FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
"PALATABLE ORAL PHARMACEUTICAL COMPOSITIONS AND SUPRA-BIO AVAILABLE FORM OF CEFUROXIME AXETIL"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, SB MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA.
THE FOLLOWING SPECD7ICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:
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ABSTRACT:
The present invention relates to a palatable oral pharmaceutical composition of cefuroxime axetil or their pharmaceutically acceptable derivatives. The disclosed formulations have improved the taste of the drug and can be given in oral dosage forms such as dry syrup, dispersible tablets, effervescent tablets, chewable tablets, orodispersible tablets, sachets and capsules etc.
BACKGROUND OF THE INVENTION:
For ease and safety of administration, most drugs are formulated as tablets or capsules for oral administration. However, patients at the extremes of age, such as children and the elderly, often experience difficulty in swallowing solid oral dosage forms. For these patients, drugs are commonly provided in liquid dosage forms such as solutions, emulsions and suspensions. These dosage forms usually permit perceptible exposure of the active drug ingredient to the taste buds, which can be a problem when the drugs have an unpleasant taste or are extremely bitter. Conventional taste masking techniques such as the use of sweeteners, amino acids and flavoring agents are often unsuccessful in masking the taste of highly bitter drugs and so other techniques are continued to be exploited for the effective taste masking of such drugs.
One such technique involves the coating of bitter drugs which has been reported for taste masking. This technique alone may prove effective for moderately bitter drugs or in products where the coated particles are formulated as aqueous preparations before administration or are formulated in a non-aqueous medium. But this technique has limited application as it may lead to in-vitro dissolution problems and then leads to less in-vivo bioavailability for some drugs.
DESCRIPTION OF RELATED ART:
Cefuroxime is disclosed in British Patent Specification No. 1453049, is a valuable broad spectrum antibiotic characterized by high activity against a wide range of gram-positive and gram-negative micro-organisms, this property being enhanced by the very high stability of the compound to 0-lactamases produced by a range of gram negative micro-organisms.
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After oral administration, cefuroxime axetil is absorbed from the gastrointestinal tract and rapidly hydrolyzed to cefuroxime by nonspecific estrases present in the intestinal mucosa and blood.
Esterification of the carboxyl group of cefuroxime as a 1-acetoxyethyl ester to give cefuroxime axetil improves the effectiveness on oral administration as disclosed in British Patent Specification No. 1571683. The presence of the 1-acetoxyethyl esterifying group results in significant absorption of the compound from the gastrointestinal tract, whereupon the esterifying group is hydrolysed by enzymes present.
US4865851 claimed Cefuroxime axetil in particulate form is coated with an integral coating of a lipid or mixture of lipids which serves to mask the bitter taste of cefuroxime axetil but disperses or dissolves on contact with gastrointestinal fluid. The resulting particles may be incorporated into pharmaceutical compositions for oral administration, for instance aqueous suspensions. These lipid-based coatings show variation in their release profiling since the lipids used is pH independent and insoluble ultimately affecting the Bio availability of drug.
US6565877 has claimed of taste masked composition which comprises a bitter tasting drug, a combination of two enteric polymers comprising, a methacrylic acid copolymer and a phthalate polymer is described. The composition of the present invention is prepared by dissolving the active ingredient, the methacrylic acid copolymer and the phthalate polymer in a solvent and recovering the composition from the solution thereof.
WO04052345A1 invention relates to coating compositions for taste masking and methods for applying the coating compositions to dosage forms to mask the taste of a medicinal substance. The taste masking coating compositions generally include a copolymer of acrylate and methacrylate with a quaternary ammonium group in combination with sodium carboxymethylcellulose and a polyvinyl alcohol-polyethylene glycol copolymer. It has been reported that use of methacrylic acid co-polymers alone results in good taste masking, but retards the rate of drug release from the matrix to an extent which would be unacceptable for an conventional immediate release dosage form
U.S. Pat No. 4,820,833 discloses that absorption can be improved by using cefuroxime axetil in pure amorphous form instead of crystalline form.
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U.S. Pat. No. 4,897,270 further discloses that absorption from film coated tablets can be improved by formulating the tablets such that, when a tablet is ingested, the film coating ruptures rapidly in the gastrointestinal fluid, and the core then disintegrates immediately.
Canadian Patent no. 2209868 discloses that, instead of using cefuroxime axetil in pure amorphous form, excellent dissolution and absorption can also be achieved by using cefuroxime axetil in the form of a co-precipitate of cefuroxime axetil and a water soluble excipient.
There are substantial difficulties to make compositions for oral administration which provide high bio-availability; that is to say, that are well absorbed from the gastrointestinal tract into systemic circulation. In particular, the crystalline form of cefuroxime axetil, which is slightly soluble in water and forms a gel upon contact with an aqueous medium, is not readily absorbable in the gastro- intestinal tract, rendering its bioavailability on oral administration very low. A second problem in formulating satisfactory solid compositions comprising cefuroxime axetil is that cefuroxime axetil is relatively unstable in the presence of many common excipients (i.e. inactive ingredients) used to make solid pharmaceutical compositions
SUMMARY OF THE INVENTION
The objective of the present invention is to provide a oral dosage form comprising palatable and supra-bioavailable form of Cefuroxime Axetil.
DETAILED DESCRIPTION OF INVENTION
The present invention provides a palatable pharmaceutical composition having in-vitro release which will lead to in-vivo bioavailability of cefuroxime axetil from the oral dosage form comprising lipid mixtures or polymer mixtures, surfactants, sweeteners, diluents, disintegrants, glidants, lubricants, antiadhesives, colours, flavours and other pharmaceutically acceptable excipients.
Initially, taste masking of cefuroxime axetil was done with polymers and waxes but was affected in-vitro drug release. So in this invention, additional excipients were taken along with the drug and coated with suitable materials to improve in-vitro drug release.
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The invention comprises mixing of Ceuroxime Axetil with diluents or channeling agents or any other pharmaceutically acceptable excipients and coated with polymers and surfactant mixture by using Fluidized Bed Processor or Modified Vacuum Plantary Mixer or any other equipmet suitable for coating. The coated granules were mixed with suitable pharmaceutically acceptable excipients and made into oral dosage forms like dry syrup, dispersible tablets, effervescent tablets, chewable tablets, orodispersible tablets, sachets and capsules etc.
This invention comprises coating materials such as include, hydrophilic cellulose derivatives are methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and hydroxyethylmethyl cellulose. Most preferred is hydroxypropylmethyl cellulose (HPMC) and various other polymers. This invention comprises diluents such as dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, mannitol, sorbitol, xyletol, and other polyols, starch starch pregelatinized, sucrose, sugar compressible sugar confectioners, and the like.
This invention comprises surfactants such as alkylglucosides, alkylmaltosides, alkylthioglucosides, lauryl macrogolglycerides, polyoxyethylene alkylphenols, polyoxyethylene alkylethers, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, polyglyceryl fatty acid esters, polyoxyethylene glycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, sterols, and mixtures thereof. The preferred non-ionic surfactants are polyoxyethylene sorbitan fatty acid esters, which are sold under the trade names Polysorbate or Tween. Specific examples are Polysorbate 80 or Polysorbate 20. Suitable ionic surfactants are selected from the group of fatty acid salts, bile salts, phospholipides, phosphoric acid esters, carboxylates, sulphates, sulphonates and mixture thereof.
This invention comprises solvents such as alcohols like methanol, ethanol, isopropanol, butanol, chlorinated hydrocarbons like dichloromethane, chloroform, ketones like methyl ethyl ketone, methyl iso-butyl ketone and acetone.
In addition to this, the invention also contains flavours, sweeteners, colours or any other pharmaceutically acceptable excipients suitable for formulation.
The manufacturing formula of the Cefuroxime Axetil Coating:
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Example:

S.NO. NAME OF MATERIAL %w/w
1. Cefuroxime Axetil 47.6 %
2. Anhydrous lactose (DCL-21) 10-200%
3. HPMC HP 55 0.5-5%
4. Span 80 0.2 - 5%
The manufacturing process for coating of Cefuroxime Axetil as follows:
1. The coating material (HPMC HP 55) was dispersed in Isopropyl alcohol and then dissolved in Dichoromethane. Then Span 80 was added in to that solution and stirred.
2. The drug Cefuroxime axetil and the excipient anhydrous lactose were sifted through 30# mesh, mixed well and transferred into the above solution under stirring. Stirring continued under vacuum till the evaporation of the organic solvent.
3. Then the above semidried material was collected and dried in a tray drier at a temperature between 25° and 30°c and RH not more man 40%. The dried material is passed through 30 # sieve.
Dated this 18th day of August 2006.
Sanjay Kher
Applicants’ Patent Agent.
To:
The Controller of Patents, Patent Office, Mumbai 400 037