United States Patent:   6,017,516

Assignee:  Lekar Pharma Limited (Mumbai, IN)

Filed:  October 31, 1997

A pharmaceutical dental formulation of therapeutically effective amounts of metronidazole benzoate and chlorhexidine gluconate is described. The formulation also includes a gelled hydrophilic and water-dipersible polymer having free carboxylic groups, an aqueous base, a penetration enhancer and a chelating agent. The formulation is for topical application in the form of an aqueous gel in the treatment of periodontal diseases including gingivitis, stomatitis, Apthous ulcers and post-extraction infection.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides the pharmaceutical dental formulation for topical application in the form of aqueous gel suitable for the treatment of periodontal diseases.

The present formulation provides the method for the prophylactic or curative treatment to individuals affected with

1. Chronic gingivitis

a. Chronic Edematous Gingivitis

b. Chronic Hyperplastic gingivitis

c. Chronic atrophic gingivitis

2. Acute gingivitis

a. Acute ulcerative gingivitis (Vincent's gingivitis)

3. Chronic Periodontitis

4. To prevent post extraction infections (Dry Sockets)

5. Recurrent Apthous Stomatitis (Ulcer)

6. Dental Pain due to infection

1. Chronic gingivitis is an inflammation of the gingival tissue. It is not associated with bone resorption or apical migration of the junctional epithelium, falls pockets of less than 2 mm size can occur due to hyperplasia of gingiva. The gingivitis is the results of low grade infection because of the presence of gram-negative anaerobes giving rise to inflammatory changes.

2. Acute Gingivitis is also known as Vincent's gingivitis is characterized by painful papulary ulcers which bleeds readily.

Many anaerobic bacteria have been said to be involved in pathogenesis of acute ulceration gingivitis (AUG) such as borellia, vincent's fuso-bacteriam fusiformis, bacteroid melanogenices and treponema species.

3. Chronic Periodontitis can be regarded as a progression of the combination of infections and inflammation of gingivitis into a deep tissues of the periodontal membrane. It is characterized by breakdown of periodontal fibre bundles and resorption of alveolar bone and apical proliferation of junctional epithelium.

Chronic periodontitis develops due to infections with gram-negative anaerobic rods and spirochaetes.

4. Dry Socket is being described as a painful tooth socket following recent extractions and accompanied by partial or total loss of the blood clotbleed. Anaerobic bacteria are implicated in the pathogenesis of dry socket.

5. Recurrent Apthous Stomatitis (Ulcer) Apthous ulcer is well-known condition occurring in 25% of population. Usually they present with one group of 1 to 6 ulcer. Usually they last for 10 days and heal without scarring. The exact etiology is not known. They get painful due to super infection.

According to the present invention there is provided a pharmaceutical dental formulation in the form of a gel for topical application comprising of:

1) a therapeutically effective amount of metronidazole benzoate and chlorhexidine gluconate as therapeutic ingredients;

2) a gelled, hydrophillic and water-dispersible polymer having free carboxylic groups which is a polyacrylic acid polymer having a molecular weight in the range of about 1,250,000 to about 4,000,000 daltons.

3) an aqueous base for the said metronidazole and chlorhexidine gluconate;

4) a chelating agent;

5) a penetration enhancer.

6) a flavouring agent and a sweetening agent;

Ingredients present in the topical oral carrier of the present invention are suitable for administration to the oral cavity of a human and are compatible with one another used in topical composition of the present invention. Metronidazole Benzoate present in the composition is in the range of 0.5% to about 3%, preferably between 0.8 to 1.6% by wt. based on total weight of the said composition.

Chlorhexidine gluconate is a component of the topical oral carriers of the composition of the present invention. Chlorhexidine gluconate is in the range of about 0.01% to 0.5%, the prefered range is 0.01 to about 0.1% by weight based on total weight of the said composition.

The polymer present in the composition is in the range of about 0.2% to about 7% by wt. based on the total wt. of the said composition. The results are better with polymer 1.5% by wt. based on the total wt. of the said composition.

The penetration enhancer present in the composition is in the range of about 2% to about 10% by wt. based on the total wt. of the said composition. The better results are obtained with penetration enhancer 0.5 by wt. based on the total wt. of the said composition.

The expression `chelating agent` as used in this specification refers to Disodium Edetate U.S.P., Edetic Acid, Citric Acid, Disodium Calcium Edetate.

However, Disodium Edetate is preferably used as chelating agent in the gel composition of the present invention in an amount of 0.01% to about 0.1% by wt. and preferably, in an amount of about 0.025% by wt. based on the total wt. of the composition.

The expression `sweetening agent` as used in this specification refers to Sacchrine Sodium, Aspartame, Dihydrochalcowes, D-tryptophan, acesulfame and cyclamate salts.

The expression `flavouring agent` as used in this specification refers to Menthol, pepermint oil, spearmint oil, Anise oil and clove oil.

The expression a `gelled, hydrophillic and water dispersible polymer` as used in the specification refers to Carbomer 940, carbomer 934, Hydroxypropylmethylcellulose, Sodium Carboxymethyl Cellulose.

The expression `penetration enhancer` as used in this specification refers to Propyleneglycol, Glycerine, Polyethyleneglycols. The preferable penetration enhancer used for the composition is propyleneglycol.

Mechanism of action of combination of metronidazole benzoate and chlorhexidine gluconate of the present composition.

This gel when applied on the affected part, flows and fills out the gingival pocket after application and thereafter comes into contact with the aqueous part of either gingival cravicular fluid or saliva containing esterases. These hydrolyse microbiologically inactive Metronidazole benzoate to free metronidazole and benzoic acid Metronidazole exerts its aerobicidal activity on anaerobic bacteria present in periodontal region.

The pharmaceutical dental formulation in the form of gel may be prepared by a process comprising of the following steps:

(a) dissolve disodium EDTA, Sodium Saccharin and chlorhexidine gluconate in a purified water.

(b) dissolve menthol separately in propylene glycol.

(c) Step (b) is added to step (a).

(d) required quantity of Metronidazole benzoate was added to the mixture and dispersed with continuous stirring.

(e) Carbomer 940 polymer was added to step (d) with continuous stirring to form a uniform viscous gel.

(f) the pH of the gel was adjusted between 5 & 6 by adding 10% NaoH solution and tested by quality Control Dept.

Claim 1 of 17 Claims

1. A phannaceutical dental formulation for topical application in the form of an aqueous gel suitable for the treatment of periodontal diseases which mainly indude gingivitis, stomatitis, Apthous ulcers, and post extraction infection, comprising:

therapeutically effective amounts of metronidazole benzoatc and chlorhexidine Gluconate as therapeutic ingredients;

a gelled, hydrophilic and water-dispersible polymer having free carboxylic groups which is a polyacrylic acid polymer having a molecular weight in the range of about 1,250,000 to about 4,000,000 daltons;

an aqueous base for the said metronidazole benzoate and chlorhexidine gluconate; penetration enhancer; a chelating agent; a sweetening agent and a flavouring agent.

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