RU2038076C1 - Local anesthetic ophthalmic remedy - Google Patents

Abstract

FIELD: medicine; pharmacology. SUBSTANCE: remedy has β-form of dicaine and methyl cellulose. The preparation causes intensive early coming anesthesia without side effects. EFFECT: high effectiveness of local anesthesia in eye, absence of side effects. 1 tbl

Description

 The invention relates to medicine, in particular to local anesthetics used in ophthalmology.

 Among local anesthetics, dicain is one of the most active, but also the most toxic. A decrease in the concentration of the drug in eye drops reduces side effects, however, it leads to a decrease in local anesthetic activity and the duration of anesthesia. To reduce the side effects and prolong the effect, pharmacopeia dicain is used in combination with polymer carriers in the form of eye films. However, the eye film upon administration to the patient causes a long uncontrolled anesthesia, which excludes the carrying out of instrumental manipulations on the eye. In this regard, in ophthalmic practice, 0.1% eye drops of pharmacopeia dicain are often used, the anesthetic activity of which is small.

 Known β-form of dicain, not inferior in pharmacological activity to pharmacopoeial dicain, which has a reduced side effect.

 The β-form of dicaine (n-butylaminobenzoic acid hydrochloride-2-dimethylaminoethyl ester) is a newly synthesized biologically active substance.

I_отн. d,

3 26,140 4 2,824 100 12,755 2 2,798 27 8,538 1 2,762 6 6,380 2 2,744 2 6,117 2 2,678 6 5,644 1 2,631 12 5,491 1 2,570 56 5,096 1 2,534 17 4,874 1 2,514 10 4,486 1 2,454 15 4,244 1 2,419 7 4,418 1 2,346 1 4,137 1 2,308 5 4,001 1 2,256 3 3,949 1 2,232 5 3,828 1 2,166 3 3,585 1 2,008 7 3,515 2 1,953 3 3,427 1 1,691 3 3,341 1 1,584 3 3,310 3 3,170 4 3,156 4 3,149 1 3,064 2 2,979 1 2,944 1 2,903
Ранее β-форма дикаина в качестве местно-анестезирующего средства в глазной практике не применялась.The β-form of dicaine is the smallest crystalline white powder, soluble in water and alcohol, practically insoluble in ether. In contrast to the well-known pharmacopeia dicain, the β-form is soluble in chloroform. An aqueous 1% solution has a pH value in the range of 4.5-6.0. A new crystalline modification of dicain (β-form) is characterized by one endothermic melting effect at 148.6 ± 0.3 ^о С and the following values of interplanar distances d and relative intensities of reflexes: I _rel. d

I _rel. d

3 26,140 4 2,824 100 12,755 2 2,798 27 8,538 1 2,762 6 6,380 2 2,744 2 6,117 2 2,678 6 5,644 1 2,631 12 5,491 1 2,570 56 5,096 1 2,534 17 4,874 1 2,514 10 4,486 1 2,454 15 4,244 1 2,419 7 4,418 1 2,346 1 4,137 1 2,308 5 4,001 1 2,256 3 3,949 1 2,232 5 3,828 1 2,166 3 3,585 1 2,008 7 3,515 2 1,953 3 3,427 1 1,691 3 3,341 1 1,584 3 3,310 3 3,170 4 3,156 4 3,149 1 3,064 2 2,979 1 2,944 1 2,903
Previously, the β-form of dicain as a local anesthetic was not used in eye practice.

 The purpose of the invention is the creation on the basis of a newly synthesized substance of a local anesthetic agent with high activity, adequate to the goals of ophthalmology, without causing side effects.

For this, a local anesthetic for the eyes for the first time was proposed, including the β-form of dicain, methyl cellulose and a pharmaceutical solvent in the following ratios of components, wt. β-form of dicain 0.05 Methylcellulose 0.1
Pharmaceutical solution
Repeater (deviations within ± 5% are possible) Up to 100.0.

 As the pharmaceutical solvent, any solvent used for the preparation of eye drops can be used.

 The essential features of the proposal should be considered the use of the β-form of dicain in the composition, as well as the selected quantitative ratios of the ingredients of the composition.

 The selected concentration of the β-form of dicain in the composition causes a sufficient anesthetic effect without complications. A further decrease in the concentration of the drug in the composition of the eye drops leads to a decrease in anesthetic activity.

 The choice of the concentration of methylcellulose is due to the fact that at this concentration the minimum time is achieved before anesthesia occurs with the optimal viscosity of the drug giving its best adhesion to the eyeball tissue. With a decrease in the concentration of methylcellulose, the time until the onset of anesthesia increases and the effect of adhesion of the drug to the eyeball tissue decreases.

 An increase in the concentration of methylcellulose does not lead to a further reduction in the time until the onset of anesthesia, but it worsens the quality of the drops.

 It should be noted that in comparison with the known local anesthetizing ophthalmic forms containing pharmacopoeial dicain and polymers, the content of the β-form of dicaine and methylcellulose in the proposed composition is reduced by 10 times while maintaining anesthetic activity. The proposed tool has a fairly high anesthetic activity, allowing for manipulation of the eyes, and does not give the complications inherent in pharmacopoeial dikain. At the same time, the combination of the β-form of dicaine and methylcellulose in the indicated ratios leads to an unexpected effect in the dynamics of the anesthetic effect, a much earlier onset of anesthesia with a sufficient duration (see table).

 The proposed local anesthetic is obtained as follows.

 1/2 volume of purified water is added to the calculated amount of methylcellulose and placed in a refrigerator for 10-12 hours to swell and dissolve, after which the solution is filtered. The required amount of the β-form of dicain is loaded into the container. A certain amount of sodium chloride is loaded into another container, 1/4 of the volume of water is added and mixed.

 After dissolving the substances, all solutions are drained, water is added to a predetermined volume and mixed.

The resulting solutions were poured into a dry sterile vials, sealed with sterile stoppers and sterilized by saturated steam under pressure at ¹²⁰ ° C for 8 min. Preparation is stored at a temperature not higher than 25 ^{° C} in a dark place. Shelf life 12 months.

 A local anesthetic for the eyes is a viscous liquid, when instilled into the eye, enveloping the eyeball and not flowing out from under the eyelid.

 A study of the local anesthetic activity of the proposed drug was carried out on chinchilla rabbits. As a comparison, we used a local anesthetic agent containing pharmacopeia dicain 0.05 g, methyl cellulose 0.1 g and isotonic solution 99.85 g (the preparation technology is similar to the preparation of the proposed tool); containing β-form of dicaine 0.05 g and an isotonic solution of 99.95 g

 Each of the prepared solutions was instilled in an equal amount of 0.06 ml into the rabbit’s eye, and the time until anesthesia and its duration were determined by touching the cornea of the animal’s eye (Rainier method). The results of experimental studies are presented in the table.

 The table shows that when using the proposed tool, the anesthetic effect occurs 3 times faster than when using the β-form of dicain without methyl cellulose. Pharmacopoeial dicain with methyl cellulose at the same concentrations does not have anesthetic effect.

 A clinical study of the proposed tool was conducted on 80 outpatients with glaucoma (Research Institute of Eye Diseases RAMS).

 Examination of patients included Maklakov tonometry, tonography and gonioscopy.

 In patients with glaucoma, on average 3-4 minutes after a single instillation of the proposed drug, maximum anesthesia was achieved for tonometry according to Maklakov with a weight of 10 g.

 The tests revealed the advantages of the proposed tool for clinical practice, the possibility of obtaining early, intensive anesthesia without complications with a single instillation of the drug. Anesthesia is adequate for performing ophthalmic manipulations such as measuring intraocular pressure, subconjunctival injection, infiltration anesthesia, etc.

 The invention is illustrated by example.

 PRI me R. To 0.1 g of methyl cellulose was added 50 ml of purified water and placed in a refrigerator for 10-12 hours to swell and dissolve. Next, the solution was filtered. 0.05 g of the β-form of dicain was loaded into the container. In another container, 0.9 g of sodium chloride, 25 ml of water were placed and mixed. After dissolving the substances, all solutions were poured, water was added to 100 ml and mixed.

The solution was poured into dry, sterile bottles were sealed with sterile closures, sterilized by saturated steam under pressure at ¹²⁰ ° C for 8 min. Agent was being kept at a temperature not higher than 25 ^C and protected from light.

 The resulting solution in an amount of 0.06 ml (2 drops of 0.03 ml) was instilled into the eye of a rabbit of a chinchilla breed weighing 3 kg and the time until anesthesia and its duration were determined by touching the cornea of the animal’s eye according to the Rainier method. The time of onset of anesthesia was 5 s, the duration was 11.5 minutes. Side effects on the cornea of the animal’s eye were not observed.

 Thus, the proposed new local anesthetic for the eyes has several advantages: in comparison with the known drugs, it causes, even with a single instillation of the drug, early anesthesia without side effects. The proposed tool will provide an opportunity to expand the arsenal of local anesthetics used in ophthalmology.

Claims (1)

 LOCAL ANESTHESIST FOR EYES, containing dicain and a pharmaceutically acceptable solvent, characterized in that it additionally contains methyl cellulose, and as dicain its β-form in the following ratios of components, wt. b-form of dicaine 0.05
Cellulose 0.1
Pharmaceutically acceptable solvent Up to 100