IL89935A - Composition for treating afflictions of the oral cavity - Google Patents

Description

89935/2 COMPOSITION FOR TREATING AFFLICTIONS OF THE ORAL CAVITY nan bbn bv rn nn.1 io^oi? t -pnon FIELD OF THE INVENTION : It has been estimated that there exist more than 400 diseases affecting the oral cavity. Many of them are of bacterial origin, amongst these, eriodontal disease is probably the most prevalent and in fact is considered to be the most widespread of human adult diseases. Most adults above 40-50 years of age suffer from chronic periodontal disease (R.J. Dubos, Editor, "Bacterial and Mycotic infections of Man", 3rd Ed. p.645, J. P. Lippincot Co. Phi la .1958) but in many undeveloped countries gingivitis and destructive periodontal disease are prevalent and severe also in the young (Schluger S. et al: Periodontaal Diseases, p.77, Lea and Farbiger, Philadelphia).

Three stages of this disease have been characterized: a) a subacute or chronic inflammation of the gingival margin (marginal gingivitis),... b) an acute ulcerative variety (vincents gingivitis), and c) periodontal breakdown (Piorrea) which is characterized by progressive development of pockets opening at the inner gingival margin.

This eventually results in weakening of attachment and is the main cause for loss of teeth in the adult stages of life.

The term gingivitis refers to an inflammatory condition of the gingiva. The term periodontitis refers to the condition when progress of lesions results in destruction of periodontal fibers.

The initial lesions are induced by an aggregate of bacteria known as plaque, which is a complex mixture of lipopoly saccharides, cario-geni'c microorganisms such as Streptococcus mutans, Actinomyces viscous and Lactobacilli, and periodontal microorganisms such as Antino Antinobaci 1 lus , Veillonella, Bacteroides, Eikenella, Capnocytophaga and Syrocheta. The amounts of patogens are enormous: it has been demonstrated that there are 1.7 x 10^ organisms per net gram of plaque. In order to prevent gingivitis it is important to increase the formation of plaque and in order to prevent periodontit s it is necessary to control gingivitis. Frequent brushing and cleaning are recognized to be excellent ways for preventing the accumulation of plaque. However the average person does not generally devote the time and effort required to achieve thorough cleaning. Moreover, even mindie amounts of food material left in the interstices between the teeth will constitute a.n excellent substrate for the growth of pathogens.

SUMMARY OF .THE INVENTIO : This invention relates to a novel gel-type bioadhesive comprising a copolymer matrix containing a therapeutic agent. The composition and properties of the gel are such that when applied to mucose tissue a film will instantly be formed, which is water-insoluble but water-swellable. The film adheres to moist tissues, such as the gingiva and will stay on for many hours, gradually releasing therapeutic, agent.

The polymer of'siich film has to fulfill several conditions: a) be completely non-toxic and non-i ritating; b) be soluble in a physiologically acceptable solvent such as ethanol, but insoluble in water; c) have good adhesion to wet mucose tissue, so as to stay in place for everal hours; d) have enough hydrophilicity to absorb water so that it can be easily removed b normal brushing procedures; e) have good compatibility and be a good solvent for the therapeutic agent. A preferred embodiment of such a polymer can be prepared from polyvi nylacetate as main monomer, and a carboxyl containing monomer such as acrylic acid, methacrylic acid maleic anhydride or itaconic acid as comonomer.

The preferred material, for toxicological reasons, is itaconic acid.

The copolymer is linear, arid is a good solvent for the therapeutic agent which is incorporated in a small quantity compared with the polymer.

Polyvinylacetate is a good solvent and retains certain organic compounds. The copolymer is soluble in ethanol, but insoluble and only swellable in water. A gel can be nrepared from such a polymer by dissolving it in ethanol and its viscosity can be adjusted by appropriate thickener such as hydroxypropylcel lulose ( lucel) or similar materials. A preferred therapeutic ingredient, is chlorhexidine.

When such a gel is applied to the mucosa of the oral cavity such as the gingiva or the inner parts of the lips, the salival fluid will dilute the ethanolic gel and precipitate the polymer as film within a few seconds. Such a film adheres to the mucose and slowly releases the chlorhexidine which penetrates the periodontal pockets and crevices thus reducing or eliminating bacterial growth. As indicated previously (Sela J. et al Oral Surg. 35: 118/1973), chlorhexidine will be reversibly retained in the oral soft tissues. Thesystem performs, in fact as a long-acting mouth rinse. The recommended manner of application is at night so that during the sleeping hours it will perform a bacterial effect. In the morning it will be eliminated by brushing the teeth.

There exist many therapeutical agents which are of use for the treatment of infections in the mouth area. See Bral M., Antimicrobial Agents in the Prevention and Treatment of Periodontal Diseases, Dental Clinics of North America, Vol., 32 No.2, p.227, April 1988 : 1. Elimination of pathogenic bacteria; 2. Nondevelopment of resistant bacteria; 3. Safety to the oral tissues at the concentration and dosages recommended; 4. Ability to significantly reduce plaque and gingivitis: . No staining of teeth or alteration of taste; 6. No advserse effect on teeth or their substitutes; 7. Ease of use; 8. Affordable Cost.

Materials which can be used by themselves or in various combinations are, for example, bisquandines such as chlorhexidine, antibiotics, fluorides, sanguinarine, quaternary ammonium compounds, phenolic compounds, thymol, eucalyptol , methyl salicylate, benzoates, borates, certain enzymes, metradi nazole and other compounds having bactericidal or bacteriostatic properties.

A preferred agent is chlorhexidine in the form of an organic salt such as digluconate, diacetate diascorbate, etc., or as the free base.

It fulfills most of the conditions mentioned above, has a wide spectrum of effectivity and reduces infection quickly without toxicological or other side-effects. The same system can also be used for the systemic delivery of various drugs via the bucal mucosa tissues.

EXAMPLE 1 : In a 3-neck glass flask provided with condenser and mechanical stirrer were put, in this order: cyclohexane 100 ml sorbitan mono-stereate 1 g., vinyl acetate 35 g. methyl metnacrylate 4 g. and itaconic acid 1.2 g. The mixture was heated to reflux in an oil bath and 1 g. of lauroyl Peroxide was added as catalyst. After 10 hours a solid Polymer Precipitate had formed which separated from the cyclohexane. The solvent was poured out and the polymer was dissolved in 80 ml of ethanol . The resulting viscous solution was spread over a teflon sheet and dried in an air oven at 60C. The dried polymer was triturated and washed repeatedly with de-ionized water. It was then dried again. It had an itaconic acid content of 2.3%.

EXAMPLE 2 : The same apparatus and procedure as in example I were used.

The materials and quantities were as follows: cyclohexane 100 ml; itaconic acid 2 g, vinyl acetate 40 g, lauroyl peroxide 0.3 g.

The itaconic acid content of the final product obtained was 2.89%.

EXAMPLE 3 : In an apparatus as described in example 1, were put: water 360 ml, and polyvinyl alcohol 0.2 g, itaconic acid 10 g, and vinyl acetate; 230 g, containing 1.6 g of benzoyl peroxide were added portionwise while refluxing. After 20 hours cooled the emulsion and poured into a beaker containing 1.5 liter of concentrated sodium chloride solution. Allowed to settle, filtered and washed with water,. and dried in an air oven. The itaconic acid content of the polymer obtained was 3,15 % .

EXAMPLE 4 : The same procedure as in Example 1 was used, but the materials employed were cyclohexane 300 ml, Acrylic acid 7 g., vinyl acetate 108 g, and lauroyl peroxide 0.9 g. The resulting copolymer contained 6.73 % of acrylic acid.

EXAMPLE 5: Same procedure as in Example 1 but using cyclohexane 200 ml, vinyl acetate 72 g, and lauroyl peroxide 0.6 g.

EXAMPLE 6 : In an apparatus as described in Example I, put in 125 g ethanol.

Gradually add 112 vinyl acetate in which are dissolved 12.5 g vinyl pyrrol idone and 0.6 g of genetron (azo-bis catalyst). Reflux during 16 hours. The polymer after drying had a Nitrogen content of 1.03 % equivalent to 8.2% of vinyl pyrrolidone.

EXAMPLE 7 : Repeat of example 6 using the following quantities of solvent and reagents: ethanol 125 g, vinyl acetate 100 g, vinyl pyrrolidone 25 g, and genetron 0.6 g. Obtained the dry polymer containing 1.97 % N, equivalent to 15.7 % of vinyl pyrrolidone.

EXAMPLE 8 : In a wide-mouth glass flask, closed by a glass cover and provided with mechanical stirring were put in. : 68.7 g of ethanol. Added under vigorous stirring 30 g. of a copolymer prepared as per examples 3, 1.3 g of Klucel HF (hydroxypropylcellulose) and a solution of 150 nig of chlorhexidine base in 5 ml of ethanol. The resulting gel was used in clinical tests.

Three patients suffering from gingivitis amd gingiva bleeding were instructed to apply every night, before sleep, about 100 mg of the gel, by smearing the upper gingiva with a cotton swab. After 7 to 14 days of this treatment, inflammation, redness, bleeding and all other symptoms of gingivitis had disappeared in all patients.

EXAMPLE 9 : A series of placebo gels were prepared as per example 8, using various polymers. The resulting gels were applied to the upper gingiva and residence time and adhesion were evaluated. Results are summarized in the table below : Polymer Hydrophilic Adhesion time* component : 1. 2.3 % It. acid good 4-8 2. 2.9 good 4-8 3 3.1 good 4-8 4 5.9 good 2-4 6.7 Ac. Acid good 1-2 6 none poor 1-4 7 8.2 VP medium 1-3 8 15.7 VP good 1-2 *Residence time (in hours) was evaluated visually. Some of these preparations were also made with addition of 1% Titanium dioxide to improve visibility on the gingiva. Adhesion was tested by trying to pull, with a fine pincette, the film from the gingival substrate.

BACKGROUND : There does not exist at present a completely satisfactory method for prevention or curing of gingivitis. There are a number of substances which are effective in reducing the infection and its symptoms such as redness, bleeding, etc. But due to the ease of re-infection any treatment gives only temporary relief unless it can be continued practically indefinitely. Treatments used at present have been summarized in "Periodontal Diseases (Bral .M. et al. Dental Clinics of North America 32:2, 217-241, 1988, indicating that antibiotics such as penicillin may lead to development of resistant strains, and have been abandoned. Other antibiotics such as Erythromicin although effective in plaque reduction have side-effects such as diarrhea.

Enzymes in the form of chewing gum have also proven to be effective in reducing plaque but they irritate the soft tissue and have an unpleasant taste.

A popular mouth rinse, Listerine, contains thymol, eucaliptol, methylsalicilate, benzoic acid and boric acid. Three daily one minute rinses with this material over a two-week study period showed great reduction in plaque and decrease in the gingivitis severity but other studies have shown no difference when using Listerine or a placebo. Still other studies comparing Listerine and Chlorhexidi e in the form of a mouth rinse showed improved oral hygiene in both cases, Chi orhexidi ne being more effective in reducing plaque and gingival index scores and slightly less effective in the resolution of gingivitis (Axelsoon P. et al. Efficiency of mouth rinses in inhibiting dental plaque and gingivitis in man. J. Clin. Periodontal 14 205 1987).

A herbal extract containing mainly as active ingredient, the alkaloid Sanguinarine has been tested as a mouthwash. It appears that it can retard acid producing ability and adherence of bacteria, however the most recent published study shows that its antiplaque efficacy is slight (Siegrist BE et al , Efficacy of Supervised rinsing with Chiorhexidine digluconate in comparison to phenolic and plant alkaloid compounds. J. Periodont. Res. 21, suppl . 16/60,1986.) Further, there may be mentioned enzymes, mouth washes such as Listerine, chlorohexidine solutions, herbal extracts such as Sanguinarine, subgingival irrigation with stannous fluoride.

It has been shown that chiorhexidine adheres to the various oral surfaces and exerts a prolonged action. One of the main problems is that of how to maintain the medication at the site of application for as long as possible. This is difficult in view of the mobility of oral tissues and the rinsing effect of salival fluid. There has been proposed the use of Orabase as carrier, but it is difficult to apply it to larger areas and in inaccessible locations of the oral cavity. A variety of lozenges are in use, as well as a large variety of mouth-washes.

There has also been suggested the introduction of fibers filled with antibiotics into periodental pockets. Numerous carriers of chlorhexidi nes have been proposed: gels, films, putty, bucal patches, etc. None of these has proved satisfactory.

The present invention provides effective means for applying a suitable agent to oral mucosa.

Claims (9)

89935/3 CLAIMS :

1. A composition for the prevention and treatment of gingivitis periodontitis and other afflictions of the oral cavity, and for the reduction of dental plaque, comprising a solution or gel of a therapeutical active agent, a suitable polymer containing an acidic comonomer imparting adhesion to the mucosa and a physiologically acceptable non-aqueous solvent, the composition being such that upon contact with the aqueous environment of the oral cavity polymer film is precipitated in said cavity.

2. A composition according to claim 1, where the polymer is a co-polymer of vinyl acetate and a hydrophylic comonomer.

3. A composition according to claim 2, where the solvent is ethanol and the therapeutic agent is selected from bis-guanidine or a physiologically acceptable salt thereof.

4. A composition according to claim 3, where the active agent is chlorohexidine base or a physiologically acceptable salt thereof.

5. A composition according to claim 2 or 3, where the hydrophilic comonomer is itaconic, acrylic, methacrylic, fumaric or maleic acid.

6. A composition according to any of claims 2 to 4 , where the co-polymer comprises 85 to 98 weight-% vinyl acetate and 2 to 8 weight-% itaconic acid.

7. A composition according to any of claims 1 to 5, containing also a thickening agent.

8. A composition according to claim 6, where the thickening agent is hydroxypropyl cellulose. -11- 89.35/5

9. A composition according to claim 2, which comprises an alcoholic solution or gel comprising 10 to 40 parts by weight of a copolymer of vinyl acetate and itaconic acid (0.5 to 5 weight-% in the copolymer), 0.5 to 2.5 weight-% of a thickener and from 0.1 to 1 weight-% of chlorohexisine base or salt.