Patent Document

TECHNICAL FIELD  
       [0001]     The present invention discloses a novel oral suspension of cefdinir. Also disclosed are methods of preparing the suspension and methods of treatment using the suspension.  
       BACKGROUND OF THE INVENTION  
       [0002]     Omnicef® for oral suspension contains the active ingredient cefdinir, an extended-spectrum, antibiotic in the cephalosporin family. Chemically, cefdinir is 7-[2-(2-aminothiazol-4-yl) -2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer). Cefdinir is active against a wide spectrum of bacteria, including  Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Hemophilus influenzae, Moraxella catarrhalis, E. coli, Klebsiella pneumoniae,  and  Proteus mirabilis.    
         [0003]     Given the large pediatric population that uses antibiotic suspension products, compliance is a critical issue. The recommended dosage of treatment with a pediatric patient is typically based on the weight of the patient. A 1999 study showed that young patient age was associated with a lower compliance in taking oral antibiotic suspensions ( Clinical Therapeutics,  1999, 21, 1193-1201). One of the factors cited as contributing to the low compliance rate in the youngest children was technical difficulty in administration of the suspensions (e.g., spillage). In a study of acute otitis media, 53% of children took less than half the prescribed medication ( J. Pediatr,  1975; 87:137-141).  
         [0004]     Omnicef® for oral suspension is indicated for the treatment of pediatric patients with acute bacterial otitis media and pharyngitis/tonsillitis. Omnicef® for oral suspension is delivered to pharmacies as a 4% (4.2% actual) cefdinir by weight powder. Upon reconstitution with water, Omnicef® is administered orally and is currently formulated as a 125 mg/5 mL suspension. In younger pediatrics, a typical dosing of Omnicef® suspension requires two 5 mL aliquots of the suspension. Administering two consecutive 5 mL aliquots can result in the loss of substantial material due to spillage. Furthermore, high concentration suspensions can show physical stability issues.  
         [0005]     A high concentration, stable formulation that allows for the administration of a single aliquot would prove beneficial.  
       SUMMARY OF THE INVENTION  
       [0006]     In its principle embodiment the present invention provides a powder for oral suspension of cefdinir comprising greater than 4.2% by weight of cefdinir.  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0007]     In its principle embodiment the present invention provides a powder for oral suspension of cefdinir comprising greater than 4.2% by weight of cefdinir.  
         [0008]     In another embodiment the present invention provides a powder for oral suspension of cefdinir comprising between about 6% to about 10% by weight of cefdinir.  
         [0009]     In another embodiment the present invention provides a powder for oral suspension of cefdinir comprising at least 8.4% by weight of cefdinir.  
         [0010]     In another embodiment the present invention provides a powder for oral suspension of cefdinir comprising  
         [0011]     (a) at least 8.4% by weight cefdinir;  
         [0012]     (b) a diluent; and  
         [0013]     (c) a buffering agent.  
         [0014]     In another embodiment the present invention provides a powder for oral suspension of cefdinir comprising:  
         [0015]     (a) about 8.4% by weight cefdinir;  
         [0016]     (b) about 89.2% by weight diluent;  
         [0017]     (c) about 0.26% by weight buffering agent;  
         [0018]     (d) about 0.16% by weight preservative;  
         [0019]     (e) about 0.33% by weight viscosity enhancer;  
         [0020]     (f) about 1.31% by weight flavoring agent;  
         [0021]     (g) about 0.07% glidant; and  
         [0022]     (h) about 0.35% lubricant.  
         [0023]     In another embodiment the present invention provides an powder for oral suspension of cefdinir comprising:  
         [0024]     (a) about 8.36% by weight cefdinir;  
         [0025]     (b) about 89.16% by weight sucrose;  
         [0026]     (c) about 0.16% by weight citric acid;  
         [0027]     (d) about 0.10% by weight sodium citrate;  
         [0028]     (e) about 0.16% by weight sodium benzoate;  
         [0029]     (f) about 0.16% by weight xantham gum;  
         [0030]     (g) about 0.16% by weight guar gum;  
         [0031]     (h) about 1.31% by weight flavoring agent;  
         [0032]     (i) about 0.06% colloidal silicon dioxide; and  
         [0033]     (j) about 0.35% magnesium stearate.  
         [0034]     The present invention also teaches a method of treating acute bacterial otitis media, pharyngitis and tonsillitis with a oral suspension of cefdinir wherein said suspension is made by reconstituting a powder comprising greater than 4.2% by weight of cefdinir.  
         [0035]     A further embodiment of the present invention teaches a method of treating acute bacterial otitis media, pharyngitis and tonsillitis with a oral suspension of cefdinir wherein said suspension is made by reconstituting a powder comprising at least 8.4% cefdinir.  
         [0036]     All publications, issued patents, and patent applications cited herein are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.  
         [0037]     As used herein, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise.  
         [0038]     As used in the present specification the following terms have the meanings indicated:  
         [0039]     The term “buffering agent,” as used herein, refers to an agent or a mixture of agents that can maintain the original acidity or basicity of a composition. Representative buffering agents include, but are not limited to, citric acid, sodium citrate, sodium phosphate, potassium citrate, and mixtures thereof. A preferred buffering agent of the present invention is a mixture of citric acid and sodium citrate.  
         [0040]     The term “diluent,” as used herein, refers to an agent or mixture of agents that when added to a formulation makes that formulation thinner or less concentrated and may also improve manufacturability. Diluents of the present invention can also serve other functions. For example, a diluent can also serve as a sweetener. Representative diluents include, but are not limited to, sucrose, sorbitol, xylitol, dextrose, fructose, malitol, sugar potassium, aspartame, saccharin, saccharin sodium, and mixtures thereof. A preferred diluent of the present invention is sucrose.  
         [0041]     The term “flavoring agent,” as used herein, refers to an agent or a mixture of agents that adds flavor to a mixture. Representative flavoring agents include, but are not limited to, artificial strawberry flavor and artificial cream flavor.  
         [0042]     The term “glidant,” as used herein, refers to an agent or a mixture of agents that facilitates the flow of powders in the manufacturing process. Representative glidants include, but are not limited to, colloidal silicon dioxide, talc, fumed silica, magnesium stearate, calcium stearate, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate, and mixtures thereof. A preferred glidant of the present invention is colloidal silicon dioxide.  
         [0043]     The term “lubricant,” as used herein refers to an agent or a mixture of agents that lessens or prevents friction. Representative lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, magnesium oxide, stearic acid, sodium stearyl fumarate, sodium lauryl stearate, hydrogenated vegetable oil, corn starch, colloidal silicon dioxide, talc, and mixtures thereof. A preferred lubricant of the present invention is magnesium stearate.  
         [0044]     The term “preservative,” as used herein, refers to an agent or mixture of agents that is used to protect a composition against antimicrobial (e.g., yeast, mold, bacteria) activity. Representative preservatives include, but are not limited to, sodium benzoate, benzoic acid, ethylenediaminetetraacetic acid, sorbic acid, benzethonium chloride, benzalkonium chloride, bronopol, butyl paraben, methyl paraben, ethylparaben, propyl paraben, thiomerosol, sodium propionate, chlorhexidine, chlorobutanol, chlorocresol, cresol, imidurea, phenol, phenylmercuric salts, potassium sorbate, propylene glycol, and mixtures thereof. A preferred preservative of the present invention is sodium benzoate.  
         [0045]     The term “viscosity enhancer,” as used herein, refers to an agent or a mixture of agents that increases the thickness of a liquid thereby making it slow to flow. For example, in a suspension a viscosity enhancer will help to keep the active ingredient suspended to allow accurate dosing. Representative viscosity enhancers include, but are not limited to, xantham gum, guar gum, acacia, povidone, alginic acid, sodium alginate, propylene glycol alginate, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, ethylcellulose, gelatin, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polydextrose, carrageenan, methylcellulose, sucrose, sorbitol, xylitol, dextrose, fructose, malitol, sugar, sodium alginate, tragacanth, hydroxypropyl methylcellulose, bentonite, a polyvinyl alcohol, cetearyl alcohol, colloidal silicon dioxide, and mixtures thereof. A preferred viscosity enhancer of the present invention is a mixture of xantham gum and guar gum.  
         [0046]     Cefdinir can be prepared according to the procedures described in U.S. Pat. Ser. No. 4,935,507, issued Jun. 19, 1990 and U.S. Pat. Ser. No. 4,559,334, issued Dec. 17, 1985, both herein fully incorporated by reference.  
         [0047]     Example 1 shows the percentage amounts used in the preparation of an 8% cefdinir oral powder formulation. As mentioned earlier, the current marketed Omnicef® for suspension is a 4% (4.2% actual) cefdinir powder by weight. The 8% formula was bioequivalent to the Omnicef® for oral suspension product.  
       EXAMPLE 1 
       [0048]                                                                          Percent Used           Ingredient   in 8% Formulation                                        Cefdinir   8.361           Sucrose, NF Extra Fine Granulated   89.157           Citric Acid, USP Anhydrous Powder   0.164           Sodium Citrate, USP Anhydrous Powder   0.098           Sodium Benzoate, NF   0.164           Xanthan Gum, NF (Xantural 75)   0.164           Guar Gum, NF   0.164           Artificial Cream Flavor 610979U-PFW   0.131           Colloidal Silicon Dioxide Anhydrous, NF   0.066           Artificial Strawberry Flavor DY04359   0.393           Artificial Strawberry Flavor FD9581-S   0.787           Magnesium Stearate, NF   0.351                        
 Examples 2 and 3 show percentage amounts that can be used in the preparation of 6% and 10% cefdinir oral powder formulations. 
 
       EXAMPLE 2 
       [0049]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                   
               
               
                   
                   
                 Percent Used 
               
               
                   
                 Ingredient 
                 in 6% Formulation 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Cefdinir 
                 6.000 
               
               
                   
                 Sucrose, NF Extra Fine Granulated 
                 91.518 
               
               
                   
                 Citric Acid, USP Anhydrous Powder 
                 0.164 
               
               
                   
                 Sodium Citrate, USP Anhydrous Powder 
                 0.098 
               
               
                   
                 Sodium Benzoate, NF 
                 0.164 
               
               
                   
                 Xanthan Gum, NF (Xantural 75) 
                 0.164 
               
               
                   
                 Guar Gum, NF 
                 0.164 
               
               
                   
                 Artificial Cream Flavor 610979U-PFW 
                 0.131 
               
               
                   
                 Colloidal Silicon Dioxide Anhydrous, NF 
                 0.066 
               
               
                   
                 Artificial Strawberry Flavor DY04359 
                 0.393 
               
               
                   
                 Artificial Strawberry Flavor FD9581-S 
                 0.787 
               
               
                   
                 Magnesium Stearate, NF 
                 0.351 
               
               
                   
                   
               
             
          
         
       
     
       EXAMPLE 3 
       [0050]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                   
               
               
                   
                   
                 Percent Used 
               
               
                   
                 Ingredient 
                 in 10% Formulation 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Cefdinir 
                 10.000 
               
               
                   
                 Sucrose, NF Extra Fine Granulated 
                 185.04 
               
               
                   
                 Citric Acid, USP Anhydrous Powder 
                 0.328 
               
               
                   
                 Sodium Citrate, USP Anhydrous Powder 
                 0.196 
               
               
                   
                 Sodium Benzoate, NF 
                 0.328 
               
               
                   
                 Xanthan Gum, NF (Xantural 75) 
                 0.328 
               
               
                   
                 Guar Gum, NF 
                 0.328 
               
               
                   
                 Artificial Cream Flavor 610979U-PFW 
                 0.262 
               
               
                   
                 Colloidal Silicon Dioxide Anhydrous, NF 
                 0.130 
               
               
                   
                 Artificial Strawberry Flavor DY04359 
                 0.790 
               
               
                   
                 Artificial Strawberry Flavor FD9581-S 
                 1.570 
               
               
                   
                 Magnesium Stearate, NF 
                 0.702

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