RU2184532C2 - Agent for topical antirheumatic therapy - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention proposes the following composition comprising dimethylsulfoxide, lithium or sodium hydroxybutyrate, topical anesthetic, antihistaminic preparation, gelatin and water. Invention provides rapid analgetic effect. Topical anesthetics have a property to inhibit activity of phospholipases and therefore they show a favorable effect on process of free radical oxidation of lipids that ensures to prevent partially possible allergic responses and potentates analgetic and anti-inflammatory effects of agent proposed. EFFECT: improved properties, enhanced efficiency of agent. 2 ex

Description

 The invention relates to medicine, namely to rheumatology, in particular to expanding the spectrum of local antirheumatic therapy based on a pathogenetic approach to the treatment of inflammation of articular and periarticular tissues.

 The relief of synovitis and periarthritis in arthrological diseases is relevant not only from the tactical point of view (reduction of pain, stiffness in the affected joints), but it is also strategically important, since even subclinical continuously recurring inflammation accelerates the progression of the degenerative process and ultimately leads to a significant limitation of the functional joint abilities.

Currently, local anti-inflammatory therapy agents are known: ointments, lipiments and gels containing a non-steroidal anti-inflammatory drug as an active active ingredient. In the various compositions, both hydrophilic and hydrophobic agents are contained as bases and carriers: polyethylene glycols, propylene glycols, polyethylene oxides, cellulose ethers, lanolin, petroleum jelly. Meanwhile, the effect of the ointment base is not indifferent to the body. Thus, the toxic effect of an ointment based on sodium carboxymethyl cellulose has been proved and the use of collagen for the preparation of an ointment with a local anesthetic substance has been proposed (AS USSR 833241, class A 61 K 9/06). However, the preparation technology of this ointment base requires grinding of collagen in a ball mill while cooling with liquid nitrogen to -150-190 ^o C, which requires special equipment.

 Regardless of the underlying cause of the inflammation, a major role in maintaining it is given to disturbances in microcirculation and hypoxia of the synovial environment and periarticular structures. Metabolic changes associated with hypoxia include a decrease in the rate of electron transport in the respiratory chain, dissociation of oxidation and phosphorylation, a decrease in the pH of the tissue medium, increased free radical oxidation, and damage to biological membranes. In this regard, it is rational to use in local therapy not only steroidal and non-steroidal anti-inflammatory drugs, but also antihypoxants and antioxidants.

 Among the substances widely used in local antirheumatic therapy, dimethyl sulfoxide has antioxidant activity (Bilenko MV, Ischemic and reperfusion damage to organs, M., 1989, p.305).

 It is also known to use dimethyl sulfoxide in agents for local therapy, not only as substances with anti-inflammatory and analgesic activity, but also as an agent that improves the penetration of other drugs into tissues (AS USSR 1196001, RF patents 2014070, 2027432, class A 61 K 9/06) .

 The use of dimethyl sulfoxide is based on the achievement of anti-inflammatory and chondroprotective effects in topical agents (RF patents 2021811, 2085194, class A 61 K 31/73). These products contain chondroitin sulfate or glycosaminoglycan polysulfate, the penetration of which is transdermally directly to the periarticular and synovial tissues due to dimethyl sulfoxide. The lanolin-vaseline base indicated in these products is an inert substance with respect to articular tissues, and the introduction of products that improve cartilage metabolism makes the ointment significantly more expensive.

 The inclusion of dimexide in compositions for balneological and phytotherapy is also known (application for the invention of the Russian Federation 96108739/14). Mostly the mineral composition of this agent does not allow its use during the period of inflammation of the articular and periarticular tissues, and the low content of dimethyl sulfoxide gives the latter only the role of a substance that promotes better penetration of bischofite minerals into the tissues.

 Closest to the proposed solution and therefore selected as a prototype is the gel according to the patent of the Russian Federation 2102980, class A 61 K 9/06, containing (in wt.%): Dimethyl sulfoxide (20-70), gelling component (1-5), glycerin (10-20), taurine (0.5-4.0), water (rest). To obtain the gels of this patent, various gelling agents are used - cellulose derivatives, gelatin, starch, polyvinylpyrrolidone, polyethylene glycols.

 The disadvantage of the prototype can be noted that the gel-forming component is assigned only a passive role, as in all previous gels, only the anti-inflammatory aspect is chosen as the goal of treatment.

 The goal to which the claimed invention is directed is to achieve an increase in the effect of local antirheumatic therapy due to antihypoxic, antioxidant and anesthetic components, as well as to prolong the duration of maintaining a satisfactory joint condition by improving the physicochemical properties of the connective tissue structures of the synovial environment .

 Our proposed tool for local anti-rheumatic therapy allows to achieve local anti-inflammatory, analgesic, antioxidant and antihypoxic effects while improving the structure of connective tissue formations of the articular and periarticular regions. The achievement of these effects is provided by the following composition (in wt.%): Dimethyl sulfoxide (40-50), lithium or sodium oxybutyrate (0.2-0.4), local anesthetic (0.1-0.05), antihistamine (0 , 05-0.1), gelatin (3-3.5), water (the rest).

 The novelty of the proposed solution lies in the fact that, firstly, the administration of hydroxybutyrates makes it possible to provide an antihypoxic and antioxidant effect. With the introduction of lithium oxybutyrate, an additional positive effect is achieved on the metabolic processes in the affected joint due to lithium ions due to its ability to form soluble salts of uric acid, which is important for patients with impaired purine metabolism. The selected concentration of oxybutyrate 0.2-0.4 wt. % is sufficient to achieve antihypoxic and antioxidant effects, with a decrease in the concentration of these effects is not achieved. A further increase in the concentration of drugs does not enhance the antioxidant and antihypoxic effects, and a significant increase in the concentration of oxybutyrates can lead to the development of a systemic manifestation in the form of inhibition, drowsiness. In the case of the use of lithium oxybutyrate with increasing concentration, there is a likelihood of a toxic effect.

 Secondly, the use of gelatin has a twofold purpose - as an acceptable non-toxic gelling agent and as a substance that improves the physicochemical state of connective tissue formations in the area of affected joints, since gelatin is a product of incomplete hydrolysis of the main structural protein of connective tissue - collagen. The use of gelatin is available in all conditions and does not require special technological costs. The amount of gelatin in the indicated concentrations of 3-3.5 wt.% Is sufficient for gel formation of properties that are optimal in consistency, with an increase in the concentration, the drug becomes inconvenient to use due to the excessive density of the colloid, with a lower concentration, the amount of collagen hydrolyzate entering the connective tissue formations decreases.

 Thirdly, the presence of a local anesthetic in this composition provides a quick analgesic effect, in addition, local anesthetics have the property of phospholipase inhibitors, due to which they favorably affect the processes of free radical lipid oxidation. The concentration of the anesthetic was chosen taking into account the analgesic effect quickly felt by the patient after a short period of time after applying the gel to the skin. Smaller concentrations require a longer time to reduce pain, therefore, the analgesic effect occurs already from exposure to dimethyl sulfoxide. An increase in concentration does not lead to an increase in the analgesic effect.

 Fourth, the introduction of an antihistamine into the composition allows you to partially prevent possible allergic reactions to dimethyl sulfoxide and other components of the gel, and also potentiates the analgesic and anti-inflammatory effects of the proposed drug.

 The novelty of the proposed tool testifies to the creative nature of the solution, that is, it indicates that the proposed solution meets the criterion of "non-obviousness".

 Example 1. Patient P., 47 years old.

 Diagnosis: Bilateral gonarthrosis, x-ray stage 2, reactive synovitis of the right knee joint, Federal Tax Service 2 tbsp.

 Concomitant: Obesity 2 degrees.

 Pain in the knee joints of the mechanical rhythm was noted for 2 years before going to the doctor. Pain at rest in the right knee joint, swelling of the joint appeared for the first time in April 1998, and therefore turned to a rheumatologist. When examining the knee joints, a slightly pronounced valgus deformity, a moderate configuration of the right knee joint was determined. Palpation was determined pain in the projection of the joint space and lower medial enthesis. The amplitude of mobility of the right knee joint was limited to 20 degrees due to pain, the circumference of the right knee joint was 44 cm. The left knee joint without signs of inflammation, painless on palpation, the amplitude of movements in full, its circumference is 42 cm.

 Ultrasonoarthrography revealed the presence of articular cartilage irregularities in both knee joints with a length of 9 mm on the right and 10 mm on the left, the thickness of the articular cartilage was not reduced, the presence of an effusion of 15 ml was determined in the right knee joint.

 A remote computer thermography of the legs was carried out, a diffuse hyperthermia zone was revealed in the projection of the right knee joint with an area of 420 ke, the average weighted temperature in this zone was 30.7 degrees.

 On radiographs of the knee joints in two projections, a narrowing of the joint spaces in the medial sections, subchondral osteosclerosis, and smoothness of the intercondylar elevation are determined.

 The gel was prescribed as follows: demixide (40 wt.%), Lithium oxybutyrate (0.4 wt.%), Diphenhydramine (0.05 wt.%), Novocaine (0.08 wt.%), Distilled water (rest) . Applications were performed 2 times a day.

 After 2 weeks during the examination, a complete restoration of the range of motion in the right knee joint was noted, there was no difference in the circumferences of the knee joints, pain on palpation of the periarticular points, a slight pain on palpation of the joint gap remained. During ultrasound examination of the knee joints, the amount of fluid in the cavity of the right knee joint is 2 ml, the left - 1 ml. Thermograms show a significant decrease in the area and intensity of hyperthermia in the region of the right knee joint.

 During the follow-up period of the patient (2 years), synovitis of the right knee joint did not recur. The patient continues to regularly use the gel as necessary (usually in the evening after significant physical exertion). The use of intra-articular administration of glucocorticosteroids in this patient has not been resorted to even once.

 Example 2. Patient K., 56 years old.

 Diagnosis: Polyosteoarthrosis, nodular form, slowly progressive course, X-ray stage 3, recurrent synovitis of both knee joints, multiple periarthritis of both knee joints, Federal Tax Service 2 tbsp.

 Concomitant: Stage 2 hypertension, beyond worsening.

 He suffers from osteoarthritis for more than 5 years, in connection with the often recurring synovitis, 6 injections of Kenalog into the knee joints (4 in the right and 2 in the left) were performed during the year before applying to the Department of Hospital Therapy of YAGMA. The effect of intra-articular introduction of kenalog was short-term, the phenomena of periarthritis of the knee joints persisted. In January 1999, a gel of the following composition was prescribed for long-term systematic use in the form of applications: dimexide 45 wt.%, Gelatin 3.5 wt.%, Lidocaine 0.1 wt. %, lithium oxybutyrate 0.2 wt.%, diphenhydramine 0.05 wt.%, distilled water (the rest). During a follow-up examination in April 1999, the patient noted the absence of episodes of recurrence of synovitis of the knee joints, facilitating the execution of active movements, and reducing joint stiffness. Objectively fixed stabilization of parameters at the level of discharge from the hospital. In November 1999, after considerable physical exertion, the patient noted an increase in the volume of the right knee joint, the appearance of pains in it at rest, and therefore was hospitalized. In the hospital, one injection of Kenalog into the right knee joint was performed. For further treatment, the proposed agent is prescribed. To date, the patient's condition is satisfactory, relapse of synovitis is not observed.

 The proposed tool for local anti-rheumatic therapy allows for treatment on an outpatient basis, and the components required for preparation are available and cheap, that is, the "Tool for local anti-rheumatic therapy" meets the criterion of "industrial applicability".

Claims (1)

Means for local anti-rheumatic therapy containing dimethyl sulfoxide, gelatin and distilled water, characterized in that it contains lithium or sodium hydroxybutyrate, local anesthetic and antihistamine in the following ratio of ingredients, wt. %:
Dimethyl sulfoxide - 40-50
Gelatin - 3-3.5
Lithium or sodium oxybutyrate - 0.2-0.4
Local anesthetic - 0.1-0.05
Antihistamine - 0.05-0.1
Distilled Water - Else