CZ353292A3 - Analgesic preparation exhibiting antiphlogistic, antiseptic a healing activity. - Google Patents

Description

(57) An analgesic agent with an anti-inflammatory, antiseptic and healing action consists of a mixture of one or more benzo / c / phenanthridine alkaloids with allantoint in a physiologically harmless vehicle. Alkaloid is present in the composition in an amount of 0.001 to 2% by weight, allantoln in an amount of 0.001 to 5% by weight. The analgesic composition is applied in the form of a gel, adhesive paste, mouthwash, spray, and the like.

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effect effect

Technical field

The invention relates to an analgesic preparation having an anti-inflammatory, antiseptic and healing effect, which is intended mainly for use in the oral cavity.

BACKGROUND OF THE INVENTION

For the treatment of inflammations in the oral cavity (eg periodontal trunks, pressure sores, mucosal ulcerations or non-fearing extractive wounds) a wide variety of preparations, most often containing compounds with antiseptic effects, usually in combination with astringent agents, are used. Effective. the components of the antiseptic preparations may be bisguanidines, bispyridines, salts of certain metals, oxidizing agents, phenols, pyrimidines, quaternary ammonium compounds and some plant extracts, most of which are chamomilla extract. More recent preparations often utilize the pronounced antimicrobial effect of Sanguinaria canadensis extract (Molinari, J.A., Molinari, G.E .: Is Mouthrinsing Before Dental Procedures Worthwhile ?, in JADA, 123, 75-80, (1992)).

Corticosteroids, used to inhibit the inflammatory response mainly at the beginning of treatment, have anti-inflammatory activity without antiseptic effect. Calcium ions can be injected topically. If analgesic efficacy is also desired, a suitable local anesthetic may be added. In connection with the renaissance of natural medicines in human medicine, a number of natural substances and their derivatives have recently been tested for anti-inflammatory effects, such as bisabolol, aescin, terpenic alcohols and plant polyphenols. Quaternary benzo (c) phenanthridine alkaloids also have significant anti-inflammatory activity (Lenfeld, J., Kroutil, M., Marsalek, E., Slavik, J., Preininger, V., Simanek,

2V .: An Antiinflammatory Activity of Quaternary Benzophenanthridine Alkaloids from Chelidoniwm majus, in Planta led. , 43, 161-165 (1981)), which have been proposed to treat inflammatory mucosal and skin diseases. In addition, the analgesic effect of some quaternary benzo (c) phenanthridine alkaloids in intravenous administration has been described (Arzneim.-Forsch. 1.0, 135-137 1960).

Recently, Solcoseryl adhesive paste, a combination of a non-protein calf blood dialysate with a surface anesthetic polidocanol, has been used to treat open wounds of the oral mucosa. It improves oxygen uptake into the cell's respiratory chain, thereby increasing ATP production and thus improving the energy supply of cells and organs. As a result, the healing process is accelerated. (Felber, P., Gasser, F., Doppelblinde klinische Prüfung der Solcoseryl-Dental-Adhesivepaste bei der Behandlung von Prothesendruckstellen, and Schweiz. Mschr. Zahnheilk., 93, 362-373 (1983)).

A major disadvantage of these preparations is that they do not combine high analgesic and anti-inflammatory activity with the desired retention in the mucosal epithelium and antiseptic activity against microorganisms in trunks and subgingival dental plaque. Long-term supplemental use of many antiseptics is often limited by their negative side effects (eg, chlorhexidine indigluconate causes increased tartar formation and loss of appetite), and anti-inflammatory corticoids also have undesirable hormonal activity.

SUMMARY OF THE INVENTION

These drawbacks are overcome by an analgesic composition having an anti-inflammatory, antiseptic and healing effect according to the invention. The present invention is characterized in that the composition comprises as active ingredient a mixture of at least one benzo [beta] / phenanthridine alkaloid and allantoin in a physiologically acceptable vehicle. Alkaloid, respectively. mixture of alkaloids are selected from the group consisting _of chelerythrine, sanguinarine, chelirubin, chelilutin, and sanguirubin sanguilutine. It has been found to be advantageous if the preparation contains 0.001 to 2% by weight of alkaloid (or a mixture of alkaloids) and 0.001 to 5% by weight. allantoin in vehicle. The alkaloid may be in the formulation in the form of a pharmaceutically acceptable salt (eg, chloride) / or in the form of a base, allantoin may be in the form of a salt with a pharmaceutically acceptable metal (eg, sodium salt). It has also been found that the analgesic composition of the invention can be administered in a variety of dosage forms, such as liquid gel, massage gel, adhesive paste, toothpaste, mouthwash, spray, and the like.

The analgesic composition according to the invention has, while significantly reducing hyperalgesia (caused by inflammatory disease), retained anti-inflammatory, antiseptic and healing effects, the addition of allantoin enhances the analgesic effect of the quaternary benzo (c) phenanthridine alkaloids alone. It is therefore suitable for the treatment of wounds and inflammation, especially in the oral mucosa (eg. Proboscis, bruises caused _from dentures, oral mucosal ulceration or poorly healing wounds extraction). In addition to the broad spectrum effect, it is also more economical.

The analgesic composition according to the invention is characterized in that in addition to benzo (c) phenanthridine alkaloids and allantoin it contains glycerol (2-10 wt%), acesulfame K (0.01-0.05 wt%), polidocanol (0.05- 0.2 wt%), ethanol (5-15 wt%), sorbic acid (0.02-0.07 wt%), carboxymetphoyl cellulose (0.1-5 wt%), flavorings and taste correction in a citrate buffer of pH 4-6, optionally also surfactants and abrasives and V / W (tuzer) t-polish buffers.

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Examples of embodiments of the invention

Example 1

Weigh out 3 g of carboxymethoxyl cellulose 300 with swirling occasionally for 24 hours in 97 g of cold purified water. It is transferred to an NTS bottle and sterilized at 105 ° C and exposure for 60 minutes. After cooling, the gel is cooled to about 5 ° C in a refrigerator. By rotating the bottle, the gel is still mixed and allowed to reach room temperature. Under strictly aseptic conditions, 25 mg of chelerythrine chloride is added, and after dissolution, 500 mg of allantoin is added. After complete dissolution, the gel is filled into aseptic medium into sterile tubes.

Example 2

A mixture of sanguinarine chlorides and cheryltrin (3: 7, 200 mg) was dissolved in 100 ml of water. The solution was basified by the addition of 3 g Na ₂ CO ₃ and the resulting precipitate of panguinarine and chelerythrine pseudobase was filtered off by means of a membrane filter. The filter precipitate was washed with water and dried under reduced pressure. The yield was 164 mg.

mg of the sanguinarine-chelerythrin pseudobase mixture thus prepared was suspended in a carboxymethoxyl cellulose gel according to the procedure of Example 1.

By analogous methods, the analgesic preparation of the invention was prepared in various combinations which were tested for hyperalgesia _; induced by yeast and carrageenin inflammation in female Wistar rats. For comparison, a formulation containing 10% deproteinated calf blood extract (Si)% polidocanol (Solcoseryl gel) and a formulation containing 1% analgesic active diclofenac (Voltaren Emulgel) was used. The results are shown in the following tables.

Table 1

Influence of inflammatory hyperalgesia and rat paw swelling caused by yeast inflammation (x ± 95% confidence limit)

Preparation

Inflammatory edema (paw diameter in mm)

Inflammatory hyperalgesia (mm Hg) san. i- chel,

3: 7, 0.0 5 (% san.! - chel.

3: 7, 0.0 5% + allan. 0.5% san. i- chel.

3: 7, 0.02% + allan. 0.5 (%

4.65 ± 0.51

4.44 ± 0.30 nesig.

4.21 ± 0.22 p <0.01

4.52 ± 0.38 nesig.

110.8 ± 29.7

128.5 ± 51.0 nesig.

211.4 ± 20.2 p <0.01

180.0 ± 46.0 p <0.01

5 Solcoseryl gel 10 4.38 ± 0.58 nesig. 186.6 ± 87.4 p <0.05 Λ 5 Voltaren-Emulgel 4.17 ± 0.32 p <0.05 195.8 ± 116.4 p <0.01 * 7 chel. Ο, οφ, + allan. 0.5 ^% 4.53 ± 0.68 nesig. I.98.3 ± 63.4 p <0.05 8 chel. 0.05 (%) 4.48 ± 0.42 nesig. 124.7 ± 45.2 nesig. 9 allan. 4.37 ± 0.25 p <0.05 132.5 ± 55.1 nesig. san. = sanguinarin, chel. = chelerythrin, allein . = allantoin p <0.01 = difference between control and sample significant with a probability of p> 99 is statistically % p <0.05 = difference between control and sample is statistically

significant with a probability of p> 95% nesig. = the difference between the control and the sample is not statistically significant. Yeast inflammation of the rat paw was induced by application of 0.1 ml of a 20% brewery yeast suspension. The gel was applied topically in an amount of 0.1 ml to the dorsum of the paw, 3 hours after induction of inflammation. Inflammatory paw edema and inflammatory pressure hyperalgesia (Randall-Seitt method) were measured 4 h after administration of test substances.

Table 1 shows that sangulnaiin, chelerythrin and allantoin (# 3) significantly reduce (p <0.01) inflammatory hyperalgesia compared to the same allantoin-free (# 2) alkaloid mixture, bringing it to the level of analgesic based diclofenac.

and

-7Table 2

Influence of inflammatory edema and inflammatory hyperalgesia of carrageenan swelling of the rat paw (x ± 95% confidence limit)

Preparation Inflammatory edema (paw diameter in mm) Inflammatory (mm hyperalgešie Hg) 3 h 5 h 3 h 5 h 1 control 1.90 ± 0.40 3.29 ± 0.40 2 ^ 1 ± 10 ^ 5 161.2 + 2 ^ 5 2 san + chel 3: 7, 0.05 (% 2.37 ± 0.26 nesig. 3.66 ± 0.35 nesig. 24.7.1 ± 10.2.4 ^r unsig. 193.5 ± 5 ^ 6 nesig. 3 san + chel 3: 7, 0.025 (% + allant. 0 2.07 ± 0.32 nesig. .5 ^% 3.09 ± 0.48 nesig. 257, .5 ± 75.8 ^r unsig. 221.8 ± 52.5 p <o, ol ~ Solcos, er. 1.61 ± 0.39 3.01 ± 0.43 260.0 ± 8.2.2 183.1 ± 33 "2 gel 10% nesig. nesig. nes, i q. nesig. 5 Voltaren -Emulgel 1.66 ± 0.38 nesig. 2.75 ± 0.43 p <0.05 307.5 ± + 5 ^ 2 nes ig. 286.8 ± 10.3 µ: p <0.05

10%

See Table 1 for the meaning of the abbreviations.

Carrageenin swelling was induced by intraplant mime by administration of 0.1 ml carrageenin, the gel was applied to the dorsum of the paw immediately after induction of swelling, measurements were taken 3 h and 5 h after gel application.

Table 2 shows that after application of the sanguinarine / chelerythrin (3: 7) mixture in conc. 0.5 there was an insignificant deterioration of the swelling. After administration of sanguinarine, chelerythrin (3: 7, 0.025%) and allantoin 0.5% (%), there was a statistically significant reduction in inflammatory hyperalgesia, as well as a decrease in inflammatory edema.

PATENTOVÉ

Claims (1)

NAPO K Y An analgesic agent having an anti-inflammatory, antiseptic and healing effect, characterized in that it contains as active ingredient a mixture of one or more benzo [beta] / phenanthridine alkaloids (i.e. chelerythrin, sanguinarine, chelirubin, chelilutin, sanguirubin) 0 001 to 2% by weight of the formulation and allantoin in an amount of from cyano to 5% by weight of the formulation in a physiologically acceptable vehicle. An analgesic composition according to feed 1, characterized in that the alkaloid is in the form of a pharmaceutically acceptable salt. The analgesic preparation of item 1, wherein the alkaloid is in a pharmaceutically acceptable base form. 4. An analgesic preparation according to claim 1, wherein the septim is 7. allantoin is in the form of a salt with a pharmaceutically acceptable metal. do not crawl pffluiOlc An analgesic composition according to claims 1-4, yyznačuj compounding ^ sejtím that besides the benzo / c / EI phenantridine alkaloids _of glycerol contains allantoin f2> dl (5 wt.% ,, j KYoVoT acesulfame-0.05 'in' .- and '' trirjy // -. wt. % <%, polidocanol ToYos-O 2 wt. %), ethanol ~ 15-15 <1 per; y ^{7 (} wt% 4, sorbic acid _of Π (5.0'2-0 / 07 wt%), J / ¹ with carboxymethylcellulose jTo7l 5 wt. flavorings and flavorings in citrate buffer of pH 4, optionally surfactants and abrasives and polishes #