The present invention relates to modified release pharmaceutical compositions of cephalexin and clavulanate and process of preparation thereof.
Cephalexin is chemically designated as 7-(D-a-Amino-a-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid and is disclosed in US 3,507,861 and US 3,655,656. Cephalexin is a semisynthetic cephalosporin (3-lactam antibiotic which could be easily cleaved by (3-lactamase enzyme to yield products which are devoid of any antibacterial activity. Clavulanic acid or 3-(beta-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo [3,2,0]heptane-2-carboxylic acid, including its pharmaceutically acceptable salts and esters, has now been well-recognized as a medium potency antibiotic which inhibits the production of (3-lactamase enzyme, thereby enhancing the efficacy of (3-lactam antibiotics. Clavulanic acid in the form of its derivatives are consequently used in formulations in combination with (3-lactam antibiotics, for example as described in GB 2005538, to suppress the activity of β -lactamase enzymes which mediate bacterial resistance to β-lactam antibiotics. Combination of amoxicillin and clavulanate potassium is being marketed under the trade name of Augmentin® for more than two decades. Although synergism of β -lactam antibiotics and β-lactamse inhibitors is well known in the art, there still remains a need to provide a modified release pharmaceutical composition of cephalexin and clavulanate.
US 5,910,322 discloses a pharmaceutical tablet formulation, comprising: a matrix which comprises a β-lactam antibiotic and a p-lactamase inhibitor, and dispersed within said matrix, granules in a delayed-release form which comprise a β-lactam antibiotic and a p-lactamase inhibitor, and dispersed within said matrix, granules in a rapid-release form which comprise a β-lactam antibiotic and a β-lactamase inhibitor.
US 5,948,440 discloses a controlled release composition of cephalexin wherein the controlled release matrix comprises a mixture of hydrophilic polymers of different viscosity grades, such as hydroxypropylmethyl cellulose and hydroxypropyl cellulose.
Further various modified release pharmaceutical compositions involving multilayered tablets are well described in the literature. However, the art does not specifically disclose any modified release pharmaceutical composition of cephalexin and clavulanate.

Our scientists have now formulated a modified release pharmaceutical composition of cephalexin and clavulanate, comprising two distinct slow and immediate release segments, wherein the slow release segment comprises cephalexin and the immediate release segment comprises clavulanate.
Hence in one general aspect there is provided a modified release pharmaceutical composition of cephalexin and clavulanate, comprising two distinct slow and immediate release segments, wherein the slow release segment comprises cephalexin and the immediate release segment comprises clavulanate.
In another general aspect there is provided a modified release pharmaceutical composition of cephalexin and clavulanate, comprising two distinct slow and immediate release segments, wherein the slow release segment comprises cephalexin and a mixture of hydrophilic polymers of different viscosity grades and the immediate release segment comprises clavulanate and one or more disintegrants.
In another general aspect there is provided a modified release pharmaceutical composition of cephalexin and clavulanate comprising;
(a) slow release segment comprising cephalexin and about 5% to about 40% w/w of
mixture of hydrophilic polymers of different viscosity grades based on the total
weight of the slow release segment, and
(b) immediate release segment comprising clavulanate and about 0.5% to about
10% w/w of one or more disintegrants based on the total weight of the immediate
release segment.
In another general aspect there is provided a modified release pharmaceutical
composition of cephalexin and clavulanate comprising;
(a) slow release segment comprising cephalexin, about 0.5% to about 5% w/w of medium or high viscosity grade of hydroxypropylmethyl cellulose, about 4% to about 39% w/w of low viscosity grade of hydroxypropylmethyl cellulose, about 0.5% to about 10% w/w of low viscosity grade hydroxypropyl cellulose based on the weight of the total slow release segment, and

(b) immediate release segment comprising clavulanate and about 0.5% to about 10% w/w of one or more disintegrants based on the weight of the total immediate release segment.
In another general aspect there is provided a process for preparing a modified release
pharmaceutical composition of the cephalexin and clavulanate, comprising the steps of;
i) blending cephalexin and mixture of hydrophilic polymers of different viscosity
grades, with one or more pharmaceutically inert excipients to form the slow
release segment;
ii) blending clavulanate and one or more disintegrants, with one or more
pharmaceutically inert excipients to form the immediate release segment; iii) combining the slow release and immediate release segments into suitable dosage forms.
In another general aspect there is provided a method of treating bacterial infections in mammals, which comprises administering to a patient in need thereof, the modified release pharmaceutical composition of cephalexin and clavulanate.
The term "cephalexin" as used herein refers to cephalexin or its pharmaceutically acceptable acid salts or esters, hydrates, solvates and mixtures thereof. Cephalexin may be present in an amount of about 25% to about 65%, preferably from about 40% to about 60% by weight of the total weight of the pharmaceutical composition.
The term "clavulanate" as used herein refers to clavulanic acid or pharmaceutically acceptable salt thereof, in particular potassium clavulanate. Further, as per the European notification directories and the UN transport recommendations, potassium clavulanate being highly flammable, it is highly recommended that potassium clavulanate to be used along with some inert excipients during transportation; and the same may be further formulated into pharmaceutical compositions. Potassium clavulanate in the form of potassium clavulanate premix comprises potassium clavulanate which is either dry granulated with an inert excipient or adsorbed on an inert excipient, the inert excipient preferably being microcrystalline cellulose. This strongly reduces the run-away hazard in comparison with that of the unblended potassium clavulanate. Potassium clavulanate in the form of a premix further improves the flowability of potassium clavulanate and thus helps in processing. The potassium clavulanate premix is available from DSM & Fermic. The potassium clavulanate premix

may be present in an amount of about 1% to about 40% by weight, preferably from about 10% to about 30% by weight of the total weight of the pharmaceutical composition.
The modified release pharmaceutical composition of the present invention comprises two distinct slow and immediate release segments, wherein the slow release segment comprises cephalexin and the immediate release segment comprises clavulanate. The two segments may be in the form of granule, powder blend or mixtures thereof, processed into suitable dosage from selected from the group consisting of tablets, capsules, sachets or any other suitable dosage form. The tablet dosage form may be bilayered, trilayered or multilayered, preferably bilayered tablet.
The slow release segment in addition to cephalexin, further comprises mixture of hydrophilic polymers of different viscosity grades, in particular the mixture of hydroxypropylmethyl cellulose and hydroxypropyl cellulose. Hydrophilic polymers may be characterized by their viscosities in a 2% w/w aqueous solution as low viscosity (less than about 1,000 cPs), medium viscosity (about 1,000 cPs to about 10,000 cPs), and high viscosity (greater than about 10,000 cPs). The mixture of hydrophilic polymers of the present invention may be present in an amount of about 5% to about 40% w/w based on the total weight of the slow release segment.
Hydroxypropylmethyl cellulose polymers of different viscosity grades such as those available from Dow Chemical Co. under the brand name Methocel™ may be used. Examples of hydroxypropylmethyl cellulose polymers of a low viscosity grade include those available under the brand names Methocel E5, Methocel E-15 LV, Methocel E50 LV, Methocel K100 LV and Methocel F50 LV whose 2% by weight aqueous solutions have viscosities of 5 cPs, 15 cPs, 50 cPs, 100 cPs and 50 cPs, respectively. Examples of hydroxypropylmethyl cellulose polymers having medium viscosity include those available under the brand names Methocel E4M and Methocel K4M both of whose 2% by weight aqueous solutions have a viscosity of 4000 cPs. Examples of hydroxypropylmethyl cellulose polymers having high viscosity include those available under the brand names Methocel K15M and Methocel K100M whose 2% by weight aqueous solutions have viscosities of 15,000 cPs and 100,000 cPs, respectively. The hydroxypropylmethyl cellulose polymers may be present an amount form about 0.5% to about 5% w/w of medium or high viscosity grade hydroxypropylmethyl cellulose and

about 4% to about 39% w/w of low viscosity grade hydroxypropylmethyl cellulose based on the total weight of the slow release segment.
The hydroxypropyl cellulose polymers of different viscosity grades available from Aqualon and Nippon Soda Co. under the brand names Klucel™ and HPC™ may be used. Examples of hydroxypropyl cellulose polymers of low viscosity grade include Klucel EF, Klucel LF, Klucel JF and Klucel GF, HPC-SL, HPC-L, and HPC-M whose 2% by weight aqueous solutions have viscosities less than 1000 cPs. Examples of hydroxypropyl cellulose polymers of medium viscosity grade include Klucel ME and HPC-H whose 2% by weight aqueous solution has a viscosity in the range from 4,000-6,500 cPs and 1,000-4000 cPs respectively. The hydroxypropyl cellulose polymers may be present in an amount from about 0.5% to about 10% w/w based on the total weight of the slow release segment.
The immediate release segment in addition to clavulanate, further comprises one or more disintegrants. The disintegrant may be selected from one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, pregelatinised starch, microcrystalline cellulose or mixtures thereof, in particular sodium starch glycolate. The amount of the disintegrant may range from about 0.5% to about 10% w/w based on the total weight of the immediate release segment.
The slow release and immediate release segments may further comprise pharmaceutically acceptable excipients. The "pharmaceutically acceptable excipients" may be selected from one or more of fillers, binders, lubricant/glidants and coloring agents.
Specific examples of fillers or diluents include lactose, pregelatinized starch, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulphate, kaolin, starch, and the like.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow
beeswax, white beeswax, and the like.

Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Coloring agents includes any FDA approved color for oral use.
The modified release pharmaceutical composition may be prepared by wet granulation, dry granulation or direct compression process. The wet granulation process involves use of water or any other suitable solvent. The dry granulation may involve use of roller compacter or any suitable technique. The preparation of layered tablets may involve preparing immediate release and slow release granules or preparing immediate release and slow release blend which could be further formulated into layered tablets.
The tablets may be further coated with one or more functional and/or non-functional coating layers comprising film forming polymers with/without coating additives.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl methylcellulose,
hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose,
hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ®; and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used.
Coating additives may be selected from the group comprising of plasticizers, coloring agents, lubricants/glidants, and the like.
Specific examples of plasticizers include triethylcitrate, acetylated triacetin, tributylcitrate, glyceroltributyrate, monoglyceride, rape oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, and
the like.

Coating may be performed by applying film forming polymer(s) with or without other pharmaceutically inert excipients, as solution/suspension using any conventional coating technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating or compression coating.
In one of the embodiment, the modified release pharmaceutical composition in the form of bilayer tablet may be prepared by a process comprising the steps of;
i) blending cephalexin and mixture of hydrophilic polymers of different viscosity
grades with one or more pharmaceutically inert excipients, lubricating the
blend to form the slow release segment; ii) blending clavulanate potassium premix and one or more disintegrants with
one or more pharmaceutically inert excipients, lubricating the blend to form
the immediate release segment; iii) compressing the above two segments into bilayer tablet using appropriate
tooling; and optionally coating with one or more layers of film forming
polymer(s) and coating additive(s).
In another embodiment, the modified release pharmaceutical composition in the form of bilayer tablet may be prepared by a process comprising the steps of;
i) blending cephalexin and mixture of hydrophilic polymers of different viscosity
grades with one or more pharmaceutically inert excipients, granulating the
blend to form slow release granules, lubricating the slow release granules to
form slow release segment; ii) blending clavulanate potassium premix and one or more disintegrants with
one or more pharmaceutically inert excipients, granulating the blend to form
immediate release granules, lubricating the immediate release granules to
form immediate release segment; iii) compressing the above two segments into bilayer tablet using appropriate
tooling; and optionally coating with one or more layers of film forming
polymer(s) and coating additive(s).
The invention is further illustrated by the following examples, which is for illustrative purpose only and should not be construed as limiting the scope of the invention in any
way.
(Table Removed)
* Clavulanate potassium and microcrystalline cellulose in 1:1 ratio
Procedure:
Preparation of Slow Release Segment
1. Sifted the ingredients (1-7), from a suitable sieve (#16BSS)
2. Mixed the sifted materials for 15-20 minutes at a medium speed.
3. Magnesium stearate was added to the above blend and mixed for
5 minutes at a medium speed.
Preparation of Immediate Release Segment
4. Sifted the ingredients (1-4), from a suitable sieve (#30BSS)
5. Mixed the sifted materials for 15-20 minutes at a medium speed.
6. Magnesium stearate was added to the above blend and mixed for
5 minutes at a medium speed.
Bilayer Tablet Compression
7. The final blends of step 3 (slow release) and step 6 (immediate
release) were compressed into bilayer tablet using approved
tooling.
Film Coating
8. Opadry Blue AMB was added to dichloromethane:isopropyl alcohol
(60:40) to obtain a coating dispersion.
9. The compressed tablets of step 7 were coated using the coating
dispersion of step 8 to form the coated tablets.

We Claim:
1. A modified release pharmaceutical composition of cephalexin and
clavulanate, comprising two distinct slow and immediate release segments,
wherein the slow release segment comprises cephalexin and the immediate
release segment comprises clavulanate.
2. The modified release pharmaceutical composition of claim 1, wherein the slow
release segment comprises mixture of hydrophilic polymers of different viscosity grades present in an amount of 5% to 40% w/w based on the weight of slow release segment.
3. The modified release pharmaceutical composition of claim 2, wherein the
hydrophilic polymers are;
(a) 0.5% to 5% w/w of medium or high viscosity grade of
hydroxypropylmethyl cellulose,
(b) 4% to 39% w/w of low viscosity grade of hydroxypropylmethyl
cellulose, and
(c) 0.5% to 10% w/w of low viscosity grade hydroxypropyl cellulose,
based on the weight of slow release segment.
4. The modified release pharmaceutical composition of claim 1, wherein the
immediate release segment comprises one or more disintegrants present in an amount of 0.5% to 10% w/w based on the weight of immediate release segment.
5. The modified release pharmaceutical composition of claim 4, wherein the
disintegrants may be selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, pregelatinised starch and microcrystalline cellulose.
6. The modified release pharmaceutical composition of any of the preceding claims
further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of fillers, binders, lubricant/glidants and coloring
agents.

7. A modified release pharmaceutical composition of cephalexin and clavulanate
prepared by a process comprising the steps of;
(a) blending cephalexin and mixture of hydrophilic polymers of different
viscosity grades, with one or more pharmaceutically inert excipients
to form the slow release segment;
(b) blending clavulanate and one or more disintegrants, with one or
more pharmaceutically inert excipients to form the immediate
release segment;
(c) combining the slow release and immediate release segments into
suitable dosage forms.
8. The modified release pharmaceutical composition of claim 7, wherein the slow
release segment of step (a) and immediate release segment of step (b) are processed into granules.
9. The modified release pharmaceutical compositions of claims 7-8, wherein the
suitable dosage may be selected from the group consisting of tablets, capsules, and sachets.
10.A modified release pharmaceutical composition of the cephalexin and clavulanate and process of preparation thereof, as described and illustrated in the examples herein.