Pyruvate and related alpha-keto carboxylates as novel adjuvants in the treatment of post tooth whitening sensitivity and the tissue protective effect of pyruvate on the oral soft tissue

Abstract

This invention describes pyruvate and related α-ketocarboxylates as novel adjuvants in the treatment of acute post-tooth-whitening pain and sensitivity; the key feature is the cytoprotective efficacy of pyruvate on oral soft tissue, especially after topical application of high and therefore cytotoxic concentrations of H 2 O 2 , currently used in tooth whitening procedures.

1 . A pharmaceutical composition to react stoichiometrically and non-enzymatically with extracellular H 2 O 2  applied during an external tooth whitening procedure, the pharmaceutical composition comprising:
 a/. an α-ketocarboxylic acid salt compound of the formula R—C(O)(COO − ), as the organic anion;   
       wherein R is an alkyl of 1 to 12 carbon atoms; substituted alkyl of 1 or 12 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, carboxyalkene of 1 to 20 carbon atoms within the alkene chain, halogen amino, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in the each alkyl group or phenyl); alkenyl of 2 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms, benzyl, substituted benzyl wherein the substituent is one of methyl, phenyl on the a carbon atom, methyl, dimethyl, halo, dihalo, or ethoxy, phenyl;
 naphthtyl, substituted phenyl or substituted naphtyl wherein the ring is mono-, di-, or trisubstituted and the substituent on the phenyl or naphthyl is alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, pyridyl, thienyl, indolyl, furyl, acridly, quinolyl; piperadine, or pyridazinyl, or a pharmaceutically acceptable salt thereof wherein the α-ketocarboxylic acid salt is in an amount sufficient to prevent deleterious tooth sensitivity following the tooth whitening procedure, to prevent the deterioration, promote the restoration and preservation of normal cell function when H 2 O 2  inadvertently comes in contact with the surrounding oral tissue. 
 b/.a mucoadhesive polymer; and 
 c/.a pharmaceutically acceptable carrier for the mucoadhesive polymer 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein R is an alkyl substituent selected from the group consisting of methyl, and propyl 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein R is methyl. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the α-ketocarboxylic acid salt is sodium pyruvate, endotoxin-free and sterile. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the sodium pyruvate is in a concentration in the range of 2 mmols per 3 cc of pharmaceutical composition to 25 mmols per 3 cc of pharmaceutical composition. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein R is a carboxy-alkyl selected from the group consisting of methyl, and propyl. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is in a sustained release formulation wherein the mucoadhesive polymer is a biodegradable biocompatible mucoadhesive polymer. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the α-ketocarboxylate compound is a pharmaceutically acceptable salt of α-ketocarboxylic acid comprising a cation from the group consisting of sodium, potassium, and possibly magnesium and calcium, all salts endotoxin-free and sterile. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the α-ketocarboxylic acid compound is esterified to compound such as methyl pyruvate, propyl pyruvate, carboxymethyl pyruvate, acetoxymethyl pyruvate, carbethoxymethymethyl pyruvate, ethoxymethyl pyruvate, ethyl alpha-keto-butyrate, ethyl alpha-keto-pentanoate, ethyl alpha-keto-3-methyl-butyrate, ethyl alpha-keto-4-methyl-pentanoate, ethyl alpha-keto-hexanoate, or a combination thereof. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the a pharmaceutically acceptable carrier for the mucoadhesive polymer is cellulose derivative, methyl cellulose, ethyl cellulose, hydroxy-ethylcellulose, hydroxyl propyl cellulose, hydroxy propyl methylcellulose, sodium carboxy methylcellulose, poly(acrylic acid) polymers, carbomers, polycarbophil, poly (hydroxyethyl methylacrylate), poly(ethylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), natural polymers, tragacanth, sodium alginate, karaya gum, guar gum, xanthan gum, lectin, soluble starch, gelatin, pectin, chitosan, of combinations thereof. 
     
     
         11 . A method of whitening teeth, comprising:
 a/. applying a teeth whitening solution to the teeth of a person, wherein the teeth whitening solution comprises hydrogen peroxide;   b/. preparing a pharmaceutical composition by mixing sodium pyruvate with a preparation comprising a mucoadhesive polymer and a pharmaceutically acceptable carrier for the mucoadhesive polymer;   c/. applying the pharmaceutical composition to the teeth and mouth of the person;   d/. allowing the pharmaceutical composition to reside on the teeth and mouth of the person for a period time from 30 seconds to 10 minutes; and   e/. rinsing the teeth and the mouth of the person with water.   
     
     
         12 . The method of  claim 12 , wherein the sodium pyruvate is in a first container and the preparation is in a second container and the mixing is performed by moving the contents of the first container into the second container and then moving the contents of the second container into the first container. 
     
     
         13 . The method of  claim 13 , wherein the pharmaceutical composition is allowed to reside on the teeth and mouth of the person for a period time from 2 minute to 10 minutes prior to rinsing. 
     
     
         14 . The method of  claim 12 , wherein the sodium pyruvate is in a concentration range between 750 mM (millimol/l) and 3.3M (mol/l), and any concentration in between the specified range. Two therapeutic solutions are recommended: 1) A Standard solution, at about five times isotonic concentration, with a 750 mM sodium pyruvate; this solution contains 250 mg sodium pyruvate in a 3 ml solution, recommended for the general purpose of neutralizing hydrogen peroxide post intraoral tooth whitening process; 2) An Emergency solution, extremely hypertonic at 3.3M (1.2 g of sodium pyruvate in a 3 ml solution, recommended for treatment of painful gingival inflammation with exudate. 
     
     
         15 . A kit for alleviating sensitivity after teeth whitening, comprising a first container containing sodium pyruvate salt; a second vial containing a mucoadhesive polymer and a pharmaceutically acceptable carrier for the mucoadhesive polymer. The container with the NaPyruvate an be connected to the second container to mix the contents to form an effective pharmaceutical composition ready to be applied to the area of interest. 
     
     
         16 . The kit of  claim 16 , wherein after mixing, the sodium pyruvate is in a concentration in the range between 750 mM in 3 ml and 3.3M in 3 ml. at room temperature, at Ph of 7.55 
     
     
         17 . The kit of  claim 16 , wherein the first container is a syringe having a first port and the second container is a syringe having a second port, and the first port may be sealingly connected to the second port. 
     
     
         18 . The kit of  claim 16 , wherein the first and second ports comprise threaded connections.