Drug – bio-affecting and body treating compositions – Dentifrices
Reexamination Certificate
2000-01-10
2002-04-02
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Dentifrices
C424S445000, C424S447000, C424S449000, C514S239200, C514S817000, C514S944000, C514S969000
Reexamination Certificate
active
06365131
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to preparation of pharmaceutical dental gel formulation for topical application of metronidazole benzoate and chlorhexidine gluconate and local anesthetic for the treatment of gingivitis and periodontitis.
DESCRIPTION OF THE PRIOR ART
The organism most often encountered in oral infections is viridans streptococci, a verity of anaerobes, and facultative streptococci. Anaerobes isolated from dentoalveolar abscesses were generally susceptible to benzylpenicillin, amoxycillin, erythromycin, clindamycin and metronidazole. Dental caries is caused by the erosion of tooth enamel due to acid produced by bacteria (especially streptococcus mutans) in plaque. Fluoride in various forms is used in dental caries prophylaxis, where it may promote remineralisation or reduce acid production by plaque bacteria. Periodontal diseases encompasses specific conditions affecting the gingiva and the supporting connective tissue and alveolar bone. Gingivitis is thought to be caused by a non-specific bacterial plaque flora that gradually changes from predominantly Gram-positive to more Gram-negative. Gingivitis may or may not develop into periodontitis, but periodontitis is always preceded by gingivitis. Priodontitis is associated with Gram-negative microflora.
Most gingivitis and periodontitis can be prevented and treated by adequate oral hygiene and plaque removal using mechanical means such as toothbrushes. Mechanical removal of calculus is necessary where the build up is significant. Disinfectants and other agents such as cetylpyridinium chloride or chlorhexidine also help to reduce plaque accumulation.
Metronidazole is a 5-nitroimidazole derivative with activity against anaerobic bacteria and protozoa. Its mechanism of action is thought to involve interference with DNA by a metabolite in which the nitro group of metronidazole has been reduced by bacterial nitroreductases to an unstable intermediate, which interacts with DNA, effectively preventing further replication.
Metronidazole is bactericidal. Minimum inhibitory concentration (MIC) for susceptible anaerobic bacteria generally ranges from 0.1 to 8 ugm/ml. It also has activity against the facultative anaerobes
Gardnerella vaginalis
and
Helicobacter pylori
and against some spirochetes. Moreover it is active against several protozoa and anaerobic bacteria, including Bacteroides and Clostridium sp. is sensitive in vitro to metronidazole. Metronidazole is also used in the treatment and prophylaxis of anaerobic bacterial infections. Activity of metonidazole against obligate anaerobic bacteria in vitro including the Gram-negative organisms
Bacteroides fragilis
and other Bacteroides sp., Fusobacterium sp., and Villanelle sp. and the Gram-positive organisms
Clostridium difficile, Cl. pergringens.
Metronidazole is administered by mouth in tablets or as metronidazole benzoate, in oral suspension. The tablets are taken with or after food and the suspension is taken at least 1 hr before food. Metronidazole is also given rectally in suppositories, applied topically as a gel, or administered by intravenous infusion of metronidazole or metronidazole hydrochloride.
This gel when applied on the affected part, flows and fills out the gingival pocket after application, thereby comes in contact with the aqueous part of either gingival cravicular fluid or saliva containing esterases which hydrolyse metronidazole benzoate to free active metronidazole which exerts it activity on anaerobic bacteria present it periodontal region.
The long term use of oral metronidazole in chronic condition like periodontal diseases may be associated with certain side effects such as gastro-intestinal disturbances, nausea, an unpleasant metallic taste, anorexia, vomiting, diarrhea, dry mouth, a furried tounge and glossitis. However, to avoid the drawbacks of systemic administration, a dental gel for topical application of metronidazole is desirable in periodontitis.
A dental gel comprising of metronidazole benzoate 25% used for gingivitis and periodontitis, and its topical use seems to be as effective as conventional therapy in the treatment of adult periodontitis. (J. Clin. Periodontal 1992, :19, 715-729). The use of metronidazole benzoate 25% dental gel is associated with a limitation viz. when applied subgingivally, the active drug reaches sulcus for which special injector is required and the procedure is cumbersome and is done by dental surgeon only.
A dental gel comprising of chlorhexidine is also used for gingivitis and prevention of plaque. Chlorhexidine is a bisbiguanide antiseptic and disinfectant effective against a wide range of bacteria, some fungi, and some viruses. It is used in various preparations as the acetate or gluconate commonly with cetrimide, for disinfection of skin, wounds, burns. The dental gel or mouthwash comprising of chlorhexidine may discolour the tounge or teeth. Chlorhexidine is bactericidal or bacteriostatic against a wide range of Gram-positive and Gram-negative bacteria. It is more effective against Gram-positive than Gram-negative bacteria. Chlorhexidine is most active at a neutral or slightly acid pH.
Similarly a dental composition consisting of chlorhexidine gluconate in various strengths of 0.1 to 1% in the form of topical application also used for periodontal diseases (Br. Dental J. 1977, 142, 366-369). Chlorhexidine gluconate is also used in a 1% dental gel and 0.2% mouthwash for the prevention of plaque and the prevention and treatment of gingivitis and in the treatment of oral candidiasis.
Lidocaine is a local anaesthetic of the amide type and is widely used in injection and for local application to mucous membranes. It has rapid onset of action and anesthesia is obtained within a few minutes depending on the site of administration. It has an intermediate duration of action.
Benzocaine is ethyl ester of p-Aminobenzoic acid. It is usually used to relieve pain associated with ulcers, wounds and mucous membrane. Normally it acts only as long as it is in contact with skin or mucosal surface. Peak effect occurs within 1 min after the application and lasts for 36 to 60 min.
Thus taking into consideration the limitation and disadvantages associated with the conventional dental gels, the inventor has come out with a unique dental gel composition comprising of metronidazole benzoate and chlorhexidine gluconate & local anaesthetic in the form of aqueous gel having the effect on aerobic and anaerobic bacteria in periodontal diseases and this combination has been found to be therapeutically better over either metronidazole benzoate or chlorhexidine gluconate individually.
This application is continuation-in-part of the U.S. patent application Ser. No. 08/962,099 filed dated Oct. 31, 1997 claming dental gel comprising of metronidazole benzoate, chlorhexidine gluconate used for gingivitis and periodontitis.
The present application relates to the preparation of dental gel having the same composition as in U.S. patent application Ser. No. 08/962,099 with additional ingredient viz. local anaesthetic. The advantage of local anesthetics is, it reversibly blocks impulse conduction in any part of the nervous system and in all nerves, including sensory, motor and autonomic types, producing a transient loss of sensation in a circumscribed area of the body without causing a general loss of consciousness. This action is used to block the pain sensation to the areas where it is applied, hence it is useful to prevent pain in dental manipulations, injury and diseases.
Accordingly, it is among the objects of the present invention to provide dental gel formulations containing metronidazole benzoate, chlorhexidine gluconate and local anesthetic, which are stable, which may be readily employed without pain and other side effects or other undesirable characteristics.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the pharmaceutical dental gel formulation for topical application in the form of aqueous gel suitable for the treatment of periodontal diseases. The present formulation comprises of M
Doshi Madhukant Mansukhlal
Joshi Milind Dattatraya
Mehta Bharat Pravinchandra
J. B. Chemicals & Pharmaceuticals Ltd.
Lackenbach & Siegel LLP
Rose Shep K.
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