CS261526B1 - A method of incorporating pentacaine hydrochloride into an antacid suspension - Google Patents

Abstract

The solution concerns a technological method of processing pentacaine hydrochloride into an antacid suspension. The drug is dissolved in ethanol with a concentration of 50 to 70% by weight and this solution is added to the suspension in the reaction phase of aluminum, magnesium and calcium compounds, when the pH of the reaction mixture ranges from 9.0 to 13.0. The advantage of this processing method is the fact that the drug substance is present in the system in the form of both salt and base, which positively affects its bioavailability. Therefore, pentacaine hydrochloride processed by this method shows better release characteristics, is more perfectly dispersed and the antacid suspension has more advantageous rheological properties in comparison with the suspension to which the drug was added in the form of a powder, or an aqueous solution containing a surfactant, or with a suspension to which the drug was added at the end. The method can be used in pharmacy for the preparation of antacid suspension containing pentacaine hydrochloride.

Description

261526 3

The present invention relates to a method of incorporating penta-kain hydrochloride hydrochloride anesthetic into an antacid suspension with a marked rate of liberation from the formulation.

Antacids play an important role in the therapy of those disease states where the presence of acidic gastric secretions is an important component of the pathogenesis of the disease. Therefore, the purpose of therapy is to suppress aggressive factors or to increase the protective ability of the mucosal barrier of the gastrointestinal tract. Since the nature of the protective mechanisms is not well known, the focus of ulcer disease treatment is to suppress gastric acidity and reduce gastric secretion (Hor-et al. E. Farm. Horizon 52, 275 (1983)). Decreasing the pH of gastric contents is used! antacids (Kišoň Š., Halko J., Lehký M.: Adverse Effects of Drugs. Bratislava 1977, p. 568), preferred are the types of adsorption type (Gómez Puch LM, Rios Solans G., Munoz Fernandez JR: Arzneim.Forsch 34 (11), 378 (1984)). In the treatment of ulcer disease, anesthetics administered simultaneously with santacides are applied locally. According to Babulová et al. (Babu-1'ová A. et al .: Czechoslovak Physiol. 31, 123/1982) The reason for their use is to push the pain and anesthetizing effects of the gastrointestinal tract and their spasmo-lytic effects. and antihistamine. This eiect also assumes pentacain hydrochloride, originally synthesized by Beneš et al. (Beneš L, Borovanský A., Kopáčová L.:Arzneim. Forsch. 19, 1902/1969 /) as a local anesthetic but even mucosa-protective effect. It results from the results of the Babulová et al. (BabuTova A. aspol .: Ceskoslov. Fysiol. 31, 123 (1982)) and Tomcikova et al. (Tomcikova O., et al., Pharmazie 40, 48 (1985)), in which its significant protective effect was found in the gastric mucosa of experimental animals.

Pentacain hydrochloride is 3-pentyloxyphenylcarbamic acid trans-2- (1-pyrrolidinyl) cyclohexyl ester, summarizing C22H34N2O3. It is stable in an acidic environment, where it is not destroyed, and even if its locally anesthetic activity increases. Since it is a newly synthesized formulation, its use in antacid suspension is described and hence the non-technological issues of its processing into this dosage form have not been addressed.

Liquid, respectively. gel formulations are preferred for application and antioxidant action. The total surface area of the suspended particles in the suspensions is greater than in solid formulations, for example in tablets, therefore, as stated (Brouwers J. R. B.J., Tijtgat G. N.:Pharm. Weekbl. 111, 1144 (1976)), are more effective. Moreover, liquid antacid preparations also have a protective effect on the gastric mucosa, in addition to their own effect, because they form a mechanical protective layer on its surface. This indirectly supports the antacid effect (Mertl L., TechnikP .: Practitioner 60, 521 (1980)). The Swiss patent (Switz. Pat. CH 643 144, May 30, 1984) deals with the antacid preparation for the treatment of gastro-duodenal ulcers and other gastrointestinal disorders. The formulation in solid or gel form contains, in addition to the substances with apitacid activity, lignocaine aoxomemazine. It is predominantly concerned with the pharmacological and clinical evaluation of the preparation for anti-ulcerative efficacy by local anesthetics. However, it does not solve the problem of preparation technology and does not deal with the way the drug is processed into the preparation. At the same time, the process of incorporating the local anesthetic can significantly influence its liberation from the formulation and thus the rate of onset of action, or the duration of its duration.

It is an object of the present invention to provide a process for the administration of pentacaine hydrochloride to a dantacid suspension. The essence of the solution is that 1.0 to 10.0 g of 5.0 to 20 wt. % penta-cain hydrochloride solution in 50-70 wt. ethanol, 50.0 to 90.0 g of the suspension to be prepared in the reaction phase of aluminum, magnesium calcium compounds, wherein the pH of the reaction mixture is between 9.0 and 13.0. The advantage of this method of processing, the fact that the drug substance is found in the salt and base system. This affects positively the biological availability of the drug through the biological membranes in the non-ionized form. The drug substance in the form of a base acts as a foliar dose which starts to work immediately. The presence of the drug in the base form thus accelerates the onset of its effect.

The suitability of the process for the preparation of pentacaine hydrochloride has been judged by the rapid liberation of the drug from the suspensions at pH 2.0, which gives rise to pathological acidity and from a suspension of pH 4.5 corresponding to physiological salinity in an in vitro experiment using semiperol. a variable membrane (used as an artificial bead).

It was found that for 180 minutes, the suspension thus prepared was released at pH 2.0 = 7.2 per cent and at pH 4.5 = 14.25 per cent of pentacaine hydrochloride at a release rate expressed as k ( h_1) = 0.025, resp. 0.055. The results of liberation were evaluated by a mathematical-statistical method which confirmed the uniformity of distribution of the incorporated drug substance. Further, the antacid activity, neutralizing potency and rheological characteristics of the suspensions prepared according to this invention are further evaluated. 1 When monitoring the antacid efficacy by the in vitro dynamic method of monitoring the pH of the antacid suspension mixture with artificial gastric juice after

Claims (1)

251326 5 hydrochloric acid (0.2 mol / l) concentration, the pH: at 10 ml of suspension was reached in 37 to 91 seconds, and in 120 minutes the pH did not exceed the physiological optima (pH = 5.0); The neutralization potency expressed as milliliters of 0.1 mol / l hydrochloric acid to neutralize 1 g of the suspension was 12.19 ml. the slurry is fasted (less than 2 minutes), its effect is prolonged (lasts more than 60 minutes) and the reaction mixture is not raised to the alkaline range, which may result in a refractory poor increase in gastric acid secretion. By altering the proposed process for incorporating penacain hydrochloride, worse characteristics of pelleting are achieved and the theological properties of suspensions have also been altered. in the form of a powder in the first phase of the preparation of the suspension, the released amount of drug in 180 minutes and 4.5 decreased to 11.1% and at pH 2.0 to 5.8%. A disadvantage of treating hydrochloridupentacaine with the suspension is also the use of a detergent, for example polysorbate 80 (TweenR80). The surfactant was used to uniformly disperse the lipophilic base of the drug substance in the hydrophilic heterogeneous system. It has been shown that when 0.5% by weight is used. the polysorbate 80 aqueous solution released in 180 minutes at pH 4.5 to 9.2% and at pH 2.0 to 4.4%, which could be justified by the formation of mixed milligrams. The surfactant addition also caused partial deflocculation of the system and reduced kinetic stability. Liberation of pentacaine hydrochloride is also reduced if the drug is added to the finished suspension. The results showed that when pentacain hydrochloride is incorporated as a spirit solution, 9.8% of the drug is released at pH 4.5 and 5.0% at pH 2.0 for 180 minutes. Example 1 To a mixture formed by the reaction between 13.1 g of aluminum sulphate, 4.2 g of magnesium sulphate, 4.3 g of calcium oxide and 53.5 g of water at a pH of 9.0 to 13.0 is added a solution of hydrocyanic acid. pentacain chloride prepared so that 0.2 g of drug substance is dissolved in 2.0 g of 60% w / w. ethanol. 7.5 g of sorbitol, 7.5 g of glycerin and finally 0.1 g of xanthene gum and 0.1 g of sodium cyclamate are then added. Example 2 5.1 g of calcium oxide, 13.3 g of aluminum sulfate and 1.6 g of magnesium oxide are mixed with 50 g of water. When this mixture has a pH of 9.0 to 13.0, a solution of hydrochloridupentacaine prepared such that 0.2 g of the drug is dissolved in 2.0 g of 60% ethanol is incorporated. Then 7.5 g of propylene glycol, 7.5 g of sorbitol, 0.1 g of xanthene guan and 0.1 g of sodium cyclamate are added. SUBSTITUTE The method of incorporating penapain hydrochloride into an antacid suspension, characterized in that 1.0 to 10.0 g of 5.0 to 20.0% by weight are present. % of pentacain hydrochloride solution in 50-70% by weight. 50.0 to 90.0 g of the suspension prepared in the reaction of aluminum, magnesium and calcium compounds are added to the invention, where the pH of the reaction mixture ranges from 9.0 to 13.0.