets without Probenecid - Cefaclor or cephalexin, a mixture of uniformly preblended hydrophilic polymers and calcium sulphate, lactose and/or microcrystalline cellulose were mixed uniformly and lubricated with magnesium stearate. The blend was compacted and the slugs obtained were milled to form granules. The-sized granules were blended with the fines and the remaining lubricant and further compressed into tablets. For Example 1 to Example 5, the tablets were tested for cefaclor release in 900 ml of 0.1 N hydrochloric- acid for 1 hr, after which the dissolution medium was changed to pH 6.8 phosphate buffer 900 ml. The dissolution medium (pH 6.8 phosphate buffer) was replaced with fresh medium every hour thereafter. The tablets were placed into a 40 mesh basket (USP apparatus type-I) and were rotated at 100 rpm. For the examples containing cefaclor the dissolution medium (pH 6.8 phosphate buffer) was replaced with fresh medium every hour thereafter. For the examples containing cephalexin only aliquots and not all of the pH 6.8 phosphate buffer were withdrawn and replaced with fresh medium at each interval. Example 1 Ingredients Weight (mg/tablet) % w/w Cefaclor 524.10 74.87 Sodium Alginate 24.50 3.50 Xanthan Gum 7.00 1.00 Calcium Sulphate 3.50 0.50 Lactose Monohydrate 126.90 18.12 Magnesium Stearate 14.00 2.00 Total 700 100 Time (hour) Percent Cefaclor Released (%) 1 30.90 2 47.10 3 68.80 4 83.40 17 Example 2 Ingredients Weight (mg/tablet) % w/w Cefaclor 524.10 74.87 Sodium Alginate 24.50 3.50 Xanthan Gum 7.00 1.00 Calcium Sulphate 3.50 0.5 Microcrystalline Cellulose 126.90 18.12 Magnesium Stearate 14.00 2.00 Total 700 100 Time (hour) Percent Cefaclor Released (%) 1 30.30 2 48.80 3 73.10 4 87.90 Example 3 Ingredients Weight (mg/tablet) % w/w Cefaclor 526.80 75.25 Sodium Alginate 24.50 3.50 Xanthan Gum 14.00 2.00 Calcium sulphate 3.50 0.50 Lactose monohydrate 117.20 16.74 Magnesium Stearate 14.00 2.00 Total 700 100 Time (hour) Percent Cefaclor Released (%) 1 24.60 2 35.30 3 46.80 4 66.30 5 83.10 6 94.10 18 Example 4 Ingredients Weight (mg/tablet) % w/w Cefaclor 526.80 75.26 Sodium Alginate 24.50 3.50 Xanthan Gum 3.50 0.50 Hydroxypropyl Methylcellulose (Methocel K4M) 10.50 1.5,0 Calcium Sulphate 4.90 0.70 Lactose monohydrate 115.80 16.54 Magnesium Stearate 14.00 2.00 Total 700 100 Time (hour) Percent Cefaclor Released (%) 1 29.60 2 49.60 3 74.70 4 92.80 Example 5 Ingredients Weight (mg/tablet) % w/w Cefaclor 789.40 75.18 Sodium Alginate 42.00 4.00 Xanthan Gum 15.75 1.50 Hydroxypropyl Methylcellulose (Methocel K4M) 21.00 2.00 Calcium Sulphate 5.88 0.56 Lactose monohydrate 154.97 14.76 Magnesium Stearate 21.00 2.00 Total 1050 100 Time (hour) Percent Cefaclor Released (%) 1 19.10 2 28.70 3 44.40 4 59.80 5 71.40 6 82.00 For Example 6 to Example 11, the tablets were tested for cephalexin release in 900 ml of 0.1 N hydrochloric acid for 2 hr, after which the dissolution media was changed to pH 6.8 19 phosphate buffer 900 ml. The tablets were placed into a 40 mesri basket (USP apparatus type-I)and were rotated at 100 rpm. Example 6 Ingredients Weight (mg/tablet) % w/w Cephalexin 536.82 74.55 Sodium Alginate 43.20 6.00 Xanthan Gum 21.60 3.00 Hydroxypropyl Methylcellulose (Methocel K4M) 21.60 3.00 Calcium Sulphate 4.32 0.60 Lactose monohydrate 81.68 11.34 Magnesium Stearate 10.80 1.50 Total 720 100 Time (hour) Percent Cephalexin Released (%) 1 28.60 2 43.90 3 55.80 4 74.10 5 98.20 Example 7 Ingredients Weight (mg/tablet) % w/w Cephalexin 799.95 74.07 Sodium Alginate 64.80 6.00 Xanthan Gum 75.60 7.00 Calcium Sulphate 7.77 0.72 Lactose monohydrate 115.60 10.70 Magnesium Stearate 16.20 1.50 Total 1080 100 Time (hour) Percent Cephalexin Released (%) 1 22.80 2 35.10 3 42.10 4 42.90 6 47.40 8 57.40 10 73.50 12 86.10 14 98.40 20 Example 8 Ingredients Weight (mg/tablet) % w/w Cephalexin 800.94 74.16 Sodium Alginate 54.00 5.00 Xanthan Gum 75.60 7.00 Calcium Sulphate 7.56 0.70 Lactose monohydrate 125.70 11.64 Magnesium Stearate 16.20 1.50 Total 1080 100 Time (hour) Percent Cephalexin Released (%) 1 21.70 2 35.20 3 45.10 4 45.30 6 50.60 8 62.50 10 78.50 12 81.70 14 93.20 Example 9 Ingredients Weight (mg/tafalet) % w/w Cephalexin 797.87 73.87 Sodium Alginate 64.80 6.00 Xanthan Gum 54.00 5.00 Hydroxypropyl Methylcellulose (Methocel K15M) 54.00 5.00 Calcium Sulphate 7.78 0.72 Lactose monohydrate 79.95 7.40 Magnesium Stearate 21.60 2.00 Total 1080 100 Time (hour) 12 14 Percent Cephalexin Released (%) 23.20 34.90 4L40 4330 47.10 57.10 70.10 86.90 97.00 21 Example 10 Ingredients Weight (mg/tablet) % w/w Cephalexin 797.87 73.87 Sodium Alginate 64.80 6.00 Xanthan Gum 32.40 3.00 Hydroxypropyl Methyl cellulose (Methocel K15M) 32.40 3.00 Calcium Sulphate 7.77 0.72 Lactose monohydrate 128.54 11.90 Magnesium Stearate 16.20 1.50 Total 1080 100 Time (hour) Percent Cephalexin Released (%) I 23.90 2 37.10 3 46.30 4 .47.20 6 58.70 8 77.60 10 92.10 12 98.20 Example 11 Ingredients Weight (mg/tablet) % w/w Cephalexin 797.87 73.87 Sodium Alginate 43.20 4.00 Xanthan Gum 43.20 4.00 Hydroxypropyl Methylcellulose (Methocel K15M) 64.80 6.00 Calcium Sulphate 5.10 0.47 Lactose monohydrate 109.63 10.15 Magnesium Stearate 16.20 1.50 Total 1080 100 Time (hour) Percent Cephalexin Released (%) 1 22.90 2 35.10 3 42.40 4 43.60 ■ 6 47.80 8 57.10 10 66.90 12 76.60 14 86.80 22 Tablets with Probenecid - Example 12 Cephalexin, a mixture of uniformly preblended hydrophilic polymers and calcium sulphate, lactose were mixed uniformly and lubricated with magnesium stearate. The blend was compacted and the slugs obtained were milled to form granules. The sized granules were blended with the fines and the remaining lubricant. Probenecid, microcrystalline sodium, sodium starch glycolate, were screened through 30 mesh sieve. The blend was compacted and the slugs obtained were again milled to obtain granules. The sized granules were mixed with remaining sodium starch glycolate and magnesium stearate and fines, followed by compression of cephalexin granules on the pre-compressed probenecid granules. The tablets were tested for cephalexin release in 900 ml of 0.1 N hydrochloric acid for 2 hrs after which the dissolution media was changed to pH 6.8 phosphate buffer 900 ml. The tablets were placed into a 40 mesh basket (USP apparatus type X) and were rotated at 100 rpm. Further, fresh tablets were analysed for Probenecid release using 900 ml of pH 7.5 simulated intestinal fluid without pancreatin, USP apparatus type II at 50 rpm. Ingredients Weight (mg) % w/w Controlled Release Part Cephalexin 536.82 74.55 Sodium Alginate 28.80 4.00 Xanthan Gum 21.60 3.00 Hydroxypropyl Methylcellulose (Methocel K4M) 28.80 4.00 Calcium Sulphate 4.03 0.37 Lactose 89.15 12.38 Magnesium Sterate 10.80 1.50 Total 720 100.00 Immediate Release Part Probenecid 500.00 79.36 Microcrystalline Cellulose 95.50 15.16 Sodium Starch Glycolate 31.50 5.00 Magnesium Sterate 3.00 0.48 Total 630.00 100.00 23 Time (hour) Percent Cephalexin Released (%) 1 25.14 2 J 37.76 3 44.80 4 47.49 6 63.61 8 78.05 10 96.40 Time (min) Percent Probenecid Released (%) 10 98.80 20 102.20 30 103.30 Example 13 Cephalexin, uniformly preblended hydrophilic polymers and calcium sulphate, microcrystalline cellulose were mixed uniformly and lubricated with magnesium stearate. The blend was compacted and the slugs obtained were milled to form granules. The sized granules were blended with the fines and the remaining lubricant. Probenecid, lactose, sodium starch glycolate were screened through 30 mesh sieve. The blend was compacted and slugs obtained were milled to obtain granules. The sized granules were mixed with remaining sodium starch glycolate, magnesium stearate and fines followed by compression of Cephalexin granules on pre-compressed Probenecid granules. The tablets were tested for dissolution in 900 ml of 0.1 N hydrochloric acid for 2 hrs after which the dissolution media was changed to pH 6.8 phosphate buffer 900 ml, using 40 mesh basket (USP apparatus type I) and were rotated at 100 rpm. Further fresh samples were analysed for Probenecid release using 900 ml of pH 7.5 simulated intestinal fluid without pancreatin, USP apparatus tvpe II at 50 rpm. Ingredients Weight (mg/tablet) % w/w Controlled Release Part Cephalexin 536.82 74.55 Sodium Alginate 43.20 6.00 Xanthan Gum 36.00 5.00 Calcium Sulphate 6.01 0.84 24 Microcrystalline cellulose 87.13 12.10 Magnesium Sterate 10.80 1.50 Total 720 100 Immediate Release Part Probenecid 500.00 79.36 Lactose 102.00 16.19 Sodium Starch Glycolate 25.00 3.97 Magnesium Sterate 3.00 0.48 Total 630.00 100.00 Time (hour) Percent Cephalexin Released (%) 1 28.10 2 41.80 3 50.30 4 57.30 6 70.10 8 83.30 10 99.70 Time (min) Percent Probenecid Released (%) 10 80.30 20 95.40 30 99.30 Example 14 Cephalexin, probenecid, a mixture of uniformly preblended hydrophilic polymers and calcium sulphate and microcrystalline cellulose were screened through 30 mesh screen and mixed with magnesium stearate. The blend was compacted and the slugs obtained were milled to obtain the granules. The sized granules were blended with fines and the remaining lubricant and further compressed into tablets. The tablets were tested for cephalexin dissolution in 900 ml of 0.1N hydrochloric acid for 2 hrs after which the dissolution media was changec to pH 6.8 phosphate buffer 900 ml, using 40 mesh basket (USP apparatus type I) and were rotated at 100 rpm. Further fresh samples were analysed for probenecid release using 900 ml of pH 7.5 simulated intestinal fluid without pancreatin, USP apparatus type II at 50 rpm. 25 Ingredients Weight (mg/tablet) % w/w Cephalexin 536.82 38.34 Probenecid 500.00 35.71 Sodium Alginate 70.00 5.00 Xanthan Gum 56.00 4.00 Hydroxypropyl Methylcellulose (Methocel K4M) 70.00 5.00 Calcium Sulphate 7.00 0.50 Microcrystalline cellulose 142.68 10.19 Magnesium Sterate 17.50 1.25 Total 1400 100 Time (hour) Percent Cephalexin Released (%) Percent Probenecid Released (%) 1 23.60 42.90 2 42.70 69.70 3 54.60 85.50 4 61.20 100.90 6 70.10 8 80.40 10 96.90 Example 15 Cefaclor, a mixture of uniformly preblended hydrophilic polymers and calcium sulphate, microcrystalline cellulose were mixed uniformly and lubricated with magnesium stearate. The blend was compacted and the slugs obtained were milled to form granules. The sized granules were blended with the fines and the remaining lubricant. Probenecid, starch, sodium starch glycolate, were screened through 30 mesh sieve. The blend was compacted and the slugs obtained were milled to obtain granules. The sized granules were mixed with remaining sodium starch glycolate and magnesium stearate and fines, followed by compression of cefaclor granules on the pre-compressed Probenecid granules. The tablets were tested for cefaclor release in 900 ml of 0.1 N hydrochloric acid for 2 hrs after which the dissolution media was changed to pH-6.8 phosphate buffer 900 ml. The tablets were placed into a 40 mesh basket (USP apparatus type-1) and were rotated at 100 rpm. The dissolution medium (pH 6.8 phosphate buffer) was replaced by fresh medium 26 every hour. Further fresh tablet were analysed for Probenecid release using 900 ml of pH 7.5 simulated intestinal fluid without pancreatin, USP apparatus type II at 50 rpm. Ingredients Weight (mg/tablet) % w/w Controlled Release Part Cefaclor 530.50 j 75.78 Sodium Alginate 28.00 4.00 Xanthan Gum 7.00 1.00 Hydroxypropyl Methylcellulose (Methocel K4M) 14.00 2.00 Calcium Sulphate 3.92 0.56 Microcrystalline Cellulose 106.08 15.15 Magnesium Sterate 10.50 1.50 Total 700 100 Immediate Release Part Probenecid 500.00 79.36 Starch 70.61 11.21 Sodium Starch Glycolate 50.40 8.00 Magnesium Sterate 9.00 1.43 Total 630.00 100.00 Time (hour) Percent Cefaclor Released (%) 1 24.60 2 45.20 3 50.60 4 61.30 6 75.90 8 89.20 Time (min) Percent Probenecid Released (%) 10 96.80 20 99.10 30 100.80 Further the bioavailability study was conducted for long acting modified release matrix formulation without probenecid, one dose of 2 tablets x (750 mg cephalexin), prepared according to present invention. Eight healthy male volunteers were selected for the study in which each volunteer was administered a dose of the drug with 180 ml of water. The volunteers had a standard breakfast before taking the drug. The desired blood levels up to 18 to 20 hours were achieved with compositions without probenecid prepared according to the invention, indicating that it can be used as once daily composition. 27 Figure 1 shows a plot of blood level concentrations of modified release composition of the present invention, one dose of 2 tablets of cephalexin 750 mg. The plot clearly reveals the favourable bio-availability of the active achieved using the formulation of the invention. 28 WE CLAIM: 1. A stable improved pharmaceutical composition for controlled release of an active ingredient comprising a controlled release matrix comprising i)a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient in amounts of 30 % to 90 % by weight, ii)a mix of hydropbilic polymers in amount of 1 % to 25 % selected from the group consisting of at least one sodium alginate in amounts of 0.1 % to 20 %, and at least one xanthan gum in amounts of 0.1 % to 20 % and iii) a calcium salt in an amount of 8 % to 20 % by weight of sodium alginate. 2. A stable improved pharmaceutical composition as claimed in claim 1 wherein said hydrophilic polymers mix comprise hydroxypropyl methylcellulose in an amount of 0.1% to 20% by weight, 3. A stable improved pharmaceutical composition as claimed in anyone of claims 1 or 2 comprising probencid. 4. The composition as claimed in claim 3 wherein the probenecid is present in the controlled release matrix. 5. The composition as claimed in claim 3 wherein the active is released at a rate suitable for once daily or twice daily administration of the composition. 6. The composition as claimed in claim 1 in a solid dosage form. 7. The composition as claimed in claim 1 wherein the calcium salt is calcium sulphate. 8. The composition as claimed in claim 2 wherein the controlled release matrix comprises from 30 % to 90 % by weight of a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters and 1 % to 20 % by weight of hydrophilic polymers comprising of a medium or high viscosity grade sodium alginate in an amount from 0.1 % to 15 % by weight, a medium or high viscosity grade xanthan gum in an amount from 0.1 % to 15 % by weight, and a medium or 29 high viscosity grade hydroxypropyl methylceUulose in an amount from 0.1 % to 15 % by weight of controlled release matrix; and calcium sulphate in an amount from 8 % to 16 % by weight of sodium alginate. 9. The composition as claimed in claim 2, wherein the controlled release matrix comprises from 30-% to 90 % by weight of a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters and 1 % to 18 % by weight of hydrophilic polymers comprising of a medium or high viscosity grade sodium alginate in an amount from 1 % to 10 % by weight, a medium or high viscosity grade xanthan gum in an amount from 1 % to 10 % by weight, and a medium or high viscosity grade hydroxypropyl methylceUulose in an amount from 1 % to 10 % by weight of controlled release matrix; and calcium sulphate in an amount from 10 % to 14 % by weight of sodium alginate. 10. The composition as claimed in anyone of claims 1, 8 or 9, wherein the betalactam antibiotic is selected from cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters. 11. The composition as claimed in claim 1, wherein the calcium salt is selected from calcium sulphate, calcium citrate, disodium calcium edetate, calcium lactate, calcium ascorbate, calcium gluconate, calcium chloride. 12. The composition as claimed in claim 1 or 2, which further comprises at least one water soluble or water dispersible diluent. 13. The composition as claimed in claim 12, wherein the water soluble or water dispersible diluent comprises 1 % to 30 % by weight of the composition. 14. The composition as claimed in claim 12, wherein the diluent is lactose. 15. The composition as claimed in claim 14, wherein the amount of lactose is from 4 % to 20 % by weight of the composition. 30 16. The composition as claimed in claim 12, wherein the diluent is microcrystalline cellulose. 17. The composition as claimed in claim 16, wherein the amount of microcrystalline cellulose is from 4 % to 20 % by weight.of the cpmposition. 18. The composition as claimed in claim 1 comprising magnesium stearate, in amount from 0.2 % to 5 % by weight of the composition. 19. A composition as claimed in any one of the preceding claims wherein a multidose contains 250 mg to 2 g active ingredient. 20. A composition as claimed in anyone of claims 1 to 18 in dosage unit form containing 100 to 1 g active ingredient. 21. The composition as claimed in claim 3, wherein probenecid is present in an amount from about 250 mg to about 1000 mg. 22. The composition as claimed in claim 3, wherein the probenecid is present as a immediate release part. 23. The composition as claimed in claim 22, which further contains a disintegrating agent from 2 % to 9 % by weight of immediate release part. 24. The composition as claimed in claim 23 wherein disintegrating agent is sodium starch glycolate. 25. The composition as claimed in claim 22 wherein, the controlled release part in a hydrophilic matrix and immediate release probenecid part are compressed together into a tablet dosage form. 31 26. The composition as claimed in claim 22 wherein, the controlled release part in a hydrophilic matrix and immediate release probenecid part are compressed separately into tablets and packed in a way to be administered simultaneously. 27. A process for the preparation of a pharmaceutical composition as claimed in claim 1, comprising mixing together the active ingredient with the pre-blended hydrophilic polymers with or without hydroxypropyl methylcellulose and calcium sulphate, in selective amounts, optionally with one or more of probenecid, djluent and lubricant to form a blend, further compacting, sizing, blending and compressing into tablets. 28. A process for the preparation of a pharmaceutical composition as claimed in claim 22, comprising mixing together the active ingredient with the pre-blended hydrophilic polymers with or without hydroxypropyl methylcellulose and calcium sulphate together with a diluent and at least one lubricant to form a blend, further compacting, sizing, blending and compressing into tablets along with immediate release probenecid part. 29. A process for the preparation of pharmaceutical composition as claimed in claim 3, comprising mixing together probenecid, diluent and disintegrating agent together, compacting, sizing and blending with lubricant and compressing the blend into tablets along with controlled release matrix. Dated this 26th day of April 2004 DR. SANCHITA"GANGULI Of S. MAJUMDAR & CO. Applicants" Agent 32

Full Text

FORM2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. Title of the invention. -

A PHARMACEUTICAL COMPOSITION FOR CONTROLLED RELEASE OF A
BETA-LACTAM ANTIBIOTIC

2. Applicant

/?-■

(a) LUPIN LIMITED
(b) 159, C.S.T. Road, Kalina, Santacruz (East), Mumbai - 400 098, State of Maharashtra, India
(c) An Indian company

The following specification particularly describes the nature of this invention and the manner in which it is to be performed

FIELD OF THE INVENTION
This invention relates to an improved stabilized pharmaceutical composition of modified release tablets comprising a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient, which would provide for controlled release of said actives \ and will also be capable of maintaining its dissolution characteristics upon storage, at ambient and accelerated conditions. The stabilized composition of the invention is also adapted to withstand the peristaltic pressure in the stomach and intestine, maintain the integrity of the composition and thereby avoid problems of dose dumping. Advantageously, the composition of the invention can be selectively provided to favour desired release of the therapeutically effective active ingredient such as at a rate suitable for once or twice daily administration of the pharmaceutical composition. The composition optionally contains probenecid as an antibiotic adjuvant.
BACKGROUND OF THE INVENTION
United States Patent No. US 6,267,986 Bl teaches preparation of a controlled release pseudoephdrine composition in combination with an antihistamine comprising two discrete zones. The first discrete zone comprises pseudoephdrine, one or more hydrophilic polymers, a salt of a polyuronic acid and a pharmaceutically acceptable salt of a group II metal ion and the second discrete zone comprises an antihistamine.
United States Patent No. US 5,419,917 discloses a controlled release hydrogel formulation for substantially zero-order release rate of drug from the hydrogel which is based on the use of an effective amount of a pharmaceutically acceptable ionizable compound. The hydrogel forming agent are being selected from the group consisting of hydroxypropyl methylcellulose, sodium alginate and xanthan and the ionizable compound being selected from the group consisting of alkali metal chlorides, organic acids, alkali metal sulfates and alkali metal alkyl sulfates, dihydrogen sodium phosphate and monohydrogen sodium phosphate.
A sustained release cephalexin tablet containing xanthan gum and sodium alginate as matrix formers was evaluated in human volunteers using in-vitrolin-vivo correlations. The optimized
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formulation containing 5 % xanthan gum and 8 % sodium alginate, decided on the basis of response surface analysis and computer simulation of cephalexin plasma levels versus time curves was used for clinical trials and was found to prolong the cephalexin blood levels up to 8 hours in humans. However, the relative bioavailability of cephalexin was reduced by about 30 % and very little absorption was seen after six to eight hours, rendering the formulation not very useful for once daily regimen (see Dhopeshwarkar V;, O"Keeffe J. C, Zatz J. L., Deeter R. and Horton M., Drug Develp. Ind. Phar., 20, 1851, 1994).
Our PCT Application No. PCT/TN00/00112 relates to a pharmaceutical composition of modified release tablets comprising a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient, and a mixture of hydrophilic polymers selected from the group consisting of at least one sodium alginate and at least one xanthan gum as controlled release matrix, and optionally probenecid. Inclusion of probenecid allows reduction in the amount of active incorporated in the polymeric matrix but can still provide desired once daily profile. The resulting modified release matrix formulation not containing probenecid may be administered in a once or twice daily regimen and the resulting modified release matrix formulation containing probenecid may be administered in a once daily regimen. However, it was observed that tablets become soft and irregular after about 6 hours ofin-vitro dissolution studies, the integrity of the tablet and its shape is not maintained at a later stage after hydration. This soft irregular mass of the composition may not withstand the peristaltic pressure in the stomach and intestine, which could possibly lead to dose dumping in later stage.
Further, it was observed that the release of the active ingredient was faster from the samples stored for stability study under ambient and accelerated conditions, when compared to initial stage in-vitro dissolution data, which may render the composition ideally not suited for use as a controlled release composition haying desired release profile.
OBJECTS OF THE INVENTION
The basic object of the present invention is to provide an improved stable composition of a betalactam antibiotic such as cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters in a modified release matrix formulation, which would avoid the
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above discussed problems associated with stability of the composition and integrity of the composition and consequential dose dumping.
A further object of the present invention is to provide an improved stable composition of a betalactam antibiotic such as cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters in a modified release matrix formulation, optionally containing probenecid such that the composition maintains its dissolution characteristics upon storage, at ambient and accelerated conditions.
Another object of the present invention is to provide an improved stable composition of a betalactam antibiotic such as cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters in a modified release matrix formulation, optionally containing probenecid such that the integrity and shape of the composition is maintained even at the later stage of hydration.
SUMMARY OF THE INVENTION
Thus according to one aspect of the present invention there is provided a stable improved pharmaceutical composition for controlled release of an active ingredient comprising a controlled release matrix comprising i)a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient in amounts of 30 % to 90 % by weight, ii)a mix of hydrophilic polymers in amount of 1 % to 25 % selected from the group consisting of at least one sodium alginate in amounts of 0.1 % to 20 %, and at least one xanthan gum in amounts of 0.1 % to 20 % and Hi) a calcium salt in an amount of 8 % to 20 % by weight of sodium alginate.
In accordance with a preferred aspect the composition of the invention, in particular the hydrophilic polymers used therein incorporate along witn the said sodium alginate and said xanthan gum optionally at least one hydroxypropyl methylcellulose, preferably in amount of 0.1 % to 20 % by weight of the controlled release matrix.
It is found that the above selective controlled release formulation of the invention avoids the shortcoming of integrity of the matrix composition comprising at least one sodium alginate and at least one xanthan gum and also takes care of the desired controlled release profile of
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the active. By inclusion of a hydroxypropyl methyicellulose in to the matrix, the integrity of the tablet is improved and its shape is maintained at a later stage after hydration so that it withstands the peristaltic pressure in the stomach and intestine thereby obviating the possibility of dose dumping.
Advantageously, the selective use of a calcium salt such as calcium sulphate in the defined range as disclosed above is also found to be advantageous in use with sodium alginate as a polymer niatrix material for controlled release formulation. This is because calcium alginate when used as such in sustained release preparation forms a water insoluble gel, which has reduced diffusivity and erosion of gel layer. But addition of the selective calcium salt in dry state in the polymer matrix containing sodium alginate acts as a matrix stabilizing agent by in situ formation of a localized calcium alginate gel, as after ingestion of the composition, the solvent front passes up to the core of the composition resulting in formation of gel layer in a manner such that a gel layer contains combination of sodium and calcium alginate, which would erode faster in comparison to a gel layer containing only calcium alginate leading to desired release profile of the active from the composition.
Importantly, the above composition of the invention attends to the problems of stability of the tablets after storage at ambient and accelerated conditions, by selective incorporation of a calcium salt such as calcium sulphate in a defined range as matrix stabilising agent.
In accordance with a preferred aspect, the invention proposes the use of a hydroxypropyl methyicellulose into the matrix, which forms a strong gel structure. These hydrophilic polymers when used in appropriate concentrations, form the integrated matrix which provides the desired release profile, when the delivery system travels through the GIT, having varying physiological condition. Surprisingly, the polymers in appropriate combinations are not only effective compared to other commonly used polymers, but works at low concentrations. The combination of these polymers compliment each other such that, it overcomes the deficiencies associated with their use, when used alone.
The composition of the invention can optionally also contain one or more water soluble and/or water dispersible diluents, wherein the quantities of the. hydrophilic polymers and water soluble and/or water dispersible diluents are such that the therapeutically effective
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active ingredient is released at a rate suitable for once or twice daily administration of the pharmaceutical composition. Inclusion of probenecid allows reduction in the amount of active incorporated in the hydrophihc polymer matrix but still provides the desired once a day profile.
The preferred betalactam antibiotic is selected from cephalexin, cefaclor or their pharmaceutical^ acceptable hydrates, salts or esters.
The modified release matrix formulation not containing probenecid prepared according to present invention may be administered once or twice daily. For Example, the effective therapeutic dose of the active that can be administered by compositions of present invention include 375 mg to 500 mg active twice daily or 750 mg to 1500 mg active once daily.
The modified release matrix formulation containing probenecid prepared according to present invention may be administered once daily. For example, the effective therapeutic dose of the active that can be administered by compositions of present invention include 500 mg to 1000 mg active and 500 mg to 1000 mg probenecid once daily.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The composition of this invention is in the form of a. matrix tablet comprising the active ingredient, hydrophilic polymers, a calcium salt, 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 cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters in a controlled release matrix. The cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters may be present in an amount from about 30 % to about 90 % by weight of the controlled release matrix.
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Further, the cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters may be present in an amount from 100 mg to 2000 mg.
Examples of other cephalosporin antibiotics which may be used include cefuroxime, cefamandole, cefoxitin, cephalothin, moxalactam, cephapirin, ceffizoxime, cefonicid and, pharmaceutically acceptable hydrates, salts or esters thereof. Examples of other betalactam antibiotics, which may be used, are amoxicillin, ampicillin, and cloxacillin.
Examples of the calcium salts useful in the present invention are calcium sulphate, calcium citrate, disodium. calcium edetate, calcium lactate, calcium ascorbate, calcium gluconate, calcium chloride. The preferred calcium salt is calcium sulphate.
Xanthan gum when used as a matrix forming agent in sustained release tablets, releases the drug slightly faster in acidic media, due to more rapid initial surface erosion than at higher pH. After hydration of the gum the drug release is essentially pH independent but the release of drug decrease exponentially.
Alginic acid is insoluble in aqueous media. However, as the pH is raised above 3, the alginic acid is partly converted to a soluble salt. Complete neutralization occurs around pH 4, where the alginic acid is completely converted to its corresponding salt. Sodium, potassium, magnesium and ammonium salts are examples of water-soluble alginate salts. Neutralization by calcium, barium and other multivalent alkali materials will produce insoluble alginate salts.
Thus when sodium alignate is used along with xanthan gum to form a controlled release matrix, it reduces the initial bursting effi ;t and in later stages acts as a channeling agent to increase the release rate of the active.
It is known in the art that in gastric fluid the hydrated sodium alginate is converted into a porous, insoluble alginic acid skin. Once passed into the higher pH of the intestinal tract, the alginic acid skin is converted to a soluble viscous layer.
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to about 1000 cPs); xanthan gum may be characterized as low viscosity (about 600 to about 1500 cPs), medium viscosity (about 1550 to about 1850 cPs) and high viscosity (greater than about 1900 cPs); and hydroxypropyl methylcellulose may be characterized by their viscosity in a 2 % w/w aqueous solution as low viscosity (less than 1000 cps), medium viscocity (about 1000 cps to about 10,000 cps) and high viscosity (greater then about 10,000 cps).
The different viscosity grade polymers may be used in the present invention, but in order to utilize minimum possible concentrations of the polymer to achieve the desired profiles, without compromising on the integrity of the matrix, medium or high viscosity grade polymers are preferred.
In a preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters and about 1 % to about 25 % by weight of hydrophilic polymers comprising of sodium alginate in an amount from about 0.1 % to about 20 % by weight, xanthan gum in an amount from about 0.1 % to about 20 % by weight, and hydroxypropyl methylcellulose in an amount from about 0.1 % to about 20 % by weight of controlled release matrix; and calcium sulphate in an amount from about 8 % to about 20 % by weight of sodium alginate. "
In a more preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters and about 1 % to about 20 % by weight of hydrophilic polymers comprising of a medium or high viscosity grade sodium alginate in an amount from about 0.1 % to about 15 % by weight, a medium or high viscosity grade xanthan gum in an amount from about 0.1 % to about 15 % by weight, and a medium or high viscosity grade hydroxypropyl methylcellulosv in an amount from about 0.1 % to about 15 % by weight of controlled release matrix; and calcium sulphate in an amount from about 8 % to about 16 % by weight of sodium alginate.
In one more preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their
9

to about 1000 cPs); xanthan gum may be characterized as low viscosity (about 600 to about 1500 cPs), medium viscosity (about 1550 to about 1850 cPs) and high viscosity (greater than about 1900 cPs); and hydroxypropyl methylcellulose may be characterized by their viscosity in a 2 % w/w aqueous solution as low viscosity (less than 1000 cps), medium viscocity (about 1000 cps to about 10,000 cps) and high viscosity (greater then about 10,000 cps).
The different viscosity grade polymers may be used in the present invention, but in order to utilize minimum possible concentrations of the polymer to achieve the desired profiles, without compromising on the integrity of the matrix, medium or high viscosity grade polymers are preferred.
In a preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters and about 1 % to about 25 % by weight of hydrophilic polymers comprising of sodium alginate in an amount from about 0.1 % to about 20 % by weight, xanthan gum in an amount from about 0.1 % to about 20 % by weight, and hydroxypropyl methylcellulose in an amount from about 0.1 % to about 20 % by weight of controlled release matrix; and calcium sulphate in an amount from about 8 % to about 20 % by weight of sodium alginate.
In a more preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters and about 1 % to about 20 % by weight of hydrophilic polymers comprising of a medium or high viscosity grade sodium alginate in an amount from about 0.1 % to about 15 % by weight, a medium or high viscosity grade xanthan gum in an amount from about 0.1 % to about 15 % by weight, and a medium or high viscosity grade hydroxypropyl methylcellulose in an amount from about 0.1 % to about 15 % by weight of controlled release matrix; and calcium sulphate in an amount from about 8 % to about 16 % by weight of sodium alginate.
In one more preferred embodiment of the present invention, the pharmaceutical composition comprises from about 30 % to about 90 % by weight of cephalexin, cefaclor or their
9

stearic acid, magnesium stearate, colloidal silicon dioxide, calcium stearate, zinc stearate, hydrogenated vegetable oil and the like. Preferably the lubricant is magnesium stearate.
The immediate release probenecid part of the present invention contains a disintegrating agent at concentration in the range of about 2 % to about 9 % by weight of immediate release part. Preferably the disintegrating agent is sodium starch glycolate.
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. All the hydrophilic polymers are uniformly pre-blended with calcium sulphate, followed by the active ingredient; one or more water soluble or water dispersible diluents are either mixed together with lubricants and the blend is directly compressed into tablets or are granulated by compaction followed by sieving and the granules obtained are compressed into tablets. The active ingredient can be given as controlled release tablets for once or twice a day administration or as controlled release tablet along with separate probenecid tablets as a combipack to be administered simultaneously or coupled with probenecid into a single monolithic or bilayered tablets for once a day administration. The fines incorporated in the blend of active granules form about 12 % to about 30 % by weight of controlled release part, preferably from about 12 % to about 20 %.
For the purpose of this patent application, fines denote the particles having size less than 250 microns.
The above-mentioned process has the advantage over its granulation by aqueous or non¬aqueous vehicle used conventionally. The active ingredient such as cephalexin or cefaclor, which are sensitive to moisture and heat, can be effectively processed without any difficulty. The polymers used in the composition of present invention, xanthan gum and sodium alginate also are unstable above 60° C and 70° C respectively. As the process is devoid of use of any solvents the potential problem of limiting the residual organic solvent is eliminated.
The controlled release matrix formulation of the present invention is not a mere admixture but has properties different from the sum total of the properties of its ingredients.
11

The probenecid part of the composition is prepared by mixing probenecid and one or more water soluble or water dispersible diluents together with lubricants and the blend is granulated by compaction followed by sieving and the granules obtained are lubricated and compressed into a tablet. The fines incorporated in the blend form about 10 % to about 30 % by weight of immediate release part, preferably from about 10 % to about 20 %.
The modified release matrix formulation not containing probenecid prepared according to present invention may be administered once or twice daily. For example, the effective therapeutic dose of the active that can be administered by compositions of present invention include 375 mg to 750 mg active twice daily or 750 mg to 1500 mg active once daily.
The modified release matrix formulation containing probenecid prepared according to present invention may be administered once daily. The effective therapeutic dose of the active that can be administered by compositions of present invention include 500 mg to 1000 mg active and 500 mg to 1000 mg probenecid once daily.
The present invention is illustrated hereunder in greater detail in relation to non-limiting exemplary embodiments as per the following examples:
EXAMPLES
In the examples given below medium viscosity grade xanthan gum manufactured by Jungbunzlauer, Austria; sodium alginate (Keltone HVCR) manufactured by ISP Alginates; and hydroxypropyl methylcellulose of medium viscocity grade (Methocel K4M™), high viscosity grade (Methocel K15M™) manufactured by Dow Chemicals, USA has been employed. The dissolution results are given in respective tables for each example.
Effect of calcium sulphate (as a matrix stabilizing agent) on in-vitro dissolution of tablets on storage at accelerated condition -
12

A) Tablet containing hydroxypropyl methylcellulose

Ingredients Tablet with Calcium Sulphate Tablet without Calcium Sulphate
Weight (mg/tablet) % w/w Weight (mg/tablet) % w/w
Cephalexin 797.82 73.87 797.87 73.87
Sodium Alginate 43.20 4.00 86.40 8.00
Xanthan Gum 54.00 5.00 43.20 ; 4.00
Hydrxypropyl Methylcellulose (MethocelK15M) 54.00 5.00 32.40 3.00
Calcium Sulphate 5.10 0.47 - -
Lactose Monohydrate 109.63 10.15 103.93 9.62
Magnesium Stearate 16.20 1.50 16.20 1.50
Total 1080 100 1080 100

Time (in hour) % Cephalexin released (Tablet with calcium sulphate) % Cephalexin released (Tablet without calcium sulphate)
Initial lMa 3Mb Initial lMa 3M"
1 22.5 22.6 21.6 22.0 224 22.9
2 35.7 34.3 33.5 37.1 36.8 37.3
3 45.0 42.3 41.3 44.5 44.7 45.0
4 44.4 43.7 43.5 45.6 50.4 52.1
6 48.5 48.5 49.1 48.6 68.0 73.6
8 58.1 58.2 58.9 56.8 89.0 94.1
10 69.4 69.9 69.8 67.2 99.9
12 79.1 82.5 78.0 83.3
14 86.8 91.1 85.2 98.9
aSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 1 month, bSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 3 months.
B) Tablet not containing hydroxypropyl methylcellulose

Ingredients Tablet with Calcium Sulphate Tablet without Calcium Sulphate
Weight (mg/tablet) % w/w Weight (mg/tablet) % w/w
Cephalexin 797.87 73.87 800.86 74.14
Sodium Alginate 64.80 7.00 86.40 8.00
Xanthan Gum 75.60 6.00 75.60 7.00
Calcium Sulphate 9.07 0.84 - -
Lactose Monohydrate 116.46 10.78 100.94 9.35
Magnesium Stearate 16.20 1.50 16.20 1.50
Total 1080 100 1080 100
13

Time (in hour) % Cephalexin released (Tablet with calcium sulphate) % Cephalexin released (Tablet without calcium sulphate)
Initial lMa 3Mb Initial lMa 3Mb
1 24.7 23.4 22.2 20.7 21.6 13.0
2 39.0 36.8 34.9 33.0 37.4 37.1
3 48.0 45.1 45.9 43.1 46.3 51.4
4 48.3 48.7 48.1 43.3 53.7 55.0
6 55.0 55.3 57.8 51.1 69.4 76.5
8 66.7 65.7 70.5 65.0 92.2 95.3
10 82.9 75.4 84.5 81.8
12 87.4 84.7 88.0 96.4
14 100.0 98.1 92.8 100.4
aSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 1 month; bSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 3 months.
It would be evident from the above, that incorporation of a calcium salt such as calcium sulphate as a matrix stabilizing agent advantageously favours maintaining the stability of the composition as a control release formulation, and can maintain its dissolution characteristics after storage at accelerated conditions. Additionally, the use of a hydroxypropyl methylcellulose in addition to a xanthan gum and a sodium alginate, though provides composition, which maintains its physical integrity/shape in the later stages of hydration, it does not provide a composition, which can maintain its dissolution characteristics after storage of samples at accelerated conditions.
In accordance the further aspect of the invention the following illustrations demonstrate the selectivity in the use of calcium sulphate within the range of the 8 % -20 % by weight of sodium alginate in the controlled release formulation of the invention.
Concentration of calcium sulphate
C) Calcium sulphate at concentration of 5 % by weight of sodium alginate

Ingredients Weight (mg/tabiet) % w/w
Cephalexin 797.87 73.87
Sodium Alginate 43.20 4.00
Xanthan Gum 54.00 5.00
14

Hydroxypropyl Methylcellulose (Methocel K15M) 54.00 5.00
Calcium Sulphate 2.16 0.20
Lactose MonohydrateO 112.57 10.42
Magnesium Stearate 16.20 1.50
Weight 1080 100

Time (hour) % Cephalexin released

Initial 1M"
1 22.1 24.1
2 34.2 36.3
3 41.3 47.6
4 42.6 47.7
6 46.6 57.4
8 55.0 72.2
10 65.9 86.4
12 72.7 108.9
14 80.1
Samples stored at accelerated conditions of 40° C, 75 % relative humidity for 1 month.
The above results demonstrate by way of an increase in the dissolution rate of sample stored at accelerated condition, that concentration of calcium salt has not been adequate for maintaining dissolution characteristics after storage at accelerated conditions.
D) Calcium sulphate at concentration of 12 % by weight of sodium alginate

Ingredients Weight (mg/unit) % w/w
Cephalexin 797.87 73.87
Sodium Alginate 43.20 4.00
Xanthan Gum 54.00 5.00
Hydroxypropyl Methylcellulose (Methocel K15M) 54.00 5.00
Calcium Sulphate 5.10 0.47
Lactose Monohydrate 109.63 10.15
Magnesium Stearate 16.20 1.50
Weight 1080 100

Time (hour) % Cephalexin released

Initial lMa
1 22.5 22.6
2 35.7 34.3
3 45.0 42.3
4 44.4 43.7
15

6 48.5 48.5
8 58.1 58.2
10 69.4 69.9
12 79.1 82.5
14 86.8 91.1
aSamples stored at accelerated conditions of 40° C, 75 % relative humidity for 1 month.
The dissolution characteristics of sample after storage at accelerated conditions can be maintained by incorporating appropriate concentration of a calcium salt by weight of sodium alginate.
E) Calcium sulphate at concentration of 25 % by weight of sodium alginate

Ingredients Weight (mg/tablet) % w/w
Cephalexin 797.87 73.87
Sodium Alginate 43.20 4.00
Xanthan Gum 54.00 5.00
Hydroxypropyl Methylcellulose (MethocelK15M) 54.00 5.00
Calcium Sulphate 10.80 1.00
Lactose Monohydrate 103.93 " 9.62
Magnesium Stearate 16.20 1.50
Weight 1080 100

Time (hour) % Cephalexin released

Initial
1 21.3
2 33.0
3 " 40.0
4 42.1
6 43.5
8 47.7
10 53.9
12 59.7
14 66.1
The above results reveal that the initial release is retarded when higher concentration of calcium salt is used which is again not acceptable.
The above illustrations clearly reveal that only when calcium salt is used in amounts within the range of 8 % - 20 % by -"■/eight of sodium alginate, the desired release profile and stability
16

of the compositions can be maintained which is lost when the amount of calcium salt used is beyond the above selected range.
Tablets without Probenecid -
Cefaclor or cephalexin, a mixture of uniformly preblended hydrophilic polymers and calcium sulphate, lactose and/or microcrystalline cellulose were mixed uniformly and lubricated with magnesium stearate. The blend was compacted and the slugs obtained were milled to form granules. The-sized granules were blended with the fines and the remaining lubricant and further compressed into tablets.
For Example 1 to Example 5, the tablets were tested for cefaclor release in 900 ml of 0.1 N hydrochloric- acid for 1 hr, after which the dissolution medium was changed to pH 6.8 phosphate buffer 900 ml. The dissolution medium (pH 6.8 phosphate buffer) was replaced with fresh medium every hour thereafter. The tablets were placed into a 40 mesh basket (USP apparatus type-I) and were rotated at 100 rpm.
For the examples containing cefaclor the dissolution medium (pH 6.8 phosphate buffer) was replaced with fresh medium every hour thereafter. For the examples containing cephalexin only aliquots and not all of the pH 6.8 phosphate buffer were withdrawn and replaced with fresh medium at each interval. Example 1

Ingredients Weight (mg/tablet) % w/w
Cefaclor 524.10 74.87
Sodium Alginate 24.50 3.50
Xanthan Gum 7.00 1.00
Calcium Sulphate 3.50 0.50
Lactose Monohydrate 126.90 18.12
Magnesium Stearate 14.00 2.00
Total 700 100

Time (hour) Percent Cefaclor Released (%)
1 30.90
2 47.10
3 68.80
4 83.40
17

Example 2

Ingredients Weight (mg/tablet) % w/w
Cefaclor 524.10 74.87
Sodium Alginate 24.50 3.50
Xanthan Gum 7.00 1.00
Calcium Sulphate 3.50 0.5
Microcrystalline Cellulose 126.90 18.12
Magnesium Stearate 14.00 2.00
Total 700 100

Time (hour) Percent Cefaclor Released (%)
1 30.30
2 48.80
3 73.10
4 87.90
Example 3

Ingredients Weight (mg/tablet) % w/w
Cefaclor 526.80 75.25
Sodium Alginate 24.50 3.50
Xanthan Gum 14.00 2.00
Calcium sulphate 3.50 0.50
Lactose monohydrate 117.20 16.74
Magnesium Stearate 14.00 2.00
Total 700 100

Time (hour) Percent Cefaclor Released (%)
1 24.60
2 35.30
3 46.80
4 66.30
5 83.10
6 94.10
18

Example 4

Ingredients Weight (mg/tablet) % w/w
Cefaclor 526.80 75.26
Sodium Alginate 24.50 3.50
Xanthan Gum 3.50 0.50
Hydroxypropyl Methylcellulose (Methocel K4M) 10.50 1.5,0
Calcium Sulphate 4.90 0.70
Lactose monohydrate 115.80 16.54
Magnesium Stearate 14.00 2.00
Total 700 100

Time (hour) Percent Cefaclor Released (%)
1 29.60
2 49.60
3 74.70
4 92.80
Example 5

Ingredients Weight (mg/tablet) % w/w
Cefaclor 789.40 75.18
Sodium Alginate 42.00 4.00
Xanthan Gum 15.75 1.50
Hydroxypropyl Methylcellulose (Methocel K4M) 21.00 2.00
Calcium Sulphate 5.88 0.56
Lactose monohydrate 154.97 14.76
Magnesium Stearate 21.00 2.00
Total 1050 100

Time (hour) Percent Cefaclor Released (%)
1 19.10
2 28.70
3 44.40
4 59.80
5 71.40
6 82.00
For Example 6 to Example 11, the tablets were tested for cephalexin release in 900 ml of 0.1 N hydrochloric acid for 2 hr, after which the dissolution media was changed to pH 6.8
19

phosphate buffer 900 ml. The tablets were placed into a 40 mesri basket (USP apparatus type-I)and were rotated at 100 rpm. Example 6

Ingredients Weight (mg/tablet) % w/w
Cephalexin 536.82 74.55
Sodium Alginate 43.20 6.00
Xanthan Gum 21.60 3.00
Hydroxypropyl Methylcellulose (Methocel K4M) 21.60 3.00
Calcium Sulphate 4.32 0.60
Lactose monohydrate 81.68 11.34
Magnesium Stearate 10.80 1.50
Total 720 100

Time (hour) Percent Cephalexin Released (%)
1 28.60
2 43.90
3 55.80
4 74.10
5 98.20
Example 7

Ingredients Weight (mg/tablet) % w/w
Cephalexin 799.95 74.07
Sodium Alginate 64.80 6.00
Xanthan Gum 75.60 7.00
Calcium Sulphate 7.77 0.72
Lactose monohydrate 115.60 10.70
Magnesium Stearate 16.20 1.50
Total 1080 100

Time (hour) Percent Cephalexin Released (%)
1 22.80
2 35.10
3 42.10
4 42.90
6 47.40
8 57.40
10 73.50
12 86.10
14 98.40
20

Example 8

Ingredients Weight (mg/tablet) % w/w
Cephalexin 800.94 74.16
Sodium Alginate 54.00 5.00
Xanthan Gum 75.60 7.00
Calcium Sulphate 7.56 0.70
Lactose monohydrate 125.70 11.64
Magnesium Stearate 16.20 1.50
Total 1080 100

Time (hour) Percent Cephalexin Released (%)
1 21.70
2 35.20
3 45.10
4 45.30
6 50.60
8 62.50
10 78.50
12 81.70
14 93.20
Example 9

Ingredients Weight (mg/tafalet) % w/w
Cephalexin 797.87 73.87
Sodium Alginate 64.80 6.00
Xanthan Gum 54.00 5.00
Hydroxypropyl Methylcellulose (Methocel K15M) 54.00 5.00
Calcium Sulphate 7.78 0.72
Lactose monohydrate 79.95 7.40
Magnesium Stearate 21.60 2.00
Total 1080 100

Time (hour)

12
14

Percent Cephalexin Released (%)
23.20
34.90
4L40
4330
47.10
57.10
70.10
86.90
97.00

21

Example 10

Ingredients Weight (mg/tablet) % w/w
Cephalexin 797.87 73.87
Sodium Alginate 64.80 6.00
Xanthan Gum 32.40 3.00
Hydroxypropyl Methyl cellulose (Methocel K15M) 32.40 3.00
Calcium Sulphate 7.77 0.72
Lactose monohydrate 128.54 11.90
Magnesium Stearate 16.20 1.50
Total 1080 100

Time (hour) Percent Cephalexin Released (%)
I 23.90
2 37.10
3 46.30
4 .47.20
6 58.70
8 77.60
10 92.10
12 98.20
Example 11

Ingredients Weight (mg/tablet) % w/w
Cephalexin 797.87 73.87
Sodium Alginate 43.20 4.00
Xanthan Gum 43.20 4.00
Hydroxypropyl Methylcellulose (Methocel K15M) 64.80 6.00
Calcium Sulphate 5.10 0.47
Lactose monohydrate 109.63 10.15
Magnesium Stearate 16.20 1.50
Total 1080 100

Time (hour) Percent Cephalexin Released (%)
1 22.90
2 35.10
3 42.40
4 43.60
■ 6 47.80
8 57.10
10 66.90
12 76.60
14 86.80
22

Tablets with Probenecid -
Example 12
Cephalexin, a mixture of uniformly preblended hydrophilic polymers and calcium sulphate, lactose were mixed uniformly and lubricated with magnesium stearate. The blend was compacted and the slugs obtained were milled to form granules. The sized granules were blended with the fines and the remaining lubricant.
Probenecid, microcrystalline sodium, sodium starch glycolate, were screened through 30 mesh sieve. The blend was compacted and the slugs obtained were again milled to obtain granules. The sized granules were mixed with remaining sodium starch glycolate and magnesium stearate and fines, followed by compression of cephalexin granules on the pre-compressed probenecid granules.
The tablets were tested for cephalexin release in 900 ml of 0.1 N hydrochloric acid for 2 hrs after which the dissolution media was changed to pH 6.8 phosphate buffer 900 ml. The tablets were placed into a 40 mesh basket (USP apparatus type X) and were rotated at 100 rpm. Further, fresh tablets were analysed for Probenecid release using 900 ml of pH 7.5 simulated intestinal fluid without pancreatin, USP apparatus type II at 50 rpm.

Ingredients Weight (mg) % w/w
Controlled Release Part
Cephalexin 536.82 74.55
Sodium Alginate 28.80 4.00
Xanthan Gum 21.60 3.00
Hydroxypropyl Methylcellulose (Methocel K4M) 28.80 4.00
Calcium Sulphate 4.03 0.37
Lactose 89.15 12.38
Magnesium Sterate 10.80 1.50
Total 720 100.00
Immediate Release Part
Probenecid 500.00 79.36
Microcrystalline Cellulose 95.50 15.16
Sodium Starch Glycolate 31.50 5.00
Magnesium Sterate 3.00 0.48
Total 630.00 100.00
23

Time (hour) Percent Cephalexin Released (%)
1 25.14
2 J 37.76
3 44.80
4 47.49
6 63.61
8 78.05
10 96.40

Time (min) Percent Probenecid Released (%)
10 98.80
20 102.20
30 103.30
Example 13
Cephalexin, uniformly preblended hydrophilic polymers and calcium sulphate, microcrystalline cellulose were mixed uniformly and lubricated with magnesium stearate. The blend was compacted and the slugs obtained were milled to form granules. The sized granules were blended with the fines and the remaining lubricant.
Probenecid, lactose, sodium starch glycolate were screened through 30 mesh sieve. The blend was compacted and slugs obtained were milled to obtain granules. The sized granules were mixed with remaining sodium starch glycolate, magnesium stearate and fines followed by compression of Cephalexin granules on pre-compressed Probenecid granules.
The tablets were tested for dissolution in 900 ml of 0.1 N hydrochloric acid for 2 hrs after which the dissolution media was changed to pH 6.8 phosphate buffer 900 ml, using 40 mesh basket (USP apparatus type I) and were rotated at 100 rpm. Further fresh samples were analysed for Probenecid release using 900 ml of pH 7.5 simulated intestinal fluid without pancreatin, USP apparatus tvpe II at 50 rpm.

Ingredients Weight (mg/tablet) % w/w
Controlled Release Part
Cephalexin 536.82 74.55
Sodium Alginate 43.20 6.00
Xanthan Gum 36.00 5.00
Calcium Sulphate 6.01 0.84
24

Microcrystalline cellulose 87.13 12.10
Magnesium Sterate 10.80 1.50
Total 720 100
Immediate Release Part
Probenecid 500.00 79.36
Lactose 102.00 16.19
Sodium Starch Glycolate 25.00 3.97
Magnesium Sterate 3.00 0.48
Total 630.00 100.00

Time (hour) Percent Cephalexin Released (%)
1 28.10
2 41.80
3 50.30
4 57.30
6 70.10
8 83.30
10 99.70

Time (min) Percent Probenecid Released (%)
10 80.30
20 95.40
30 99.30
Example 14
Cephalexin, probenecid, a mixture of uniformly preblended hydrophilic polymers and calcium sulphate and microcrystalline cellulose were screened through 30 mesh screen and mixed with magnesium stearate. The blend was compacted and the slugs obtained were milled to obtain the granules. The sized granules were blended with fines and the remaining lubricant and further compressed into tablets.
The tablets were tested for cephalexin dissolution in 900 ml of 0.1N hydrochloric acid for 2 hrs after which the dissolution media was changec to pH 6.8 phosphate buffer 900 ml, using 40 mesh basket (USP apparatus type I) and were rotated at 100 rpm. Further fresh samples were analysed for probenecid release using 900 ml of pH 7.5 simulated intestinal fluid without pancreatin, USP apparatus type II at 50 rpm.
25

Ingredients Weight (mg/tablet) % w/w
Cephalexin 536.82 38.34
Probenecid 500.00 35.71
Sodium Alginate 70.00 5.00
Xanthan Gum 56.00 4.00
Hydroxypropyl Methylcellulose (Methocel K4M) 70.00 5.00
Calcium Sulphate 7.00 0.50
Microcrystalline cellulose 142.68 10.19
Magnesium Sterate 17.50 1.25
Total 1400 100

Time (hour) Percent Cephalexin Released (%) Percent Probenecid Released (%)
1 23.60 42.90
2 42.70 69.70
3 54.60 85.50
4 61.20 100.90
6 70.10
8 80.40
10 96.90
Example 15
Cefaclor, a mixture of uniformly preblended hydrophilic polymers and calcium sulphate, microcrystalline cellulose were mixed uniformly and lubricated with magnesium stearate. The blend was compacted and the slugs obtained were milled to form granules. The sized granules were blended with the fines and the remaining lubricant.
Probenecid, starch, sodium starch glycolate, were screened through 30 mesh sieve. The blend was compacted and the slugs obtained were milled to obtain granules. The sized granules were mixed with remaining sodium starch glycolate and magnesium stearate and fines, followed by compression of cefaclor granules on the pre-compressed Probenecid granules.
The tablets were tested for cefaclor release in 900 ml of 0.1 N hydrochloric acid for 2 hrs after which the dissolution media was changed to pH-6.8 phosphate buffer 900 ml. The tablets were placed into a 40 mesh basket (USP apparatus type-1) and were rotated at 100 rpm. The dissolution medium (pH 6.8 phosphate buffer) was replaced by fresh medium
26

every hour. Further fresh tablet were analysed for Probenecid release using 900 ml of pH 7.5 simulated intestinal fluid without pancreatin, USP apparatus type II at 50 rpm.

Ingredients Weight (mg/tablet) % w/w
Controlled Release Part
Cefaclor 530.50 j 75.78
Sodium Alginate 28.00 4.00
Xanthan Gum 7.00 1.00
Hydroxypropyl Methylcellulose (Methocel K4M) 14.00 2.00
Calcium Sulphate 3.92 0.56
Microcrystalline Cellulose 106.08 15.15
Magnesium Sterate 10.50 1.50
Total 700 100
Immediate Release Part
Probenecid 500.00 79.36
Starch 70.61 11.21
Sodium Starch Glycolate 50.40 8.00
Magnesium Sterate 9.00 1.43
Total 630.00 100.00

Time (hour) Percent Cefaclor Released (%)
1 24.60
2 45.20
3 50.60
4 61.30
6 75.90
8 89.20

Time (min) Percent Probenecid Released (%)
10 96.80
20 99.10
30 100.80
Further the bioavailability study was conducted for long acting modified release matrix formulation without probenecid, one dose of 2 tablets x (750 mg cephalexin), prepared according to present invention. Eight healthy male volunteers were selected for the study in which each volunteer was administered a dose of the drug with 180 ml of water. The volunteers had a standard breakfast before taking the drug. The desired blood levels up to 18 to 20 hours were achieved with compositions without probenecid prepared according to the invention, indicating that it can be used as once daily composition.
27

Figure 1 shows a plot of blood level concentrations of modified release composition of the present invention, one dose of 2 tablets of cephalexin 750 mg. The plot clearly reveals the favourable bio-availability of the active achieved using the formulation of the invention.
28

WE CLAIM:
1. A stable improved pharmaceutical composition for controlled release of an active ingredient comprising a controlled release matrix comprising i)a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient in amounts of 30 % to 90 % by weight, ii)a mix of hydropbilic polymers in amount of 1 % to 25 % selected from the group consisting of at least one sodium alginate in amounts of 0.1 % to 20 %, and at least one xanthan gum in amounts of 0.1 % to 20 % and iii) a calcium salt in an amount of 8 % to 20 % by weight of sodium alginate.
2. A stable improved pharmaceutical composition as claimed in claim 1 wherein said hydrophilic polymers mix comprise hydroxypropyl methylcellulose in an amount of 0.1% to 20% by weight,
3. A stable improved pharmaceutical composition as claimed in anyone of claims 1 or 2 comprising probencid.
4. The composition as claimed in claim 3 wherein the probenecid is present in the controlled release matrix.
5. The composition as claimed in claim 3 wherein the active is released at a rate suitable for once daily or twice daily administration of the composition.
6. The composition as claimed in claim 1 in a solid dosage form.
7. The composition as claimed in claim 1 wherein the calcium salt is calcium sulphate.
8. The composition as claimed in claim 2 wherein the controlled release matrix comprises from 30 % to 90 % by weight of a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters and 1 % to 20 % by weight of hydrophilic polymers comprising of a medium or high viscosity grade sodium alginate in an amount from 0.1 % to 15 % by weight, a medium or high viscosity grade xanthan gum in an amount from 0.1 % to 15 % by weight, and a medium or
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high viscosity grade hydroxypropyl methylceUulose in an amount from 0.1 % to 15 % by weight of controlled release matrix; and calcium sulphate in an amount from 8 % to 16 % by weight of sodium alginate.
9. The composition as claimed in claim 2, wherein the controlled release matrix comprises from 30-% to 90 % by weight of a betalactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters and 1 % to 18 % by weight of hydrophilic polymers comprising of a medium or high viscosity grade sodium alginate in an amount from 1 % to 10 % by weight, a medium or high viscosity grade xanthan gum in an amount from 1 % to 10 % by weight, and a medium or high viscosity grade hydroxypropyl methylceUulose in an amount from 1 % to 10 % by weight of controlled release matrix; and calcium sulphate in an amount from 10 % to 14 % by weight of sodium alginate.
10. The composition as claimed in anyone of claims 1, 8 or 9, wherein the betalactam antibiotic is selected from cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters.
11. The composition as claimed in claim 1, wherein the calcium salt is selected from calcium sulphate, calcium citrate, disodium calcium edetate, calcium lactate, calcium ascorbate, calcium gluconate, calcium chloride.
12. The composition as claimed in claim 1 or 2, which further comprises at least one water soluble or water dispersible diluent.
13. The composition as claimed in claim 12, wherein the water soluble or water dispersible diluent comprises 1 % to 30 % by weight of the composition.
14. The composition as claimed in claim 12, wherein the diluent is lactose.
15. The composition as claimed in claim 14, wherein the amount of lactose is from 4 % to 20 % by weight of the composition.
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16. The composition as claimed in claim 12, wherein the diluent is microcrystalline cellulose.
17. The composition as claimed in claim 16, wherein the amount of microcrystalline cellulose is from 4 % to 20 % by weight.of the cpmposition.
18. The composition as claimed in claim 1 comprising magnesium stearate, in amount from 0.2 % to 5 % by weight of the composition.
19. A composition as claimed in any one of the preceding claims wherein a multidose contains 250 mg to 2 g active ingredient.
20. A composition as claimed in anyone of claims 1 to 18 in dosage unit form containing 100 to 1 g active ingredient.
21. The composition as claimed in claim 3, wherein probenecid is present in an amount from about 250 mg to about 1000 mg.
22. The composition as claimed in claim 3, wherein the probenecid is present as a immediate release part.
23. The composition as claimed in claim 22, which further contains a disintegrating agent from 2 % to 9 % by weight of immediate release part.
24. The composition as claimed in claim 23 wherein disintegrating agent is sodium starch glycolate.
25. The composition as claimed in claim 22 wherein, the controlled release part in a hydrophilic matrix and immediate release probenecid part are compressed together into a tablet dosage form.
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26. The composition as claimed in claim 22 wherein, the controlled release part in a hydrophilic matrix and immediate release probenecid part are compressed separately into tablets and packed in a way to be administered simultaneously.
27. A process for the preparation of a pharmaceutical composition as claimed in claim 1, comprising mixing together the active ingredient with the pre-blended hydrophilic polymers with or without hydroxypropyl methylcellulose and calcium sulphate, in selective amounts, optionally with one or more of probenecid, djluent and lubricant to form a blend, further compacting, sizing, blending and compressing into tablets.
28. A process for the preparation of a pharmaceutical composition as claimed in claim 22, comprising mixing together the active ingredient with the pre-blended hydrophilic polymers with or without hydroxypropyl methylcellulose and calcium sulphate together with a diluent and at least one lubricant to form a blend, further compacting, sizing, blending and compressing into tablets along with immediate release probenecid part.
29. A process for the preparation of pharmaceutical composition as claimed in claim 3, comprising mixing together probenecid, diluent and disintegrating agent together, compacting, sizing and blending with lubricant and compressing the blend into tablets along with controlled release matrix.
Dated this 26th day of April 2004

DR. SANCHITA"GANGULI Of S. MAJUMDAR & CO. Applicants" Agent
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Documents:

250-mumnp-2004-abstract(28-4-2004).doc

250-mumnp-2004-abstract(28-4-2004).pdf

250-mumnp-2004-claims(granted)-(28-4-2004).doc

250-mumnp-2004-claims(granted)-(28-4-2004).pdf

250-mumnp-2004-correspondence(1-10-2007).pdf

250-mumnp-2004-correspondence(ipo)-(6-10-2006).pdf

250-mumnp-2004-form 19(28-4-2004).pdf

250-mumnp-2004-form 1a(28-4-2004).pdf

250-mumnp-2004-form 2(granted)-(28-4-2004).doc

250-mumnp-2004-form 2(granted)-(28-4-2004).pdf

250-mumnp-2004-form 3(28-4-2004).pdf

250-mumnp-2004-form 5(28-4-2004).pdf

250-mumnp-2004-form-pct-ipea-409-(28-4-2004).pdf

250-mumnp-2004-power of attorney(4-6-2003).pdf

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Patent Number

210476

Indian Patent Application Number

250/MUMNP/2004

PG Journal Number

45/2007

Publication Date

09-Nov-2007

Grant Date

05-Oct-2007

Date of Filing

28-Apr-2004

Name of Patentee

LUPIN LIMITED

Applicant Address

159,C.S.T. ROAD, KALINA, SANTACRUZ (EAST), MUMBAI-400 098`

Inventors:

#	Inventor's Name	Inventor's Address
1	SEN HIMADRI	LUPIN LABORATORIES LIMITED, A-28/1, MIDC CHIKALTHANA, AURANGABAD-431210
2	KSHIRSAGAR RAJESH SURESH	A-28/1, MIDC CHIKALTHANA, AURANGABAD-431210
3	BHAMARE SHAILESH SURESH	A-28/1, MIDC CHIKALTHANA, AURANGABAD-431210

PCT International Classification Number

A61K 9/22

PCT International Application Number

PCT/IN01/00204

PCT International Filing date

2001-11-19

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA