UA119260C2 - INJECTION GELPHOUS WATER COMPOSITION FOR LOCAL ANESTHESIA - Google Patents

Abstract

The invention relates to an injectable gel-like aqueous composition for local anesthesia containing anesthetic (eg lidocaine hydrochloride), water for injection, which further comprises sodium hyaluronate, in the following ratio of components: anesthetic (eg, hydrochloride) ) 0.2-0.4 sodium hyaluronate 0,018 gvod for injection up to 1 ml viscosity of the solution at 20 ° C5 MPa · s, pH = 5.

Description

The invention belongs to medicine, specifically to stomatology, and can be used when local anesthesia is necessary for dental treatment, surgical interventions, and long-term nerve blockades.

Today, the use of anesthetics for local anesthesia is known - lidocaine, articaine, mepivacaine, novocaine, prilocaine, bupivacaine and others.

To increase the duration of the anesthetic solution, it was proposed to add adrenaline to its composition (N. Vgaip, 1903). The presence of adrenaline in the local anesthetic solution improves the quality of anesthesia, but at the same time creates a number of relative and absolute contraindications for the use of such drugs. This is primarily due to the direct effect of adrenaline on the work of the cardiovascular system, which in some cases can be quite significant, especially if patients have associated diseases or conditions.

Another disadvantage of adrenaline is its influence on the therapeutic effect of a number of drugs that the patient can take, for example, digoxin, tricyclic antidepressants, MAO inhibitors, antiparkinsonian and antidiabetic drugs, beta-blockers, and so on. This creates another group of increased risk for the development of complications associated with pharmacological incompatibility of drugs.

The most likely way to solve the problems, we calculated the change in the consistency of the solution by adding a gelling agent to the local anesthetic solution. When considering the possible use of gelling agents, we determined a number of basic requirements - the least number of allergic and toxic reactions, the possibility of rapid metabolism without the formation of active metabolites, the absence of an irritating effect on body tissues, the possibility of storage and sterilization. In the search process, sodium hyaluronate - hyaluronic acid turned out to be the most promising. This substance is a non-sulfonated glycosaminoglycan, which is part of connective, epithelial and other tissues.

Hyaluronic acid is known to be used not only as an independent drug, but also as a means of transferring other medicinal substances in the tissue, as well as their controlled release. By changing the concentration of hyaluronic acid, it is possible to control the rate of its degradation or diffusion and, thus, the rate of drug delivery in the tissue.

Penetrating into tissues, hyaluronic acid is able to capture substances,

Z are covalently connected to it or simply included in its mesh structure.

An additional advantage of this substance for us was its wide and long-term use in many areas of medicine and cosmetology.

The source of hyaluronic acid is the drug Giaral Plus (NUAKAI RGOB5, certificate of state registration 711/12-300200000) - an immunobiological hyaluronic acid preparation, the active substance of which, sodium hyaluronate, is obtained by a biotechnological method from b5igeriosossi5 2gooeridetisi5. The drug and its analogues are widely used in ophthalmology for intraocular administration. The Hyaral plus syringe contains 0.85 ml of 15 95 hyaluronic acid solution, which corresponds to 0.12 g per 0.85 ml.

The invention is based on the task of improving the anesthetic solution for local anesthesia by introducing a gel-like agent into its composition, due to which the consistency of the solution changes, there is slower absorption in the tissues, a greater concentration of the anesthetic solution at the target points of anesthesia, its own viscosity, a higher pH, which will allow to ensure safe introduction of the solution and biodegradation in tissues without the formation of active metabolites, to achieve significant efficiency and safety and local anesthesia.

The problem is solved by the fact that an injectable gel-like aqueous composition for local anesthesia containing an anesthetic (for example, lidocaine hydrochloride), water for injections, which is distinguished by the fact that it additionally contains sodium hyaluronate in the following ratio of components: anesthetic (for example , lidocaine hydrochloride 0.2 g) 02-04 g sodium hyaluronate 0.018 g water for injections up to 1 ml solution viscosity at 207 5 mPa:s, pH-5.

Causal relationships:

Introduction of sodium hyaluronate - due to this, there is a slower absorption in the tissues, a higher concentration of the anesthetic solution at the target points of anesthesia, its own viscosity, a higher pH, which will allow to ensure the safe introduction of the solution and biodegradation in the tissues without the formation of active metabolites, to achieve significant efficiency and safety and local anesthesia.

The drug was prepared in aseptic conditions.

To obtain an anesthetic solution with a 2 95 concentration of lidocaine, 0.2 ml of a 10 95 solution of lidocaine hydrochloride was added to 0.85 ml of a 15 95 aqueous solution of hyaluronic acid.

In this way, we obtained 1.05 ml of a solution containing 20 mg of lidocaine, which corresponds to 2 95.

Next, 8 ml of 2 95% lidocaine hydrochloride solution was added. As a result, we got a solution in which 1 ml contained 18 mg of pure lidocaine, which corresponds to 1.8 95. 0.2 ml of 10 95 lidocaine hydrochloride solution was added to the solution.

Thus, we received 10.2 ml of anesthetic solution, which contains 12 mg of hyaluronic acid and 200 mg of lidocaine hydrochloride, which corresponds to 1.96 95.

The composition of the anesthetic solution. 1 ml of the finished anesthetic solution contains lidocaine hydrochloride 0.2 g, sodium hyaluronate 0.018 g.

The viscosity of the solution at 20 "C-5 mPa: z, рН-5.

Clinical studies.

The first anesthesia was performed by the author on himself and research assistants. It was noted that the first signs of anesthesia in the form of numbness of the tongue and lips on the corresponding side developed almost immediately after the injection, anesthesia of the teeth was noted after 3-5 minutes, the duration of anesthesia was 150-210 minutes. No complications were noted. This provided the basis for conducting clinical research on volunteers.

32 volunteers (group 1) took part in the research, who gave written informed consent to participate in the clinical trial, aged from 22 to 55 years, who are physically healthy and do not have a severe allergic history. Skin tests were performed before local anesthesia. Local anesthesia of the teeth on the lower jaw was performed using the retromolar technique.

A total of 32 retromolar anesthesias were performed: 14 - right-sided and 18 - left-sided. 1 ml of anesthetic solution was administered to 14 patients, 1.3 ml to 10 patients; 7 patients - 1.5 ml and one - 0.6 ml. The comparison group (group 2) consisted of 31 patients who underwent dental treatment using retromolar anesthesia 4 95 with a solution of articaine hydrochloride with adrenaline 1:100000. The effectiveness of anesthesia was evaluated on the basis of the data of electroodontodiagnostics (Ry!rtTezieg - R), subjective sensations and objective signs.

The dynamics of clinical manifestations of anesthesia with our proposed solution is presented in the table.

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Table

Dynamics and effectiveness of anesthesia with the proposed solution

Keel-! Numbness EOD, ma! ROD, | OD, and Number of g. g. o. g. MA MA bone Numbness | Numbness schokil/shchichni| Numbness to the anesthetized patient's tongue, lips, surface of the teeth, anesthetized rez | through ents of solution, ml of gums for 15 minutes minutes 3 42 seconds from 34 sec. from 132 sec. -i3 52 sec. 14 1 ml - 119 min |-185 min |102 min -124 min | 6.5:0.48 100 96 100 96 64 96 100 96 3 40 sec.|from 27 sec. 3 121 sec -| from 47 sec - 10 13 ml -141 min |-202 min |110 min 134 min 6.5:0.76 100 96 100 96 66 to 100 96 3 32 sec -| with 16 sec-| with 116 sec -| from 45 sec - 7 1.7 ml 181 min 226 min 129 min 159 min 6.43520.70 100 Fo 100 96 74 90 100 96 from 250 sec

KINSSYA with aNee NSNNNNIEZZ 55 min 70 min partially

As can be seen from the research results, the intensity and duration of anesthesia depends on the amount of injected anesthetic gel. In all cases, when 1 ml to 1.5 ml was injected, deep and prolonged anesthesia was observed. In addition to our assessment, this was confirmed by painless treatment of teeth on the side of anesthesia in five people (1 deep caries, C medium caries, 1 depulpation of 36 teeth according to orthopedic evidence, 1 extraction of 48 teeth). In one case, during the treatment of deep caries, moderate pain in the gums was noted during the installation of the matrix, which we attributed to the absence of buccal nerve blockade, since no pain was noted during the preparation of the carious cavity.

Also, among the volunteers who were injected with 1.5 ml of the anesthetic solution, in several cases, the development of anesthesia in the ear region was observed, which they described as congestion during a rapid change in external pressure, which is observed when flying on an airplane or diving. These sensations began at the peak of anesthesia and passed after 20-30 minutes. These sensations, in our opinion, are related to the spread of the anesthetic solution in the interpterygoid anatomical space and the involvement of the ototemporal nerve, which in turn departs from the third branch of the trigeminal nerve and provides sensitivity to the corresponding anatomical area - part of the external ear and auditory canal.

The analysis of the obtained data gave us reason to believe that 1-1.3 ml of anesthetic solution is enough to achieve adequate anesthesia, and the introduction of 1.5 ml can cause excessive anesthesia, which is not clinically necessary. At the same time, the introduction of anesthetic solution in the amount of less than 1 ml, in particular 0.6 ml, did not provide adequate anesthesia, which met our expectations.

For a comparative assessment of the effectiveness of anesthesia (except for the case of administration of 0.6 ml), a similar assessment was carried out for a control group of 31 patients, who for future treatment were subjected to conductor anesthesia with 1.7 ml of 4 95 articaine hydrochloride solution with an adrenaline content of 1:100000 (ope) . There were no significant differences in the effectiveness of anesthesia in the main group and the comparison group. This testifies to the clinical effectiveness of our proposed anesthetic solution, which is not inferior to the effectiveness of widely used anesthetics in dentistry today.

It should be taken into account that the average dose of 4 95 solution of articaine with adrenaline 1:100000 in the Mo 2 group was 1.7 ml, and in the Mo 1 group the average amount of anesthetic gel administered by us was 12 ml, which, when comparing the clinical results, allows us assume a higher efficiency of the drug developed by us. It should also be noted the absence of any immediate complications or adverse reactions in patients, as well as in the subsequent 4-month follow-up. Patients of the main group noted significantly less pain during the injection compared to patients of the second group.

The obtained data unequivocally indicate: - the possibility of increasing the clinical effectiveness and time of action of the anesthetic gel by

From increasing the viscosity of the solution; - the possibility of using a significantly smaller amount of local anesthetic, which, together with a lower rate of absorption, should lead to a decrease in the systemic toxicity of the drug in comparison with the local anesthetics used today.

Claims (1)

FORMULATION OF THE INVENTION An injectable gel-like aqueous composition for local anesthesia containing an anesthetic (for example, lidocaine hydrochloride), water for injection, which is distinguished by the fact that it additionally contains sodium hyaluronate, in the following ratio of components: anesthetic (for example, lidocaine hydrochloride 02 g) 0.2-04 g sodium hyaluronate 0.018 g water for injections up to 1 ml solution viscosity at 207 5 mPa:s, pH:-5. 00 Computer keyboardG. Payalnikovo (00000000 Ministry of Economic Development and Trade of Ukraine, str. M. Hrushevsky, 12/2, m. Kyiv, 01008, Ukraine SE "Ukrainian Institute of Industrial Property", str. Glazunova, 1, m. Kyiv - 42, 01601