Cefdinir and cefixime formulations and uses thereof

Abstract

The invention features pharmaceutically acceptable salts of cefdinir, including primary, secondary, and tertiary amine salts of cefdinir, and preparation methods, and pharmaceutical compositions including cefdinir. The invention also features water dispersible pharmaceutical dosage forms including cefdinir as active agent and methods for preparing the dosages. The invention also features tablet forms of cefixime characterized in that the tablets are in effervescent form. The invention also features the process for preparing effervescent tablet forms with cefdinir as active agents and pharmaceutical formulations obtained by the process.

1 . A salt with Formula II; 
       
         
           
           
               
               
           
         
         wherein A stands for a C 1 -C 15  primary, secondary and/or tertiary amine comprising at least one hydroxy group. 
       
     
     
         2 . The salt according to  claim 1 , wherein A is selected from the group consisting of: ethanolamine, 1-deoxy-1-methylamino-sorbitol, isopropanolamine, 1-deoxy-1-methylamino-D-glucitol-(2S,4R)-4-Hydroxy proline, tris(hydroxymethyl)aminomethane, N-(Tri(hydroxymethyl)methyl)glycine, thiamine, 2-methyl-aminophenol, and N,N-Bis(2-hydroxyethyl)glycine. 
     
     
         3 . The salt according to  claim 1 , wherein said salt is used in a solid pharmaceutical dosage form; wherein said dosage form is suitable for oral, buccal, or sublingual application; and wherein said dosage form is film coated tablets, extended release tablets, modified release tablets, chewable tablets, effervescent tablets, effervescent granules, suspensions, water dispersible tablets, or water dispersible granules. 
     
     
         4 . A process for preparing the salt according to  claim 1 , comprising the steps of:
 a) dissolving cefdinir and an organic amine comprising more than one hydroxy group in a suitable solvent and stirring at a temperature range of 0-100° C.,   b) separating the product that precipitates upon cooling of the reaction mixture, and purifying the product.   
     
     
         5 . The process according to  claim 4 , wherein the amine comprises at least one hydroxy group selected from the group consisting of: ethanolamine, isopropanolamine, 1-deoxy-1-methylamino-sorbitol, 1-deoxy-1-methylamino-D-glucitol, (2S,4R)-4-hydroxyproline, tris(hydroxymethyl)aminomethane, N-(tri(hydroxymethyl)methyl)glycine, thiamine, 2-methyl aminophenol, and N,N-Bis(2-hydroxyethyl)glycine. 
     
     
         6 . The process according to  claim 4 , wherein the solvent used in said process is selected from the group consisting of: water, ethanol, methanol, isopropanol, dimethylformamide, dimethylsulfoxide, methylenechloride, tetrahydrofuran, toluene, acetonitrile, hexane, heptane, diethylether, benzene, ethyl acetate, acetone, t-butyl alcohol, t-butyl methyl ether, chloroform, cyclohexane, 1,2-dichloroethane, 1,2-dimethoxyethane, dioxane, methyl ethyl ketone, ethylene glycol, 2-propanol, pyridine, and triethylamine. 
     
     
         7 . The process according to  claim 4 , wherein the reaction is carried out at a temperature of 0-100° C., at a temperature of 10-70° C., or at a temperature of 20-60° C. 
     
     
         8 . A pharmaceutical composition comprising cefdinir, wherein said composition is in a water dispersible form. 
     
     
         9 . The composition according to  claim 8 , wherein said composition can be in the form of an effervescent powder, effervescent tablet, effervescent granule, water dispersible powder, water dispersible granule, water dispersible tablet, water soluble tablet, water soluble granule, or water soluble powder. 
     
     
         10 . The composition according to  claim 8 , wherein said composition comprises an organic base. 
     
     
         11 . The composition according to  claim 10 , wherein the organic base is selected from the group consisting of: ethanolamine, isopropanolamine, 1-deoxy-1-methylamino sorbitol, 1-deoxy-1-methylamino-D-glucitol, tris(hydroxymethyl)aminomethane, N-(tri(hydroxymethyl)methyl)glycine, N,N-Bis(2-hydroxyethyl)glycine, 2-methyl aminophenol, 1-deoxy-1-methylamino-sorbitol, and tris(hydroxymethyl)aminomethane. 
     
     
         12 . The composition according to  claim 8 , wherein the composition comprises 5-60% of cefdinir or a pharmaceutically acceptable derivative, 1-30% of an organic base, 1-30% of a binder, 0.1-3% of a lubricant, 0.1-5% of a sweetener, 0.1-8% of a coloring or flavoring agent, and 0-90% of an effervescent couple, with respect to the total weight of the unit dose. 
     
     
         13 . A method for preparing an effervescent formulation comprising cefdinir, characterized in that cefdinir is granulated with an aqueous solution of organic basic compound. 
     
     
         14 . The method according to  claim 13 , wherein said method comprises:
 I. preparing a first granulation solution comprising an organic basic agent and water in an amount ranging from 80-98% of the total water amount(first granulation solution),   II. mixing an effervescent base and cefdinir with said first granulation solution,   III. preparing a second granulation solution comprising a binding agent, ethanol, and water in an amount ranging from 2-20% of the total water amount (second granulation solution),   IV. mixing said first granulation solution and a sweetener with said second granulation solution,   V. drying and sieving said mixture to obtain granules,   VI. mixing said granules with a lubricant, a flavoring agent, a sweetener and a coloring agent, storing said mixture in accordance with a desired dosage form.   
     
     
         15 . The method according to  claim 14 , wherein said organic basic agent is 1-deoxy-1-methylamino-sorbitol, or tris(hydroxymethyl)aminomethane. 
     
     
         16 . The method according to  claim 14 , wherein said water is in an amount ranging from 80-98% the total amount of water. 
     
     
         17 . The method according to  claim 13 , wherein the formulation comprises 5-60% of cefdinir or a pharmaceutically acceptable derivative, 1-30% of an organic base, 1-30% of a binder, 0.1-3% of a lubricant, 0.1-5% of a sweetener, 0.1-8% of a coloring or flavoring agent, and 0.1-90% of an effervescent couple, with respect to the total weight of the unit dose. 
     
     
         18 . The method according to  claim 13 , wherein said formulation further comprises potassium clavulanate. 
     
     
         19 . A pharmaceutical composition comprising cefixime characterized in that cefixime is formulated in the form of effervescent tablets or granules, wherein said composition further comprises povidone. 
     
     
         20 . The composition according to  claim 19 , wherein cefixime and povidone are in a ratio of 20:1, 15:1, or 10:1. 
     
     
         21 . The composition according to  claim 19 , wherein said composition comprises 1-60% cefixime or a pharmaceutically acceptable derivative, 10-90% of an effervescent couple, 0.1-5% of a sweetener, 0.1-10% of a binder, 0.1-5 of a water soluble lubricant, and 0.1-5% of a flavoring agent. 
     
     
         22 . A process for preparing the composition according to  claim 19  comprising, granulation of cefixime, an effervescent couple, a sweetener, and a binder, mixing said granulation with a flavoring agent and a water soluble lubricant, and compressing said granulation in the form of tablets.