EA016400B1 - Pain-relieving formulation for topical use - Google Patents

Abstract

The invention relates to medicine and provides formulation for topical use comprising a red bell pepper extract and a pharmaceutically acceptable carrier characterized in that comprises an analgesic and/or nonsteroid anti-inflammatory agent. The formulation provides enhanced effectiveness, increased pain-relieving action and also serves for wider assortment of formulation for topical use.

Description

The invention relates to the pharmaceutical industry, and in particular to the production of products for external use containing extract of chilli pepper.

Capsicum extract belongs to herbal remedies and is used in medicine in the form of various dosage forms as a distracting, irritating and painkiller. Capsicum extract contains the substance capsaicin, which causes the irritating effect of pepper. However, this tool not only stimulates the receptors of the skin and subcutaneous formations (including muscle tissue), but also has a general humoral effect on the body. It has been proved that irritation of skin receptors and subcutaneous formations is accompanied by stimulation of the formation and release of enkephalins, endorphins, dynorphins and other peptides that play an important role in the regulation of pain, vascular permeability and other processes.

It is known to use the extract of capsicum in the form of tincture for grinding with neuralgia, radiculitis, myositis, lumbar ischialgia, etc. in the form of an ointment against frostbite of pepper and ammonia and pepper-camphor liniments, Espol ointment, Nikoflex cream, and pepper patch. Adhesive plasters - a dosage form used to protect the skin area from external damaging effects, to hide skin defects, to fix dressings on the surface of the skin, to treat corns, etc. Patches can be used for transdermal delivery of drugs into the body (KI 2177311, 12/27/2001).

For the manufacture of adhesive plasters using various compositions. Adhesive plasters contain as a basis a layer of adhesive material, which is an alloy of rubber with resins, fat-like and some other substances, in particular, that have a specific therapeutic effect on the patient’s skin (I.A. Muravyov, Drug Technology.- M .: Medicine, 1988).

Thus, a painkiller for external use is known in the prior art in the form of a pepper patch consisting of leucomass and pepper mass containing extract of capsicum pepper, rubber, pine rosin, anhydrous lanolin, thick belladonna extract, liquid paraffin, etc. ( NI 2133115, 07.20.1999). In essence, this tool is closest to the claimed invention. The disadvantage of this tool is its relatively low (compared with the claimed tool) painkiller activity.

To enhance the analgesic effect of the agent and expand the range of products for external use, work was carried out to create a cutaneous therapeutic system containing a physiologically active substance, preferably an analgesic or non-steroidal anti-inflammatory agent, since it was unexpectedly discovered that the irritating effect of the pepper patch can be used to improve the penetration of these substances through the skin and to increase the effectiveness of their action.

To solve the problem according to the proposed invention, an external agent is provided comprising extract of capsicum and a pharmaceutically acceptable carrier, characterized in that it contains an analgesic and / or non-steroidal anti-inflammatory agent. In a preferred embodiment of the invention, the claimed agent contains an analgesic. As analgesics, agents such as analgin, antipyrine, amidopyrine, phenacetin and paracetamol can be used. Non-steroidal anti-inflammatory drugs (NSAIDs) can also be used, since, as you know, the latter are also able to exhibit an analgesic effect. As NSAIDs, such agents as aspirin, acellisine, sodium salicylate, salicylamide, methyl salicylate, butadion, ibuprofen, ortofen, indomethacin, naproxen, piroxicam, ketoprofen, sulindac, mefenamic acid, niflumol acid, and diafluol acid can be used. As analgesics in the claimed invention, it is preferable to use non-narcotic analgesic agents, preferably selected from the groups of pyrazolone derivatives, preferably analgin.

The claimed tool can be applied to the skin in the form of a patch, patches, gels, ointments, liniments, tinctures for rubbing, creams, as well as in other transdermal systems. Thus, despite the fact that the following examples relate to the use of the claimed funds in the form of a patch, which is the most preferred, they cannot limit the scope of use of the claimed funds.

If the claimed agent is used in the form of a patch, a leukomass can be used as a carrier, which is an acrylic or preferably rubber adhesive based on natural or synthetic rubbers (including hot melt) or compositions based on them. In order to mitigate the irritating effect of pepper extract on the skin, peppers can be administered painkillers, anti-inflammatory and distracting agents of plant origin, selected from the group including belladonna extract, peppermint extract, menthol, mustard powder, burdock extract, marsh cinquefoil extract, South Siberian Limestone Extract and others. In a preferred embodiment of the invention, the quantitative content of pepper ingredients is, wt.%:

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Rubber - 20 -24 Antioxidant additives - 0.5 - 0.7 Pine Rosin - 15-17 Analgin - 13-25 Anhydrous lanolin -18 - 20 Medical Vaseline Oils - 1.8 -2.2 Dry wheat flour -6-8 Zinc oxide Extract belladonna thick -4-6 - 0.5 - 0.7 Dried Capsicum Extract Converted to Dry -7-9

The quantitative content of the leukomass ingredients is, wt.%:

Rubber - 24 - 28 Antioxidant additives - 0.7 - 0.8 Pine Rosin - 20 - 21 Anhydrous lanolin -9-11 Medical Vaseline Oils - 10 -12 Zinc oxide - 31 - 33

In the manufacture of the patch, both natural (for example, Smoked Sheets) and synthetic rubber can be used. As an antioxidant additive, 4-methyl2,6-ditretic butylphenol (Agidol-1) can be used.

To determine the optimal content of analgin in the patch, tests were performed on samples made using leukomass containing from 5 to 25% analgin. The experimental results showed that the optimum content of analgin in the patch with pepper extract should be at least 13%, and the optimal content of analgin in the composition of pepper mass is 20%. The ratio of the content of dipyrone and pepper extract in terms of dry is about 5: 2.

The pepper patch according to this invention has an analgesic, anti-inflammatory and antipyretic effect, which allows it to be used both on an outpatient basis and in a clinical setting for the treatment of bronchopneumonia, radiculitis, arthritis, sciatica, lumbago and other diseases accompanied by pain and fever. The use of the patch will avoid such a known effect of oral administration of drugs as an irritating effect on the gastric mucosa.

At the same time, the patch has a local anesthetic effect, which softens the unpleasant painful sensations that arise when using a pepper patch. The introduction of analgin and / or non-steroidal anti-inflammatory drugs helps to reduce local pain and reduces the discomfort associated with the irritating effect of pepper extract.

The invention is illustrated by the following examples.

Example 1. The manufacture of analginic-pepper patch.

The technological process for the production of analginic-pepper patch consists of the following stages:

1. Preparation of raw materials.

The stage includes the preparation of fabric, rubber, rosin, flour, lanolin, pepper extract, belladonna extract, analgin.

2. Preparation of intermediates.

The step includes preparing a solution of rosin, a zinc base, rubber glue, pepper paste and analgin paste.

Cooking Analgin Paste

The required amount of analgin and lanolin is weighed.

Analgin + lanolin is loaded into the mixer. Stirring of the analginic paste is carried out for at least 1 hour until a homogeneous mass is obtained. The analginic paste prepared in the mixer is discharged into a special container.

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3. Preparation of plaster masses (leukomass soil and plaster mass with analginum).

Composition and technology for the preparation of leukomass: in a mixer with prepared rubber glue (rubber + nefras + rosin + agidol), the zinc base (lanolin + vaseline oil + zinc oxide) is loaded. Then, the rosin solution is loaded in portions and mixed.

Preparation of a plaster mass with analgin

A portion of the rosin solution is poured into the mixer with ready-made rubber glue and mixed for 40 minutes. Then pour a portion of a solution of rosin and dry wheat flour and mix for at least 1 hour.

The analginic paste is loaded and mixed for at least 1 hour. The pepper base is loaded (lanolin + capsicum extract + belladonna extract + liquid paraffin) and mixed for at least 1 hour. The zinc base is charged and mixed for 30 minutes.

Then pour one portion of the rosin solution and mix for 40 minutes, a second portion and mix for 40 minutes, a portion of nefras and mix for 40 minutes.

4. Application of plaster on the fabric.

5. Cutting tapes of the analginic-pepper patch into bobbins.

6. Assembly, cutting and packaging of the analgin-pepper patch.

Example 2. Pharmacokinetics of dipyrone from an analgin-pepper patch.

It is known that the level of a drug substance in the blood, as well as the main pharmacokinetics parameters, primarily depend on the intensity of the biotransformation processes of this drug substance in the body and the route of administration.

It has been shown that in healthy volunteers with oral administration of analgin tablets, the maximum concentration of 4-methylaminoantipyrine occurs in the blood from 0.79 to 1.8 hours, and the blood level of this metabolite is proportional to the applied dose of analgin. Analgin is rapidly excreted from the body, and the rate of excretion is highly dependent on age.

To assess the effectiveness of absorption of dipyrone from an analginic patch, we studied the pharmacokinetics of dipyrone when administered intravenously and calculated the absolute bioavailability, which is considered to be 100%. In addition, the study of the pharmacokinetics of dipyrone when administered intravenously gives the true values of the elimination constant, which are essential for calculating the clearance of dipyrone when using the patch.

The pharmacokinetics of dipyrone from the analgin patch when administered intravenously was studied in rabbits of both sexes weighing 2.0-3.2 kg. An analgin patch was applied at a dose of 200 mg / kg to a 50 cm ² area of skin that was previously shaved for 24 hours. Such conditions were chosen in order to obtain sufficient plasma concentrations of analgin for analysis.

Analgin was administered intravenously as a 10% aqueous solution at a dose of 100 mg / kg.

To analyze the content of analgin in the blood plasma when applying the analgin patch, blood (3 ml) was taken into a heparinized tube from the marginal vein of the rabbit ear 1, 2, 4, 6, 8, 12, 20, 24 and 30 hours after applying the patch after 3, 10, 20, 40, 60 and 120 minutes after intravenous administration of a solution of dipyrone.

When studying the pharmacokinetics of dipyrone from a patch, we obtained chromatograms containing signals of endogenous substrates of blood plasma of an animal, dipyrone and its metabolites.

In FIG. 1 shows the pharmacokinetic curves for dipyrone and its two metabolites observed in plasma.

The pharmacokinetic curve for analgin is characterized by a fairly rapid absorption of analgin into the systemic circulation with a maximum time of 4 hours and its slow removal from the animal's body. Considering the sufficiently strong scatter of experimental data that is characteristic of the cutaneous route of administration, we can say that the pharmacokinetic curve for analgin from 3 to 20 hours has a plateau shape. Moreover, at 24 hours the amount of dipyrone is only 30% of the maximum concentration, and at 30 hours only trace amounts are observed.

The observed (Fig. 2) from 2 to 20 h plateau (maintaining a constant level of concentrations of dipyrone and its metabolites, i.e., stationary concentration) indicates that the transdermal supply of dipyrone from the analgin patch occurs at a constant speed, and the value of the stationary concentration (2.02 μg / ml) of a drug substance in blood plasma is determined by the ratio of the rate of delivery of dipyrone from the analgin patch through the skin to the systemic circulation and the rate of clearance of dipyrone from the blood in accordance with the steady-state equation Nosta

I = X C1 / 5, where I is the transdermal delivery rate from the analgin patch, the slowest stage, which determines the kinetics of drug intake into the systemic circulation, μg / (cm ² -h);

C ₈₈ — stationary concentration of the drug substance in the blood during transdermal delivery from the analgin patch, μg / ml;

C1 - the total clearance of the drug substance, determined by the results of its intravenous administration, l / kg / h;

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- the area of application of the analginic patch, cm ² / kg

So, as a result of studying the pharmacokinetics of analgin during skin application of the patch, it was found that analgin leaves the matrix of the therapeutic system and is rapidly absorbed through the skin into the systemic circulation, followed by slow elimination (T% = 13.86 h) from the animal’s body (up to 30 h). The pharmacokinetic curve from the 2nd to the 20th hour has the form of a plateau. With the intravenous administration of a solution of analgin and its transdermal entry from the patch into the bloodstream, metabolites are formed, which, like analgin, are eliminated from the body. The calculated rate of transdermal delivery of dipyrone to the systemic circulation is capable of maintaining it at a stationary level in the body.

Example 3. The analgesic effect of the analginic-pepper patch.

The analgesic effect of the analgin-pepper patch was studied on Wistar rats and white mice by methods using the burning effect, mechanical and chemical irritation factors.

With thermal exposure to animals - the hot plate method 1 = 52 ° C - the pain response was taken into account by licking the hind limbs, the appearance of which was recorded in seconds. Three groups of mice were taken in the experiment: intact, with the application of pepper and analgin patches. First, the initial threshold of pain sensitivity was determined in animals, then the latter was taken into account 2, 3, 4, 5, and 24 hours after the preliminary application of the patches.

In the experiments on rats weighing 160-190 g on the model of paw serotonin edema in rats, the analgesic effect of the analgin-pepper patch was studied by changing the threshold of pain sensitivity 1 and 4 hours after subplanetary administration of 0.1 ml of a 0.5% solution of phlogistic. The threshold of pain sensitivity during mechanical action on the paw of an animal was determined by the reaction in the form of a squeak and simultaneous release of the limb from under a pressure load.

As a chemical factor of irritation, 3% acetic acid was used at the rate of 300 mg / kg with intraperitoneal administration to mice weighing 18-20 g. The latter led to the appearance of cramps in experimental animals, registration of which was carried out within 21 minutes from the moment of acid injection.

Example 4. The anti-inflammatory effect of the patch on a model of formalin arthritis

The model of the pathological inflammatory process was formalin arthritis in rats, which were subplanted (into the cavity of the knee joint) with 0.1 ml of a 2% formalin solution in accordance with the Guidelines for the experimental (preclinical) study of non-steroidal anti-inflammatory pharmacological substances. After 1 day, a model of acute arthritis was obtained, on which an anti-inflammatory effect could be experienced.

The anti-inflammatory effect was antiexudative, analgesic and antipyretic.

Decongestant effect was evaluated by the oncometric method.

Analgesic properties were evaluated by the change under its influence of the threshold of pain sensitivity in contact-thermal irritation. The studies were performed on an optoelectronic analgesimeter TF 003 NINTZ Pharmacologist. The recorded indicator was the latent withdrawal time of the affected limb of the rat in response to thermal pain.

The antipyretic effect of the drug was determined by its ability to lower the temperature of the skin of the paws of the rat over the focus of inflammation. Skin temperature was measured by an electrothermometer company Νίηοη KoMei.

In addition, unified biochemical and hematological methods evaluated the general activity indicators of the inflammatory process: ESR, CRH, sialic acids, fibrinogen, and white blood cell count.

For morphological studies, the rat knee was taken. The material was fixed in 15% formalin, decalcified in nitric acid, followed by treatment in alum-potassium alum, and then embedded in paraffin. Sections were stained with hematoxylin-eosin.

All research results were evaluated using nonparametric and parametric statistics.

Male rats weighing 180-200 g were used in the experiments. Each experimental group included 10 animals. The test drug and the comparison drug began to be applied to the skin around the affected knee joint, capturing an area of 1 cm above and below the joint, one day after administration of formalin daily for 7 days. The comparison preparation (pepper patch without analgin) and pepper patch with analgin were applied based on a dose of 400 mg / kg (2x2 cm), and the place of application was bandaged up until the next application (day).

In total, 3 experimental groups were investigated:

1. Formalin (without treatment);

2. Formalin + pepper patch with analgin;

3. Formalin + pepper patch without analginum.

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The results are presented in table. 1-4.

Table 1. The volume of the inflamed limb of the rat (cmx10; n = 10) in dynamics after subplanetary administration of formalin and the use of test drugs, (M ± t)

Experimental group (drug) Observation time, days Total point active ty Therapeutic index for plaster without analgesia Before inflammation, baseline one 4 8 1 cm x 10 22 + 1 33 + 2 34 + 2 28 + 2 fifteen -

decrease.% - - 0 fifteen 2 cm x 10 22 + 1 34 + 2 25 + 1 22 + 2 63 2.53 decrease.% - - 27 36 3 cm x 10 22 + 1 33 ± 1 30 ± 2 25 + 1 34 one decrease.% - - 10 24

The total activity score is the sum of the percent reduction in the volume of the affected limb over 7 days. Therapeutic indices were calculated using the formula

A-B

C-B, where A is the total activity score of the patch with analgin;

B is the total activity score of the group with formalin;

C is the total activity score of the patch without analgin.

Table 2. The time of development of the pain signal in rats (cx10; n = 10) after standard thermal stimulation against formalin arthritis and local application of the tested drugs, (M ± t)

Experimental group (drug) Observation time, days Total activity score Therapeutic patch index without analgin Before inflammation, baseline one 4 8 one sec x 10 30 + 1 25 + 2 27 + 2 30 + 2 28 - elongation.,% - - 8 twenty 2 sec x 10 27 + 3 26 ± 2 52 ± 3 36 ± 2 139 12.3 elongation.,% - one hundred 39 3 sec x 10 28 ± 2 27 ± 3 36 ± 2 28 ± 2 37 one elongation.,% - - 33 4

Table 3. The temperature difference (LES) of the inflamed and intact extremities of rats (n = 10) against the background of formalin arthritis and local application of the tested drugs, (M ± t)

Experimental Observation time, days | Amount | Therapist naya group (drug) Before inflammation, baseline one 4 8 activity score Patch index without analgin one D1 ° C 1 + 1 20 + 1 20 + 2 10 ± 2 fifty decrease% - - 0 fifty decrease% - - thirty 80 2 D1 ° C 2 ± 1 20 ± 2 10 ± 2 2 + 1 140 2,31 decrease% - - fifty 90 3 DES 1 ± 1 18 ± 1 16 ± 2 4 ± 1 89 one decrease% - - and 78

The results of the study of antiexudative, analgesic and antipyretic effects indicate that the pepper patch with analgin possesses the greatest therapeutic activity. The new drug is much more effective than a pepper patch without analgin. There is an excess of the analgesic effect by 12 times, as well as a significant decrease in the processes of inflammation and irritation. This is confirmed by the dynamics of the restoration of the activity of the affected joints and stopping the activity of the inflammatory process (table. 4).

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Table 4. Indicators of the activity of the inflammatory process in the dynamics of the course of formalin arthritis and the use of tested drugs (n = 10), (M ± t)

Experimental group (drug) Reliance on the limb, ± The number of animals with arthritis morphology to 8th day of observation soe, mm / hour CRP, mm recipes Sialic acids, Mmol / l Fibrinogen, g / l The content of white blood cells, 10 ³ / mm ³ Observation day Intact animals + 0 611 0 2.010.5 2.510.5 6.510.5 one one - - 3013 > 4 6.510.5 10.510.5 16.511.0 4 - - 3015 > 4 7.511.5 10.5 + 1.5 15.5 + 0.5 8 - 10 25 + 5 > 4 6.511.0 9.510.5 15.510.5 2 one - 2515 411 6.310.2 8.411.2 14.210.5 4 - 1213 1 + 1 2.5 + 0.5 3.0 + 1.0 7.8 + 1.2 8 0 6 ± 2 1 ± 1 1.810.2 2.010.5 6.310.6 3 one - - 2515 4 ± 1 6.810.5 10.011.2 17.310.7 4 - - 1212 311 4.210.1 5.510.5 12.110.3 8 + 3 8 ± 1 211 3.610.3 3.810.5 8.610.2

At the autopsy of the experimental rats (artificially caused arthritis), an increase in the joint and a smoothness of its contours were observed. In the section, periarticular tissues were edematous. In the joint cavity there was a small amount of slightly turbid fluid, the articular surfaces of the cartilage were smooth.

Microscopic examination of the knee joint revealed plethora and swelling of the periarticular tissues, as well as changes in the synovial membrane of the joint. In the villi of the synovial membrane, plethora, edema, and lymphoid infiltration of the loose connective tissue of the villi were observed.

At autopsy of rats in which a pepper patch with analgin was used, no (macroscopic) joint changes were observed. Periarticular tissues did not differ from intact animals. No effusion was observed in the joint cavity. The articular surfaces of the cartilage were smooth.

The synovial membrane of the knee joint of the treated animals did not represent any changes. The synovial membrane lining the inside of the joint surface consisted of little differentiated connective tissue cells with round or oval nuclei. Cells were more densely located at the base of the villi. Anemia or lymphoid infiltration was not observed (Table 1).

Studies have shown the high efficiency of the patch in experimental arthritis. Pepper patch with analginum was superior in activity to a pepper patch without analginum. This suggests that the introduction of analgin into the drug, on the one hand, significantly increased the therapeutic effectiveness of the patch, and on the other hand, reduced the local inflammatory manifestations caused by pepper extract.

The results allow us to recommend the claimed invention as an effective drug for the treatment of arthritis, arthrosis, radiculitis, myositis, lumbago and other diseases.

Claims (8)

CLAIM 1. An analgesic for external use, comprising capsicum extract and a pharmaceutically acceptable carrier, characterized in that it further comprises analgin in a mass ratio of capsicum extract: analgin from 7:25 to 9:13. 2. The painkiller according to claim 1, characterized in that it additionally contains an agent that affects the skin, selected from the group including belladonna extract, peppermint extract, menthol, mustard powder, burdock extract, marsh cinquefoil extract and southern penny extract Siberian. 3. The painkiller according to claim 1, characterized in that it is a patch, and leukomass is used as a carrier. 4. Analgesic according to claim 3, characterized in that rubber or acrylic glue is used as leukomass. 5. Analgesic according to claim 4, characterized in that rubber glue is used as leukomass. 6. The painkiller according to claim 5, characterized in that the rubber adhesive comprises rubber, an antioxidant additive, pine rosin, anhydrous lanolin, anhydrous vaseline oil, zinc oxide and wheat flour. 7. The painkiller according to claim 3, characterized in that it contains rubber, an antioxidant additive, pine rosin, anhydrous lanolin, medical vaseline oil, zinc oxide, dried wheat flour, capsicum extract, analgin and belladonna extract in the following 6 016400 in relation to components, wt.%: Rubber 20-24 Antioxidant additives 0.5 - 0.7 Pine Rosin 15-17 Anhydrous lanolin 18-20 Medical Vaseline Oils 1.8 - 2.2 Dry wheat flour 6 - 8 Zinc oxide 4-6 Dry pepper extract in terms of dry 7-9 Analgin 13-25 Belladonna extract 0.5 - 0.7 8. The analgesic according to claim 7, characterized in that the antioxidant additive is 4-methyl-2,6-ditretic butylphenol (Agidol-1). Chromatogram of a standard solution of dipyrone (0.5 μg / ml) in blood plasma extract - 7 016400 FIG. 2 Calibration graph of the area of the chromatographic peak on the content of dipyrone in the blood plasma The equation of the calibration curve has the form Υ = a + b-X, where a and b are equal to 1.675 and 16.677, respectively. The correlation coefficient r = 0.999928. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2