Lidocaine poyacrylate eliciting prolonged topical anesthetic effect

FIELD: organic chemistry, polymers, medicine.

SUBSTANCE: invention describes lidocaine polyacrylate eliciting the prolonged topical anesthetic effect of the general formula: wherein n means (number of links) = 50-70; means a link of polyacrylic acid; means N,N-diethylaminoacetic acid 2,4-dimethylanilide.

EFFECT: valuable medicinal properties of compound.

1 cl, 2 tbl, 1 ex

 

The present invention relates to medicine, in particular to pharmacology, namely to a new derivative of lidocaine with prolonged local anesthetic action in terminal (surface) anesthesia.

The most effective drugs used as local anesthetics under terminal anesthesia, are dikain, pyromation, trimekain, lidocaine and benzocaine.

Dikain widely known as an anaesthetic for terminal anesthesia. Dikain is derived butylaminoethyl acid (2-dimethylaminoethanol ether-n-butylaminoethyl acid hydrochloride). On analgesic activity it surpasses cocaine 2-3 times 10-12 times novocaine, however, like cocaine has a high toxicity (Mashkovsky PPM, medicine, 15th ed., Rev. and more., M.: Medicine, 1998, s-382). In addition, at concentrations above 1% dikain irritating conjuctiva and desquamation of the epithelium of the cornea, as well as side effects (tachycardia, convulsions, loss of consciousness, paralysis of the respiratory center), impeding its widespread use (Konovaltsev OF, Field, for EXAMPLE, by the Action of aqueous solutions dikaina and pyrromethene on the epithelium of the mucous membrane of the oral cavity. Dentistry, 1990, t, No. 3, p.39-41).

For terminal anesthesia also use the form trimekain (2,4,6-trimethylaniline Diethylaminoethanol acid hydrochloride).(Mashkovsky PPM, Medicines, 15th ed., Rev. and more., M.: Medicine, 1998), but in many cases he does not have sufficient depth and duration of analgesic action is also contraindicated in diseases of the liver and kidneys. (Belikov VG Synthetic and natural medicines, M.: Medicine, 1993).

Well-known local anesthetic substance used in terminal anesthesia is promicin(2’,4’,6’-trimethylsilyl-1-butyl-pyrrolidinecarbonyl-2 acid hydrochloride). Pyromation used as in solutions and ointments (Mashkovsky PPM, medicine, 15th ed., Rev. and more., M.: Medicine, 1998). However, pyromation, like novocaine, causes side effects such as weakness, dizziness, hypotension, convulsions, fainting, shock, dermatitis (Wegelius. Synthetic and natural medicines, 1993). In addition, pyromation causes a burning sensation of the eye that prevents the wide use of it in ophthalmology (Pryanishnikova N.T. Pharmacology and clinical use of pyrromethene. In kN. The success in creating new medicines. - M.: Publishing house of Medicine 1973 s.255-262).

The closest the structure of matter, accepted us as a prototype, is lidocaine hydrochloride, which finds application in terminal, infil the traditional, conductor and methods spinal anesthesia (Levchenkov A.I., Kostyuchenko A.L., Rostomashvili IT and other Caudal epidural anesthesia during operations on the lower extremities in traumatology and orthopedics. Anestesiol. and Reanimator., 1992, No. 5-6, p.15-17; Mashkovsky PPM, medicine, 15th ed., Rev. and more., - M.:Medicine, 1998). Lidocaine hydrochloride, which is the hydrochloride of 2,4-dimethylaniline N,N-Diethylaminoethanol acid has the following structure:

However, in terms of surface anesthesia lidocaine does not always cause analgesic effect of sufficient depth and duration, which limits its wide application (Apparence-Yaroshevsky, Laverkin, Won. Kuban. the scientific. the honey. news. 2002. No. 4. P.12-17; Mashkovsky PPM, medicine, 15th ed., Rev. and more., - M.: Medicine, 1998).

The task was to synthesize a substance possessing prolonged analgesic effect when the terminal anesthesia and less toxicity than many known anesthetics.

To solve the technical problem is proposed lidocaine polyacrylate with a molecular mass of 14000-20000, manifesting in a terminal anesthesia longer anesthetic effect than used now lidocaine hydrochloride. The resulting material has the following structure:

where n (number of links) = 50-70.

The technical result is achieved by using the obtained aqueous solution of polyacrylate lidocaine concentration of the active substance of 1-2%.

The basis of lidocaine produced by the action of excess of alkali to the solution of lidocaine hydrochloride. Precipitated white crystalline precipitate is filtered off and dried to constant weight.

The polyacrylic acid solution is obtained by heating a solution of acrylic acid in distilled water in the presence of initiator is hydrogen peroxide.

To the resulting basis lidocaine add the estimated amount of the polyacrylic acid. The resulting mixture is heated on a water bath under stirring.

Example. The basis of lidocaine besieged by the action of excess 10% sodium hydroxide 10% aqueous solution of the hydrochloride lidocaine, which was prepared by dissolving 5 g of the hydrochloride lidocaine (0,0185 mol) in 45 ml of distilled water. Precipitated white crystalline precipitate the base of lidocaine was filtered with suction on a water-jet pump and washed with 100 ml of distilled water. The resulting crystalline substance representing dehydrate lidocaine, dried for 2 days in a desiccator over KOH.

The polyacrylic acid solution was obtained put the m heating 12 g (0,167 mol) of acrylic acid, dissolved in 250 ml of distilled water for 20 hours at a temperature of 80°C. To the mixture was added hydrogen peroxide in 0.1 ml (30%) every 3 hours to achieve a relative solution viscosity of 2.38-2,42.

To obtain a 1% (pH 7.0) and 2% (pH 6.6) were received as follows: 0,00037; 0,00074 mol Foundation of lidocaine (or 0.1; 0.2 g) was added to 9.3; 8,6 ml of distilled water and was added 0,00037; 0,00074 mol of 4.5% polyacrylic acid (or 0.6; 1.2 ml). The resulting mixture was heated to 75-85°With water bath for 3 hours with stirring. The obtained solutions polyacrylate lidocaine left at room temperature for 2 hours to obtain a clear solution.

From these solutions after evaporation of water at 75 to 85°and 15 mm Hg and further drying at 80°1 mm Hg samples polyacrylate lidocaine in the form of a colorless amorphous substance, soluble in water. Decomposition temperature 190-195°C.

Found (%): 60.36; N, 8.53; N, 7.82.

Calculated (%): (C14H27N2With 61.96; H 10.03: N 10.32.

Received polyacrylate lidocaine formula:

where n=65 calculated by known methods (water-Soluble polymers, Africalink, Hijioka, Leningrad, Khimiya, 1979, pp. 80) from the obtained values of the characteristic viscosity [η]=0,113.

Acute toxicity PAL and lidocaine (1% solution) IP who was ladowali in mice after subcutaneous administration. Each dose was tested on 5 animals were observed for 48 hours. Determined the median lethal dose (LD50) and its confidence intervals (Arzamastsev E.V., gouskova T.A., Berezovskaya IV and other // Guidance on experimental (preclinical) study of new pharmacological substances. M., 2000. P.18-24; Prozorovsky V.B. have been / Farmakol. and toxicol. 1962. V.25, No. 1. S-119.)

Table 1
Comparative activity of polyacrylate lidocaine and lidocaine under surface anesthesia in experiments on the cornea of rabbits
SubstanceLocal anesthetic activityAcute toxicity1Therapeutic index
 EC50, %relativeLD50mg/kgrelativeabsoluterelative
Polyacrylate lidocaine0.89 (0.73-1.10, k=24)5.67352 (339.0-365.6, k=24)0.83395.56.82
lidocaineof 5.05 (3.87-6.57, k=241292 (286.8-299.1, k=40)158.01
Note1.
For mice after subcutaneous administration. In parentheses are confidence intervals at p=0.05.

We offer the drug at mestoobitraniya activity (EC50superior to lidocaine in 5,67 times, and therapeutic index in 6,82 times (table 1). The toxicity study showed that the polyacrylate lidocaine 1.2 times less toxic than lidocaine (table 1).

In addition, the studied surface anaesthesia of the mucous membrane of the pharynx and trachea anesthetized (teminal sodium, 30 mg/kg intraperitoneally) cats (Ignatov UD, Chernyakova I., Vasiliev, Y. etc. // Guidance on experimental (preclinical) study of new pharmacological substances. M., 2000. S-192.) see table 2.

Table 2
Comparative activity of polyacrylate lidocaine and lidocaine under surface anesthesia in experiments on the mucous membrane of the pharynx and trachea cats (M±M, k=5)
SubstanceConcentration %Local anesthetic activity
  The time of onset, minDuration, min
    Throattrachea
Polyacrylate    
lidocaine11.9±0.318.0±1.1*24.0±1.1*
Lidocaine11.7±0.24.2±0.46.0±0.4
Polyacrylate    
lidocaine21.7±0.229.6±2.1*36.0±3.2*
Lidocaine21.6±0.36.5±0.68.2±0.9
Note2.
p<0.05 compared with lidocaine.

Studies have shown that the polyacrylate lidocaine 1% and 2% causes more long-term loss of sensitivity (4.3 and 4 times, respectively), exceeding thus the lidocaine. On anestesiologia effect on the mucous membranes of the pharynx and trachea polyacrylate 2% superior to lidocaine in 4.6 and 4.4 times, respectively

Polyacrylate lidocaine with prolonged local anesthetic action, of General formula:

where n (number of links) = 50-70,

- link poliakrilovaya acid,

- 2,4-dimethylaniline N,N-diethylamino-acetic acid.



 

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