PHARMACEUTICAL COMPOSITION OF TWO ANALGESICS COMBINED IN A TOPICAL PREPARATION

Abstract

The preparation and therapeutic properties of a gel composed of the active ingredients diclofenac sodium and lysine clonixinate, combined for the first time for the topical treatment of pain in musculoskeletal inflammatory processes, are described.

Description

[0001] “PHARMACEUTICAL COMPOSITION OF TWO ANALGESICS COMBINED IN A TOPICAL PREPARATION”

[0002] Description of the Invention

[0003] The present invention relates to the field of pharmacology and pharmaceuticals, specifically to the preparation of analgesic drugs for topical use.

[0004] In particular, the present invention relates to pharmaceutical compositions containing two non-steroidal anti-inflammatory drugs (NSAIDs) combined for the first time in a topical preparation, one being diclofenac sodium in an amount of between 0.5% and 2.0% w / w, and the other lysine clonixinate in an amount of between 2.5% and 6% w / w. The invention is designed for the treatment of inflammatory conditions and to provide relief from musculoskeletal pain amenable to topical treatment. Furthermore, the present invention provides a method for manufacturing this composition.

[0005] Background of the invention

[0006] Several documents have been published as background (Verma et al., Int. J. Pharm. Sci. Rev. Res. 2013, 60:374). In particular, documents have been published concerning the preparation and characteristics of gels containing diclofenac sodium, such as US patents: 4,543,251, 4,575,515, 4,652,557, 7,132,452, 7,335,379 and PCT application 2014009241.

[0007] Patent MX 267736 refers to a pharmaceutical composition containing a combination of diclofenac sodium and lysine clonixinate in proportions that may vary from 1:3 to 1:5 (w / w) respectively, which, when administered intraperitoneally, demonstrates an analgesic synergy.

[0008] None of the references to the previous technique describe or suggest topical gel formulations containing a combination of diclofenac sodium and lysine clonixinate, with the important benefit that this combination can be applied topically to achieve efficacy in acute and chronic painful conditions without the consequent adverse effects that occur with oral or injectable administration. NSAIDs

[0009] NSAIDs are used in therapy for the treatment of inflammatory and painful processes such as osteoarthritis, rheumatoid arthritis, postoperative pain, menstrual cramps, and in general to reduce fever and acute or chronic pain of both visceral and somatic origin.

[0010] NSAIDs have been used since the 19th century, beginning with the introduction of aspirin in 1897 by Felix Hoffmann of Bayer (US 644,077). Since then, numerous molecules of this class have been synthesized and marketed in oral forms such as tablets and capsules, as well as in parenteral solutions and topical or transdermal forms.

[0011] The general mechanism of action responsible for the anti-inflammatory and analgesic effects of NSAIDs is the inhibition of the prostaglandin endoperoxide synthase enzymes (PTGS-1 and PTGS-2), also called cyclooxygenases (COX-1 and COX-2). These enzymes participate in the synthesis of a very important group of molecules, including prostaglandins (PGs): PGE₂, PGD₂, PG₂a, and PGH (prostacyclin), and thromboxane TX₂. The synthesis of these molecules occurs from arachidonic acid (AA) released from the cell membrane by the action of phospholipase, which is activated by the stimulation of specific surface membrane receptors (Yao Ch. and Narumiya S. British Journal of Pharmacology. 2019, 176:337).

[0012] The gene responsible for COX-1 synthesis is present in most cells, and the resulting activity of this enzyme has been canonically associated with the maintenance of multiple biological functions. Meanwhile, COX-2 gene expression has been primarily attributed to inflammation and cancer, being induced by inflammatory cytokines, mitogens, endotoxins, and tumor promoters. Therefore, COX-2 has been associated with immune system cells, including leukocytes and macrophages, as well as fibroblasts, chondrocytes, and renal endothelial and mesangial cells, playing a crucial role at sites of inflammation in the body (Emer SJ Lipid Res. 2009. 50: S423-S428).

[0013] In addition to their role in inflammatory processes, prostaglandins (PGs) also participate directly in the generation of pain, both peripherally and centrally. Specifically, prostaglandins PGE2 and PGE12 sensitize peripheral nerve endings, lowering the threshold of nociceptors to painful stimuli.

[0014] Although the use of NSAIDs is the first line of analgesic and anti-inflammatory treatment, their use can lead to adverse reactions because both COX-1 and COX-2 have a fundamental function as mediators in various physiological processes, so the inhibition of their activity by NSAIDs can cause some type of alteration or pathology (Bindu et al., Biochem. Pharmacol. 2020, 180: 114147).

[0015] In particular, COX-1 is constitutively expressed in most cells and produces prostanoids that act, for example, to protect the gastric mucosa, regulate acid secretion and homeostasis, and maintain renal functions.

[0016] On the other hand, COX-2 has mainly been associated with immune cells, with its activity located at inflammatory sites in the body; however, the accumulated evidence now clearly suggests that COX-2 is also constitutively expressed in various tissues, including the brain, intestine, lung, thymus, and kidney, where it produces prostanoids.

[0017] The type of unwanted effects of NSAIDs depends on their specific nature, as there are marked differences between them in their inhibition of the two cyclooxygenase subtypes, COX-1 and COX-2. Acetylsalicylic acid, in particular, is a selective COX-1 inhibitor and causes a decrease in prostaglandin production in the stomach lining, making it much more vulnerable to corrosion by gastric acids—its main side effect. Many medications have been designed to target COX-2 inhibition as a way to minimize the gastrointestinal effects of other NSAIDs such as aspirin. However, in practice, the use of some COX-2 inhibitors has resulted in numerous cardiac arrests in patients who did not tolerate the treatment.

[0018] The effect of NSAIDs in reducing inflammation and pain by inhibiting COX-1 and COX-2, with the consequent inhibition of prostaglandins (PGs), depends on the type of NSAID. Almost all NSAIDs at therapeutic doses inhibit both COX isoforms. The classification of these analgesics is based on their selectivity and potency in inhibiting COX-1 or COX-2. Using the IC50 (the concentration that inhibits 50% of the enzyme's activity) as a basis, the inhibitory ratio is expressed as IC50COX-1 / IC50COX-2. If the ratio is 1, both enzymes are inhibited equally. If the ratio is greater than 1, the NSAID is more selective in inhibiting COX-1, and vice versa. If the ratio is less than 1, the NSAID shows greater selectivity in inhibiting COX-2.

[0019] With respect to their potency in inhibiting one or the other isoform, NSAIDs can be divided into four main categories: 1) Non-selective inhibitors for COX-1 and COX-2, e.g. Indomethacin, Aspirin, Diclofenac, Naproxen, Ibuprofen, Lysine Clonixinate; 2) Inhibitors that are 5 to 50 times more potent towards COX-2 than towards COX-1, e.g. Meloxicam, Celecoxib, Nimesulide, Etodolac; 3) Inhibitors with a potency 50 times greater towards COX-2, e.g. NS-398; and 4) Inhibitors with very low potency towards COX-1 and COX-2 (Warner T. et al, Proc Nati Acad Sci US A. 1999 96(13): 7563).

[0020] Diclofenac and Clonixinate Lysine

[0021] Diclofenac is a heteroaryl acetic acid derivative and belongs to the NSAID family. It is indicated for musculoskeletal disorders, sports and accidental injuries, muscle, tendon and ligament strains, non-rheumatic pain, acute and chronic treatment of the signs and symptoms of rheumatoid arthritis, osteoarthritis, spondylarthrosis, extra-articular rheumatism, osteoarthritis, spinal pain syndrome, acute gout attack, post-traumatic and postoperative inflammation and pain, orthopedics, primary dysmenorrhea, and cases involving inflammation, pain, and muscle contracture (van Walsen et al., Arthritis Res. Ther. 2015 17:66).

[0022] The primary mechanism of action responsible for its anti-inflammatory and analgesic effects is the reduction of prostaglandin synthesis caused by the inhibition of the cyclooxygenase enzyme in its two isoforms. Diclofenac has a low to moderate preference (approximately tenfold) for blocking the COX-2 isoenzyme, and this is believed to explain its low incidence of gastrointestinal side effects compared to indomethacin and aspirin. Topically, diclofenac is an effective alternative when administered to patients with osteoarthritis (Bariguian et al, Rheumatol Ther (2020) 7:217). Lysine clonixinate is a nonsteroidal anti-inflammatory drug (NSAID) with predominantly analgesic action.Its action is developed by inhibiting the synthesis of prostaglandins, and it has been shown that this action is predominant on the enzyme that catalyzes the synthesis of prostaglandins that mediate inflammation (cyclooxygenase 2 or COX-2) with less activity on the enzyme that catalyzes the synthesis of prostaglandins in the gastrointestinal mucosa and kidneys (cyclooxygenase 1 or COX-1) than other NSAIDs such as ketorolac, (Pallapies et al., Life Sci. 1995, 57:83). CL has been used in painful and inflammatory conditions of traumatic origin of ligaments, muscles, tendons and joints (contusions, strains, sprains, strains) as well as in localized rheumatic diseases (osteoarthritis, arthritis) and localized forms of extra-articular rheumatism such as tenosynovitis, bursitis or periarthropathies (Eberhardt et al, Curr. Ther. Res. 1995, 56:573).

[0023] Although there are commercial formulations for topical use of CL, there are no preclinical or clinical reports of this pharmaceutical form.

[0024] Previous studies in animal models have demonstrated the analgesic synergy between diclofenac and lysine clonixinate when administered intraperitoneally in combination. These studies also showed that the combination reduces inflammation. Therefore, the combination described in the present invention is designed for the topical relief of muscular and joint pain, with the added benefit of potentially fewer adverse effects on the gastrointestinal tract.

[0025] Topical formulations

[0026] Topical NSAID formulations are an effective alternative for mild to moderate pain. Their indications include the treatment of pain and inflammation associated with musculoskeletal conditions, and they are particularly effective in pathologies affecting muscles, tendons, and ligaments, such as tendinitis, bursitis, and osteoarthritis.

[0027] These preparations are frequently used in sports medicine. In many cases, they allow for avoiding prolonged oral administration of anti-inflammatory drugs and reduce the risk of side effects such as gastrointestinal disturbances. These preparations are applied locally to the affected area, diffusing the active ingredient through the skin into the bloodstream. They produce a high concentration of the drug in the dermis, muscle, synovial membrane, and articular cartilage. Specifically, after topical application of ketoprofen, the concentration of this NSAID in synovial fluid was determined to be 12.8 ng / ml, which is higher than the in vitro IC50 concentration for COX-2, which is 6.86 ng / ml. The concentration of ketoprofen was even higher in cartilage (568.9 ng / ml), synovial tissue (56.7 ng / ml), and menisci (349 ng / ml).3 ng / ml), so it is likely that this and other topical NSAIDs exert their analgesic action both by the local reduction of pain and inflammation in periarticular structures and by the systemic delivery to intracapsular structures (Rolf et al, Rheumatology 1999; 38:564).

[0028] After topical administration, plasma concentrations of NSAIDs are only a fraction (usually much less than 5%) of the levels found in plasma after oral administration, so topical application can potentially limit adverse events by increasing local effects and minimizing systemic effects of the drug (Haroutiunian, et al., Pain Medicine 2010; 11:535).

[0029] Topical NSAIDs are available in various pharmaceutical forms: creams, ointments, gels, sprays, roll-ons, liniments, and even adhesive patches. Drug release depends on the physicochemical properties of the active ingredient and the pharmaceutical form; that is, it is a function of pharmacotechnical factors that ultimately control appropriate release and, consequently, its pharmacological action. In this sense, an active ingredient that has been released may not be absorbed. For example, if the drug molecule only adheres to the surface of the skin or mucous membrane, the phenomenon is called adsorption; if the active ingredient reaches the inner layers of the skin but not the capillaries, the phenomenon is called penetration; finally, absorption occurs when the active ingredient also crosses the capillary walls and enters the systemic circulation.Semi-solid NSAID preparations can be hydrophilic ointments, creams, or gels of homogeneous consistency, formulated to achieve local release of the active ingredients. Gels, in particular, consist of liquids gelled with appropriate gelling agents, forming a simple or compound base in which one or more active ingredients are usually dissolved or dispersed. Oleogels are preparations whose bases consist of liquid paraffin with polyethylene, fatty oils gelled with colloidal silica, or aluminum or zinc soaps.

[0030] Hydrogels are preparations whose base is water, glycerol or propylene glycol gelled with the help of appropriate gelling agents such as starch, cellulose derivatives, carbonates and magnesium and aluminum silicates.

[0031] The present invention describes topical pharmaceutical compositions in gel form combining for the first time the drugs diclofenac sodium and lysine clonixinate in a ratio that allows increasing skin permeability, the anti-inflammatory effect and the analgesic effect observed when both active ingredients are administered separately.

[0032] CLD gel formulation

[0033] For the formulation of the lysine clonixinate and diclofenac gel described in the present invention, various factors have been taken into account, such as appearance, odor, viscosity, pH, texture, potential for microbial contamination, and bioavailability, making the skin surface more permeable to the drug. The formulation ingredients consist of gelling agents, solvents, the active pharmaceutical ingredient, and excipients.

[0034] The content of the active ingredients in the present invention is 2.5% to 5% by weight for chlorhexidine (Cl) and 0.5% to 1.0% for diclofenac. Both drugs have a molecular weight of less than 500 Daltons, allowing them to penetrate the skin and thus be administered topically in a gel dosage form.

[0035] Carbomer interpolymers can be used as gelling agents in quantities of 1.7% to 2.0% w / w. These are frequently used due to their ability to thicken gels over a wide pH range, serving as both stabilizers and thickeners. Examples of these include Carbopol 934, Carbopol 940, and Carbopol 941, which can be used in the present invention. The medium used in the preparation of the present invention includes water and may contain alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and similar alcohols, as well as glycols such as ethylene glycol, propylene glycol, and 1,3-butylene glycol. The water-to-organic solvent ratio in the medium is preferably 70% to 80% by weight or less. The preferred weight proportions of the medium used in the present invention are water, alcohols, and glycols of approximately 80% to 70%, 15% to 20%, and 10% to 30% respectively.The most suitable combinations for the medium of the three solvents above are water:ethanol:propylene glycol or water:isopropanol:propylene glycol or water:isopropanol:1,3-butylene glycol.

[0036] The pH of the gel described in the present invention has values ​​from 6 to 8, preferably a pH of 6.5 to 7.5. In the preparations of the present invention, weak basic substances are used as neutralizing agents in an amount of 0.1% to 5% by weight; aliphatic amines are preferred, such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, dimethylamine, diethylamine, trimethylamine, triethylamine, and the like.

[0037] The described formulation must include compounds that prevent the oxidation of the gel ingredients. Examples of compounds that may be used in this invention include sodium metabisulfite, sodium formaldehyde sulfoxylate, methylparaben, and propylparaben in amounts of 0.05% to 0.1%. Chelating agents such as EDTA salts, a compound used in gels to promote paracellular permeability by chelating the calcium necessary for intercellular junctions, may also be used. Emollients such as isopropyl myristate, which promotes absorption, may also be employed. The proportion of these agents may range from 0.02% to 0.1% by weight.

[0038] Odorants or rubefacients, such as lavender, peppermint oil, 1-menthol, methyl salicylate, ethyl salicylate and glycol monosalicylate, can be added to the preparation of the gel of the present invention in proportions of 0.5% to 1%.

[0039] The gel formation process of the present invention consists of mixing the solvents water and alcohols in a mixing tank and gradually adding the solid excipients, mixing until completely dissolved. Subsequently, the gelling agent is added slowly and gradually.

[0040] Separately, water and alcohols are mixed with the active ingredients diclofenac and lysine clonixinate, adding neutralizing amines until the established pH is reached. Finally, while continuously mixing, the active ingredient mixture is added to the mixing tank containing the gelling agent, solvent, and excipients. Gelling agent and solvent are added until the established volume is reached, ensuring a balance between their concentrations for the formation of the semi-solid gel. The gel is left to stand for one or two days before reaching its final consistency.

[0041] The following examples illustrate the invention:

[0042] Example 1.

[0043] Example 2. Example 3.

[0044] In vitro diffusion test

[0045] Using Franz-type diffusion cells, the degree and speed of penetration through pig skin of a gel formulation (CLDgel) containing 1 mg of diclofenac and 50 mg of lysine clonixinate contained in 1 g was studied, compared with 2 commercial control gels: 1) A gel with 20 mg / g of sodium diclofenac (Dgel) and 2) A gel with 50 mg / g of lysine clonixinate (CLgel).

[0046] The study's evaluation criteria are based on parameters that measure the rate and extent to which the drug penetrates the skin and becomes available in the recipient's solution. Specifically, the drug permeation rate is characterized by the flux (J), and the degree of drug permeation is defined by the total cumulative amount of drug permeating into the recipient's solution during the study. According to the equation Cs = Js.At, Cs is the cumulative amount of solute crossing the membrane of area A in a time period t with a flux Js through a constant concentration gradient at steady state.

[0047] To calculate the flow rate, the degree of drug permeation must be plotted graphically as the cumulative amount of drug permeated on the Y-axis in units of mass / area versus time on the X-axis. Therefore, the steady-state flow rate (Js) will be the slope of the line in the linear region of the graph. To estimate the degree of penetrability, the penetrability coefficient (kp) is also determined from the relationship Kp = Js / Cs, where Cs is the cumulative amount (pg / cm²). 2 )

[0048] To determine the penetration flow of each drug according to the test, 1 g of CLDgel and 0.5 g and 1.0 g of the control gels Dgel and CLgel, respectively, were used. The time course of the cumulative amount of drug per skin area (pg / cm²) was analyzed. 2 ) up to 24 hours, from an average of 3 independent determinations.

[0049] Figure 1 shows the diclofenac flow rate for both CLDgel and diclofenac gel (Dgel) as a control, illustrating the time course of the cumulative amount of diclofenac from: 1) 1 g of CLDgel and 2) 0.5 g of Dgel per skin area (pg / cm²). Data represent the mean ± standard error. *p < 0.0284 using Student's t-test.

[0050] The diclofenac penetrability flux of the control Dgel was calculated directly from the linear zone of the graph as the slope, which is Js = 0.39 pg / cm 2 / h, subsequently the permeability coefficient Kp was calculated by the slope between the total dose (10mg), resulting in 0.13 h.cm 2 For CLDgel the results were Js = 0.67 pg / cm2.hy Kp 0.067 h.cm 2 .

[0051] Therefore, it can be concluded that the CLDgel formulation shows a higher penetration rate of diclofenac than that of uncombined Dgel.

[0052] The lysine clonixinate flux from CLDgel was compared to CLgel. Figure 2 shows the time course of the cumulative amount of CL from 1 g of CLDgel and 1 g of CLgel per skin area (pg / cm²). Data are represented as mean ± standard error, *p < 0.0012 using Student's t-test.

[0053] The penetration flux of lysine clonixinate calculated directly from the graph as the slope is Js = 2.52 pg / cm 2 .h, and the permeability coefficient Kp calculated by the slope / total dose, resulted in 0.05 h.cm 2 For the CLDgel, these parameters resulted in: Js = 11.83pg / cm 2 .hy Kp = 0.23 h.cm 2 By comparing these data, it is shown that CLDgel offers better penetrability of lysine clonixinate than CLgel.

[0054] Evaluation of the temporal profile of the anti-inflammatory and anti-hyperalgesic effect of the CLDgel formulation, compared with Dgel and CLgel formulations, in a carrageenan-induced edema and hyperalgesia model in rats.

[0055] Test of the anti-inflammatory effect in vivo

[0056] Adult male Wistar rats weighing approximately 300–350 g were used. The experimental protocol was approved by an authorized ethics committee. Four experimental groups of five animals each were used. Control group 1 consisted of animals that received only an intraplantar injection of 0.1 mL of 1% carrageenan solution in the left hind foot. Groups 2, 3, and 4 also received intraplantar injections of carrageenan, but these groups also received simultaneous injections of 0.25 g of Dgel, 0.5 g of CLgel, and 0.5 g of CLDgel, respectively.

[0057] The thickness of the leg was measured at 0, 1, 2, 4, 6, 8, 12 and 24 hours after carrageenan administration using a digital vernier caliper.

[0058] The anti-inflammatory effect of the treatment is obtained as follows: the thickness measurement obtained after carrageenan injection and treatment is subtracted from the baseline thickness measurement of the leg, expressed as delta (A). For analysis, the time course of each of these values ​​is plotted, and from this, the areas under the curves (AUC) of the time course are obtained, reflecting a measure of the total anti-inflammatory effect.

[0059] Figure 3 shows the time course of the percentage decrease in thickness (% A) of the local treatments of 0.25 g of Dgel, 0.5 g of CLgel and 0.5 g of CLDgel. The data represent the mean ± standard error (n=5).

[0060] Figure 4 shows the areas under the curve (AUC) of the anti-inflammatory effect, representing the total effect up to 24 hours. The total anti-inflammatory effect is expressed as the AUC of the local treatment with Dgel, CLgel, and CLDgel. Data represent the mean ± standard error. Statistical differences were found with p-values ​​of * < 0.04, ** < 0.0037, and **** < 0.0001 using Tukey's ANOVA. A greater total anti-inflammatory effect was observed with CLDgel compared to Dgel and CLgel.

[0061] Test of the antihyperalgesic effect

[0062] The antihyperalgesic effect of Dgel, Clgel, and CLDgel was evaluated simultaneously with the measurement of the thickness of the injected paw. Therefore, the same experimental groups used for the anti-inflammatory effect evaluation were used for this purpose, and the tests were performed concurrently. The animals were placed in the analgesimeter, which applied a uniformly increasing pressure to the paw. When the animal exhibited the slightest withdrawal reflex, the pressure was stopped, and the hyperalgesia threshold (force applied in grams) was determined. An analgesic will produce an antihyperalgesic effect when the treated paw can continue to withstand high pain thresholds.The antihyperalgesic effect of the treatment is obtained as follows: the threshold after the injection of carrageenan is subtracted from the baseline threshold of the leg obtained before the injection of carrageenan (control group) and from the different treatments with Dgel, CLgel and CLDgel.

[0063] Figure 5 shows the time courses of the difference (A) in the mechanical threshold (before and after carrageenan) for the different local gel treatments applied to the experimental groups. The percentage increase in the mechanical threshold for the local treatment of Dgel, CLgel, and CLDgel is indicated. Data represent the mean ± standard error (n=5).

[0064] The total antihyperalgesic effect, also expressed as the area under the curve of the time course of the difference between the initial or baseline threshold and the threshold determined over time, is greater in the control group, given that there is no treatment. Figure 6 shows the areas under the curve of the antihyperalgesic effect as a representation of the total effect up to 24 hours for each treatment. Total antihyperalgesic effect, expressed as area under the curve, p-values ​​*** < 0.0003 and **** < 0.0001 with Tukey's ANOVA. Data represent the mean ± standard error (n=5).

[0065] All treatments: Dgel, CLgel and CLDgel, show a significant decrease, conferring an antihyperalgesic effect. These differences, when analyzed by ANOVA statistics, show that there are differences between all groups, in particular a greater total antihyperalgesic effect of CLDgel is observed than that of the Dgel and CLgel gels.

[0066] Conclusions

[0067] The present invention shows the method of preparation and benefits of a gel composed of the combination of diclofenac and lysine clonixinate, demonstrating that its performance in terms of the penetration speed of the active ingredients as well as the anti-inflammatory and anti-hyperalgesic effects are superior to those obtained with gel formulations with the individual drugs, so that the CLDgel represents a therapeutic advantage over the commercial gels Dgel and CLgel by accessing subdermal structures faster, including musculoskeletal structures, and exerting a greater anti-inflammatory and anti-hyperalgesic effect.

Claims

A topical analgesic pharmaceutical composition characterized in that it comprises: a combination of diclofenac and lysine clonixinate as well as their salts and hydrates or any of their pharmaceutically acceptable salts in a ratio of 1 / 5 (w / w) respectively, formulated in the form of a gel wherein the chemical compound of diclofenac is 2-(2-{(2,6-dichlorophenyl)amino}phenyl)acetic acid, and the chemical compound of lysine clonixinate is 2-(3-chloro-2-methylphenyl)aminopyridin-3-carboxylic acid, formulated with excipients that confer a faster rate of penetration of the active ingredients through the skin than that obtained with the topical formulations of the drugs separately.

2. The composition according to claim 1, wherein diclofenac and lysine clonixinate are mixed with pharmaceutically acceptable excipients.

3. The pharmaceutical composition according to claims 1 and 2, characterized in that the carbomer interpolymers as gelling agents are employed in an amount of 1.7% to 2.0% w / w preferably.

4. The pharmaceutical composition according to claims 1 to 3, further characterized in that the pH of the gel has values ​​of 6 to 8, preferably a pH of 6.5 to 7.

5.

5. The pharmaceutical composition according to claims 1 to 4, further characterized in that weak basic substances as neutralizing agents are employed in an amount of 0.1% to 5% by weight, preferably aliphatic amines selected from one or more of monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, dimethylamine, diethylamine, trimethylamine, triethylamine and the like.

6. The pharmaceutical composition according to claims 1 to 5, further characterized in that water is used in the water to solvents weight ratio of 70% to 80% by weight or preferably less.

7. The pharmaceutical composition according to claims 1 to 6, further characterized in that the alcohols are selected from one or more of methanol, ethanol, propanol, isopropanol, butanol and the like, and glycols such as ethylene glycol, propylene glycol and 1,3-butylene glycol.

8. The pharmaceutical composition according to claims 1 to 7, further characterized in that the weight proportions of water, alcohols and glycols are approximately 80% to 70%, 15% to 20% and 10% to 30% respectively, preferably in the combinations of water: ethanol: propylene glycol or water: isopropanol: propylene glycol or water-isopropanol: 1,3-butylene glycol.

9. The composition according to claims 1 to 8 wherein the composition is presented as a topical medicinal product.

10. The use of the pharmaceutical composition claimed in claims 1 to 9 for the preparation of a topical medicament for the relief of pain and inflammation.