SE465905B - DENTALS CONTAINING AN ACETATE OR GLUCONATE SALT OF AN ANTIMICROBIAL BISBIGUANIDE - Google Patents

Description

465 905 2 Chlorhexidine also prevents the development of already existing dental diseases. In addition to being used in rinsing liquids, chlorhexidine can also be used in the form of toothpaste or gel for brushing teeth, with the same effect as previously stated.

It would be believed that, due to the above beneficial properties, these chlorhexidine salts and similar bisbiguanides should have found widespread use in dentistry and dentistry. A serious limitation with these preparations, however, is the significant discoloration of the teeth which occurs with the use of chlorhexidine or other similar bisbiguanide salts after a certain time. The discoloration occurs especially between the teeth, is dark brown to black in color, and difficult to remove because it is calcified. The discoloration probably consists of calcified pellicle protein which is discolored by metal sulphides, especially iron, which comes from the diet. The discoloration is likely to be caused by the pellicle protein, which covers the tooth surfaces with a thin layer, being denatured by the bisbiguanide. Thereafter, exposed sulfur groups bind metals which are thus discolored, after which the entire pellicle mass is calcified in the longer term.

It has long been a desire to be able to utilize the good plaque-inhibiting properties of chlorhexidine and other bisbiguanide salts while avoiding the above-mentioned discoloration.

Thus, the discoloration of the teeth must not be prevented at the expense of the antimicrobial effect.

It has now been found that the good plaque-inhibiting properties of bisbiguanide salts, such as chlorhexidine, can be utilized in their entirety and the occurrence of discoloration on the teeth is reduced if one uses a dentifrice, such as a toothpaste, solution, tablet, or chewing gum, contains an acetate or gluconate salt of an antimicrobial bisbiguanide, also adds a water-soluble, physiologically acceptable copper (II) salt.

It has also surprisingly been found that a combination of bisbiguanide and copper (II) salt such as copper acetate or copper gluconate has a synergistic plaque inhibitory effect, while the appearance of discolorations is small and of such a nature that they can be easily brushed off by the patient by toothbrushing which is not possible for discolorations that occur in connection with the use of chlorhexidine alone.

To illustrate the effect of a dentifrice according to the invention, a solution containing 0.05 wt% chlorhexidine and 0.04 wt% copper acetate was prepared. A group of 15 healthy subjects participated in a double-blind cross-over study, where each subject participated in three studies, each lasting 3 weeks. During each three-week period, the subjects did not perform oral hygiene. As a positive control, the subjects rinsed with a 0.12% by weight chlorhexidine solution for three weeks and as a negative control, they rinsed with physiological saline. Plaque and gingival indices were recorded according to standard clinical methods, (Loe, H., J. of Periodontology 38: 610-616, 1965, Loe, H., Theilade, E. and Jensen, SB, J. of Periodontology 36: 177-187, 1965). The results of the study have been compiled in the following table 465 905 4 TABLE Experimental Plaque index Gingival index person m .95 1.00 0.56 0.76 0.95 2 1.12 0.90 1.03 0.09 0.09 1.00 3 0.65 1.42 1.75 0.95 1.23 1 , 52 4 0.09 0.71 1.62 0.91 0.77 1.11 5 0.60 0.96 1.75 1.32 1.24 1.30 6 0.09 0 0.67 1, 70 1.03 1.21 1.16 7 0.39 0.52 1.27 0.75 0.70 1.27 0 1.02 0.40 1.54 0.30 0.35 0.30 9 0 .50 0.71 1.51 1.12 1.03 1.21 10 0.06 0.90 1.47 1.32 1.14 1.05 11 1.04 1.27 1.75 0.07 1 .05 1.00 12 0.54 1.10 1.06 1.03 1.56 1.49 13 0.70 0.56 1.59 1.13 1.13 1.06 14 0.35 0.01 0.91 1.09 15 ~ I 1602160550 _ 0.74 0.07 1.59 0.94 1.01 1.12 X * solution of 0.12 wt. Chlornexiain 1 11.6 wt. Alcohol, pa 5.5 UPERIDEX ”from Procter and Gamble) ** solution of 0,04% by weight of copper (II) acetate and 0,05% by weight of clochexidine in distilled water prepared from 20% chlorhexidine gluconate PHIBITANE ') 5 465 905 The solution of chlorhexidine and copper acetate in inhibiting plaque formation was comparable to the solution of chlorhexidine alone, which was present in more than twice the concentration.

These two solutions were in turn significantly more effective than the saline solution. It is further well known that a 0.05% chlorhexidine solution has no clinical effect (Skorland et al, Scand.

J. Dent. Res. 86: 103-107, 1978).

The clinical examination also gave the surprising result that the chlorhexidine / copper acetate solution gave less discoloration compared to pure chlorhexidine and this mild form of discoloration could be easily removed with conventional toothbrushing.

To further elucidate the synergistic effect between copper acetate and chlorhexidine, microbiological experiments have been performed in vitro with Streptococcus mutans and Actinomyses viscosus, two very common oral bacteria that are considered essential for the development of caries and periodontitis. MIC (minimal inhibitory concentration) test was performed with chlorhexidine or copper acetate alone and various combinations of these salts. All% values in the following refer to weight percent unless otherwise stated.

Streptococcus mutans serotype C and Actinomyces viscosus isolate were grown in trypticase soy broth (TSB) supplemented with yeast extract (YE) (0.5%) in a 5% CO 2 incubator for 24 hours. The cultures were harvested by centrifugation, washed and resuspended in double strength TSB-YE and set to a suitable optical density with reference to a predetermined standard curve. Serial dilutions of chlorhexidine gluconate and copper acetate were made in 0.15 M NaCl. The assay mixtures consisted of a standardized inoculum of washed cells (final conc. 5 x 105 cfu / ml) and of the same volume of the test compound. To determine any synergistic effect, different concentrations of each compound were combined and inoculated as above. All tubes were incubated for 24 hours in 5% CO 2 at 37 ° C.

The results are shown in Figures 1 and 2. The MIC value for chlorhexidine was 9.76 x 106% (w / v) and for copper acetate 0.02% (w / v).

In the first series of experiments, different concentrations of copper (II) acetate were mixed with chlorhexidine gluconate as shown in Fig. 1. The highest concentration of copper acetate used was 0.02%, the previously determined MIC value. Dilutions were made until a final concentration of 6.25 x 104% was reached. The chlorhexidine concentration was kept constant at 2.44 x 106%, ie 0.25 x the MIC value. It should be noted that a significant inhibition of growth (30 - 60%) was obtained with combinations of the two compounds at concentrations that allowed growth in experiments with only one substance.

In the second series of experiments, an even more pronounced effect could be observed when copper (II) acetate at a concentration of 0.125 x the MIC value was mixed with chlorhexidine gluconate at a concentration ranging from the MIC value to 0.063 x the MIC value, such as is shown in Fig. 2. At the lowest concentration examined, 0.125 x the MIC value for copper acetate and the 0.063 x MIC value for chlorhexidine gluconate, an inhibition of growth of 30-40% was achieved. Similar results were obtained with A. viscosus isolate.

It thus appears that a combination of chlorhexidine and a copper (II) salt has a synergistic growth inhibitory effect on the bacterial strains examined.

A dentifrice according to the invention which comprises an antimicrobial bisbiguanide in combination with a physiologically acceptable copper salt exhibits not only an improved plaque inhibitory effect at lower concentration but also a minor degree of side effects in the form of discoloration of the teeth. A solution may suitably contain 0.5 - 5.5 mM bisbiguanide in combination with 0.55 - 55 mM copper salt and a solid dosage form suitably 2.1 - 21 mM bisbiguanide in combination with 0.55 - 550 mM copper salt.

The dentifrice according to the invention may be in the form of a rinsing liquid, toothpaste or gel and may also be in a dosage form such as a tablet or chewing gum. A rinsing liquid may contain 0.05% to 0.5% by weight of bisbiguanide as acetate or gluconate and 0.01 to 1% of copper acetate or copper gluconate.

A toothpaste or gel should contain 0.2 to 2% by weight of bisbiguanide as acetate or gluconate and 0.01 to 10% by weight of copper acetate or copper gluconate. A tablet or chewing gum should contain 0.2 to 2% by weight of bisbiguanide as acetate or gluconate and 0.01 to 10% by weight of copper acetate or copper gluconate. (1

Claims (6)

7,465,905 Patent claims Dental care products containing an acetate or gluconate salt of an antimicrobial bisbiguanide, characterized in that it also contains a water-soluble, physiologically acceptable copper (II) salt. Dental care product according to claim 1, characterized in that the antimicrobial bisbiguanide is chlorhexidine. Dental care product according to claim 1 or 2, characterized in that the copper (II) salt is copper acetate or copper gluconate. Dental care product according to one of Claims 1 to 3, characterized in that it is in the form of a rinsing liquid, which contains 0.05 to 0.5% by weight of bisbiguanide as acetate or gluconate and 0.01 to 1% by weight of copper acetate, or copper gluconate. Dental care product according to one of Claims 1 to 3, characterized in that it is in the form of a toothpaste or gel containing 0.2 to 2% by weight of bisbiguanide as acetate or gluconate and 0.05 to 10% by weight of copper acetate or copper gluconate. . Dental care product according to one of Claims 1 to 3, characterized in that it is in the form of a tablet or chewing gum containing 0.2 to 2% by weight of bisbiguanide as acetate or gluconate and 0.01 to 10% by weight of copper acetate or copper gluconate. .