MX2007012517A - Synergistic pharmaceutical composition comprising lysine clonixinate and carisoprodol. - Google Patents

Abstract

The invention relates to pharmaceutical compositions containing a muscle relaxant known as carisoprodol and a non-steroidal anti-inflammatory analgesic known as lysine clonixinate. When the aforementioned drugs are combined in specific proportions pharmacological effects are produced, indicating synergy, and consequently smaller amounts of the drugs can be used in order to obtain the same degree of analgesia and muscle relaxation as when they are used alone, but with the advantage of fewer side effects.

Description

"SYNERGISTIC PHARMACEUTICAL COMPOSITION OF CARISOPRODOL AND USINA CLONIXINATE" Description of the invention The present invention relates to pharmaceutical compositions containing two active ingredients, one of them being a skeletal muscle relaxant, known as carisoprodol, and the other a non-steroidal anti-inflammatory analgesic known as lysine clonixinate. The carisoprodol to which the present invention relates is [2-methyl-2- (l-methylethylcarbamoyloxymethyl) pentyl] aminomethanoate. This also includes the individual stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts, solvates and polymorphs of the carisoprodol material. The lysine clonixinate to which the present invention refers is the lysine salt of 2- (3-chloro-2-methyl-phenyl) aminopyridine-3-carboxylic acid.

When carisoprodol and lysine clonixinate are combined in specific proportions, the combination (CLC) produces analgesic pharmacological effects that indicate a superadditivity (synergy), the CLC combination also produces the enhancement of the muscle relaxant effect maintaining an adequate side effect profile.

Due to the characteristics of the drugs that make it up, the CLC combination is designed to produce an analgesic drug with relaxing effect of the striated muscle that is effective in the moderate to severe painful processes of acute presentation, which appear in situations such as: sprains , fractures, muscle contractures (torticollis), lumbago, bursitis; osteo-muscular and odontological surgical processes, etc.

The profile of adverse effects observed after the administration of the combination suggests that this therapeutic strategy may be a promising tool in the relief of moderate to severe acute pain with the advantage of having fewer adverse effects that occur with the use of more powerful relaxants.

Background of the Invention Spasticity and muscle spasms are frequent conditions that affect both the functional capacity and the quality of life of patients who suffer from it. The first one 5 presents as a sequela of lesions or diseases of the central nervous system and the second in peripheral nervous system lesions, or muscle injuries as in trauma, myofascial syndromes, fibromyalgia syndromes, spasms of protection, etc. Spasticity is not a single disorder, the term applies relatively globally to alterations in skeletal muscle tone regulation due to motor pathway lesions J O descending at different levels of the central nervous system. Intense or long-term spasticity can lead to contractures and joint stiffness, which can greatly limit care and rehabilitation. The main symptoms associated with it are often affecting the movements, painful muscle spasms, stiffness and sleep disturbance. The predominant component of these conditions is 15 finds the hyperexcitability of the tonic stretch reflexes. The tendon jerks are exaggerated, painful spasms may appear and muscle weakness and loss of function and tendency to muscle retraction are almost always observed.

For its part, muscle spasm is a painful contraction of muscles that can cause involuntary movements, and interfere with function. It is usually a symptom, and the primary cause must be treated. Central muscle relaxants and benzodiazepines are used for the treatment of muscle spasms such as hardening that occurs in response to local trauma or joint or musculoskeletal disorders. Contracture or reflex muscle spasm produces stiffness and acts as a protective mechanism to prevent movement and subsequent damage to the affected part. Cramps are muscular spasms of abrupt onset, occur at rest and generally last seconds or minutes. Some are precipitated by dehydration and hyponatremia, by vigorous exercises, excessive sweating, diarrhea or vomiting, drugs or hemodialysis. 30 In both cases the treatments have the objective of preserving and optimizing the Functionalism and mobility, relieve painful muscle spasms, prevent complications such as contractures and facilitate nursing care and rehabilitation. The clinical management of these physiopathological conditions of the musculature usually involve the combination of medications and the use of physical means and sometimes even surgical treatments. Regarding pharmacological treatment, the therapeutic agents used have in common their ability to improve skeletal muscle function mainly through their actions on the central nervous system so they are called spasmolytic or centrally acting muscle relaxants. Most of these medications (those used for the treatment of spasticity and acute muscle spasms) reduce the transmission of impulses from the spinal cord to the skeletal muscle, because they act on the internuncial spinal neurons to depress the polysynaptic pathways, depressing with variable degree of selectivity certain neuronal systems that control muscle tone (Roberts et al., 2003; Turk and Melzac, 2001; Farkas et al., 2005). Spasmolytic drugs can be subdivided into: a) Minor spasmolytics which are used to treat painful spasms with acute self-validating states, some of these are: chlorphenecin, carisoprodol, methocarbamol, chlorzoxasone, cyclobenzaprine, metaxalone, and orphenadrine; and b) Major spasmolytics which are used to treat more severe spasticity associated with pathological processes such as multiple sclerosis or spasticity secondary to a spinal cord transaction, some examples are: baclofen, diazepam, and dantrolene (Hardman et al., 1996) .

The continuous search for new alternatives to alleviate muscle spasm and associated pain have made it necessary to develop new pharmacological strategies, such as the combination of analgesics and muscle relaxants. Taking this into consideration, the present invention consists of the combination of clonixinate of Usina and carisoprodol (CLC) in a single drug in order to improve the level of analgesia and limit the risk of occurrence of adverse effects associated with the administration of high doses of a single drug.

Particularly in the case of the combination lysine clonixinate and carisoprodol, no pre-clinical or clinical studies of the interaction between these drugs have been published.

In the present invention, information is presented at the experimental level that lays the foundations of future clinical applications in the treatment of different stages of associated muscle spasm and pain.

Lysine clonixinate The lysine clonixinate (CL) used in the present invention has the chemical name: lysine salt of 2- (2-methyl-3-chloroanilino) -3-nicotinic acid, represented by the formula Ci3HnClN202, its structural formula is shows in figure 1.

Lysine clonixinate is classified as a "G", which belongs to the family of non-salicylic analgesics and to the subgroup of anthranilic derivatives. Its chemical structure is similar to flufenamic acid, although it is a derivative of nicotinic acid. Its pharmacological efficacy is recognized for the treatment of moderate to severe pain syndromes such as headaches, muscular pains, joints, neuritic; odontalgia, otalgia, dysmenorrhea, post-traumatic or post-surgical pain and even in the treatment of migraine (rymchantowski et al., 2001).

Due to its chemical properties, CL is rapidly absorbed through the gastrointestinal tract and its main mechanism of action is the reversible inhibition of cyclooxygenase enzymes, important catalysts of prostaglandin synthesis; specifically inhibits the enzyme prostaglandin synthetase, responsible for the synthesis of prostaglandins (PGE2 and PGF2alpha), direct stimulants of pain neuroreceptors; by blocking its production, it avoids the acquisition of painful sensitivity, regardless of the cause, intensity and location. It has also been shown that CL inhibits bradykinin and PGF2alpha already produced, so it is considered as a direct antagonist of pain mediators. Lysine clonixinate has an effect powerful analgesic, without altering the vital signs or the state of consciousness of patients, since it is a non-narcotic analgesic. It does not depress the bone marrow or interfere with the coagulation factors, so it does not alter the platelet number or function (Kramer et al., 2001).

Carisoprodol The carisoprodol (CAR) used in the present invention has the chemical name: [2-methyl-2- (l-methyl-ethylcarbamoyloxymethyl) pentyl] aminomethanoate, represented by the formula Ci2H24N204, its structural formula is shown in figure 2.

Carisoprodol is a centrally acting muscle relaxant commonly used in the treatment of musculoskeletal conditions that occur with muscle spasm. This drug is frequently used in association with non-steroidal anti-inflammatories. It is indicated to relieve acute pain in musculoskeletal conditions such as torticollis (muscle contractions), traumatic sports and accidental pain, trauma and muscle strains in fractures. Painful post-traumatic and postoperative inflammations, as well as in painful syndromes of the spine.

The appearance of its effect is rapid and lasts for 4 to 6 hours. The exact mechanism of action of carisoprodol is unknown, however, it is considered that the drug acts causing a state of sedation rather than an authentic muscle relaxation (Littrell et al., 1993).

Lysine Clonixinate and Carisoprodol (CLC) The combination of a muscle relaxant with an analgesic confers a greater benefit to patients who have musculoskeletal problems than the use of an analgesic alone. Commercially there are different combinations of this type for the treatment of different pain syndromes such as: carisoprodol / aspirin; chlorsoxazone / paracetamol; methocarbamol / aspirin; methocarbamol / ibuprofen; diclofenac / carisoprodol and others. To date, there are no experimental or clinical reports about the use of combination of carisoprodol and clonixinate of Usina. The joint formulation of these two drugs aims to improve the level of analgesia and limit the risk of occurrence of adverse effects associated with the administration of high doses of a single drug, while maintaining or even improving the analgesic effect.

Pharmacological Efficacy of the CLC Combination.

To demonstrate the pharmacological efficacy of the clonixinate combination of lysine and carisoprodol, the antinociceptive behavior of CLC was evaluated in experimental models of formalin as an inflammatory pain test, and of abdominal distension as a test of visceral pain in mice. Subsequently, the analgesic interaction between lysine clonixinate and carisoprodol was evaluated by isobolographic analysis for the determination of addition, antagonism or synergism of the antinociceptive effect.

The efficacy as a relaxant of the CLC combination measured in the experimental models of Traction (Tightrope) and generation of the "Straub-Tail" effect by morphine was also evaluated in mice. Finally, the toxicity of CL, CAR and CLC was determined, through a histological study of gastrointestinal damage, and the evaluation of the neurological profile.

In this, as in all the models studied, Balb / C male 6-8 weeks of age, weighing 20-30 g were used. The animals were kept in boxes with food and water ad libitum until the moment of the experiment, and with light-dark cycles of 12 x 12 h. The animals were set for at least one hour.

The duration of the experiment was as short as possible, always considering that the number of animals used was the minimum necessary. Each animal was used for a experiment and was sacrificed immediately after the same following the ethical guidelines for the investigation of pain in experimental animals (Zimmermann, 1983).

Both CAR and CL were used, as raw material provided by Rayere SA Pharmaceuticals. The other reagents were reactive grade and were purchased from Sigma Chemical S.A. or from commercial sources.

Experimental model of formalin administration to evaluate the analgesic response for acute inflammatory pain.

The formalin model representing a model of acute inflammatory pain was used; consists of the subcutaneous administration of formalin (40% sion of formaldehyde) in the dorsal area of the right hind leg of the mouse and the subsequent observation of its behavior which consists of nibbling and / or licking of the injected paw, among others . The cumulative total time of licking of the injected paw was quantified in periods of 5 minutes until completing 60 minutes of observation (Dubuisson and Dennis, 1977). Different groups were used to characterize the dose-response curve of the drugs, administering the two drugs individually, intraperitoneally, 20 minutes before the injection of formalin. The doses for CAR that were used were: 1, 10 and 100 mg / kg, and for CL were: 0.5, 5.0 and 50 mg / kg. Groups of animals with an n of at least 5 mice were used. 0.9% physiological saline was administered intraperitoneally as a control of each experimental set.

The intraperitoneal administration of both drugs 20 minutes before the injection of formalin decreased the biphasic behavior typical of this model of licking / nibbling of the damaged limb. The drugs administered by this route did not modify the motor behavior or reflexes of the animal (pineal and corneal). To determine the analgesic efficacy, the percentage of antinociception was established according to the dose of the two analgesics individually or in combination. The percentage of antinociception was obtained from according to the following equation: Lick time without drug ,,, ?? % Antinociception = - - - X \ 00 licking time without drug - drug licking time Figures 3 and 4 show the dose-response curves (semilog) of CL and CAR, in this phase of the formalin test.

It can be seen that both drugs decrease in a dose-dependent manner the nociceptive behavior, reaching a maximum effect of around 55% and 71.2% for CL and CAR, respectively. Based on the response, in this model the combinations were evaluated by taking the doses of the drugs that generated 50% of the maximum effect (ED50) (Tallarida, 2000). The values obtained from the DE5o (± e.e.) were: 13.42 ± 6.83 mg / kg for CAR and 13.9 ± 2.8 mg / kg for CL.

Subsequently, the theoretical ED50 of the combination carisoprodokclonixinate of Usina (CLC) was calculated from the estimates of the individual ED50 values. Thus, in this model of inflammatory pain, a ratio of 1: 1 .04 was used with different doses of the combination (Table 1).

Table 1.

The result of the systemic administration of the CLC combination in different doses was a decrease in the nociceptive behavior in both phases of the formalin test (Figure 5). The dose-effect curve of the intraperitoneal administration of the CLC combinations revealed a dose-dependent antinociceptive effect in phase 2 of the formalin model without presenting a significant effect on phase 1.

When making the transformation to percentage of antinociception, the semi-logarithmic dose-effect curve of the CLC combination shows the antinociceptive effect dependent on the dose (Figure 6). The maximum effect achieved by the highest dose of the combination is around 70%. It is important to mention that the sum of the individual effects expected (ED50 of each drug) would suggest that for that dose the carisoprodol would contribute 50% of its maximum effect (Emax 71.2%), that is, 35.6% of the maximum possible effect in the model . On the other hand, if it is considered that the Emax of lysine clonixinate was 55.7%, the ED50 of this drug would provide 27.8% of the maximum possible effect of the experimental model, therefore the algebraic sum of such effects would be around 63.4%, which is lower than the 70% mentioned above, that is, the combination produced a maximum effect that exceeds the maximum expected by the sum of the individual effects (Figure 7).

In this way, the experimental DE5o (± e.e.) that was obtained after administering the combinations was 2.06 ± 0.03 mg / kg. Which was significantly lower (p <0.05) than the theoretical additive ED50 (the dose of the combination that only produces a summing effect) of 13.68 ± 3.70 mg / kg. This means that intraperitoneal coadministration of CAR and CL in this nociception model produces a discrete synergistic interaction. The magnitude of the interaction was calculated based on the following formula: dose of drug 1 in the DEso of the combination DEso individual of the drug 1 + two.i.s. of the drug 2 in the DEso of the combination DEso individual of the drug 2 Where? is the drug interaction index, individual ED50 is the dose of drug 1 that has the same effect (50% antinociception) as drug 2 of the combination, and ED50 of the combination, is the dose that has the same 50% of the effect of antinociception.

The interaction index describes the experimental ED50 as a fraction of the theoretical ED50; values close to 1 indicate an additive interaction, while higher values that 1 implies an antagonistic interaction and values less than 1, indicate an enhancement. The value of ? calculated was 0.150 (± 0.042), which confirms the synergistic interaction between the drugs after an intraperitoneal administration. That is to say after a co-administration i.p. of CAR and CL the same level of antinociceptive effect is reached (50%), being able to reduce the doses of both drugs approximately 6.6 times.

For isobolographic analysis, due to the nature of the model and the fact that both CAR and CL have limited effects in the first phase of this test, only the effect of both drugs in the second phase was considered. The interaction between the drugs in terms of the effect Antinociceptive can be clearly seen in the isobologram (figure 8). In this graph are plotted in each axis, the dose values of CL and CAR, the line that connects the points that represent the ED50 of each drug, is called isobola or line of additivity and in this line are all possible combinations of the two drugs that will produce only a theoretical effect of additivity or summation, in this case the experimental point is below the line of additivity or isobola, indicating a synergistic interaction when coadminister CAR and CL. If, on the contrary, the experimental point had fallen above this line of additivity, it wobe said that an antagonism occurred when co-administering the two drugs, which was not the case.

Experimental model of abdominal stretching to evaluate the analgesic response to visceral pain.

The visceral pain model used in this study was the "Writhing Test" abdominal stretching model (Frussa-Filho et al, 1996). According to this method, 0.5 ml of 1% acetic acid was administered intraperitoneally in mice previously set in transparent acrylic cylinders. Immediately after administration, the number of contortions (characterized by a slight arcing of the back, development of tension in the abdominal muscles, elongation of the body and extension of the extremities) was observed during 30 min at 5 min intervals.

For the characterization of the temporal curve and the analgesic response, groups of animals with an n of at least 5 mice were used to which they were applied via i.p. Different doses of the drugs, 20 minutes before the administration of acetic acid. The doses for CAR were: 1, 10, and 100 mg / kg and for CL of: 0.5, 5 and 50 mg / kg of weight. As a control of each experimental game, it was administered via i.p. a 0.9% physiological saline solution.

The pretreatment with both analgesics 20 minutes before the nociceptive agent caused a decrease in the behavior of abdominal contortions. However, neither the CAR nor the CL completely ablated the behavior at the dose level evaluated. Both drugs they partially reduced this behavior, even at doses of 50 mg / kg and 10 mg / kg, for CL and CAR, respectively. Likewise, the drugs administered by this route did not modify the motor behavior or reflexes of the animal (pineal and corneal). Figures 9 and 10 represent the dose response curves (semilog) transformed to percentage of antinociception vs dose. The percentage of antinociception was calculated from the formula: num of contortions sm drug% Antinociception - - r X \ 00 num. of contortions without drug - num. of contortions with drug It can be seen that both drugs diminish in a dose-dependent manner the nociceptive behavior although, in neither of the two cases, a total suppression of the nociceptive behavior triggered by the administration of acetic acid was achieved. When carrying out the dose-effect curves of the two drugs, it was possible to demonstrate that while CL is only possible to reach a maximum effect of around 50%, in the case of CAR the maximum effect observed was around 70%, for that reason reason was decided to use the DE5o as an efficacy parameter to evaluate the nature of the analgesic interaction.

The estimates of the DE5o (± e.e.) of the drugs were: CAR 6.3 ± 0.02 mg / kg and CL 64.8 ± 10.5 mg / kg. From the estimates of the values of the previous ED50, the CAR: CL ratio of 1: 10.3 was obtained, with which different doses of CAR and CL were prepared.

The total dose of the combination, as well as the dose of each drug in each combination is shown in Table 2.

Table 2 The systemic administration of the different doses of CLC decreased the nociceptive behavior in this pain model (Figure 11). In addition, the semilogarithmic dose-response curve revealed a dose-dependent antinociceptive effect (Figure 12).

From these graphs we can see the maximum effect achieved by the highest dose of the combination (ED50 of each drug) is around 82.1%. It is important to mention that the sum of the individual effects expected (ED50 of each drug) would suggest that for this dose the CAR would contribute 50% of its maximum effect (71.3%), that is, 35.6% of the maximum possible effect in the model. On the other hand, if it is considered that the Emax of CL was 48%, the ED50 of this drug would contribute around 24% of the maximum possible effect of the experimental model, therefore the algebraic sum of such effects would be around 59.6%.

In contrast, the highest dose of the combination produced a maximum effect close to 82%, which exceeds the maximum expected by the sum of the individual effects.

In this way, the experimental ED50 (+ e.e.) That was obtained after administering the combinations was 5.75 ± 0.01 mg / kg. Which was significantly lower (* p < 0.05) than the theoretical additive ED50 of 35.5 ± 16.1 mg / kg which is the dose of the combination that only produces a summing effect (Figure 13). This means that the intraperitoneal coadministration of CAR and CL in this nociception model produces a synergistic interaction. The interaction index was 0.162 (± 0.05), which confirms the synergistic interaction between the drugs for the relief of visceral pain after an intraperitoneal administration. That is, after an intraperitoneal coadministration of CAR and CL, the same level of antinociceptive effect is reached (50%) but the doses of both drugs can be reduced approximately 2.8 times.

The visual representation of the interaction at a systemic level between the drugs can be clearly observed in the isobologram (Figure 14), in which the experimental point (*) is well below the line of additivity or isobola, indicating the presence of a synergistic interaction when co-administered intraperitoneally by CAR and CL.

Efficacy As Relaxer of the CLC Combination To evaluate the relaxing effect of the CLC combination, the experimental models of inhibition of the "Straub-tail" effect by morphine and "Tight Rope" traction in mice were used, determining the magnitude of the pharmacodynamic interaction underlying this combination of drugs.

The effect of Straub-tail (tail straightening) is caused by the action of morphine at the spinal level. In this model, the mice are injected subcutaneously with morphine, which triggers the straightening of the tail at an angle greater than 45 degrees, and this effect is maintained for at least 3 hours after the administration of the opioid. »The previous administration of a muscle relaxant inhibits this effect, so it is used as a method to evaluate the potential as a muscle relaxant of different drugs (Farkas et al., 2005).

In this study, morphine was used at a dose of 60 mg / kg of weight to cause the Straub-tail effect, 5 minutes later and in order to validate the usefulness of the model, an agent with recognized relaxing effect was administered orally as the clonazepam (CLON), 15 minutes after the administration of the relaxant, the Straub-tail effect was clearly inhibited. In the study groups, v.o. CAR, CL and the CLC combination.

The experimental model of traction (tightrope), unlike the previous model that measures recovery from a state of abnormal muscle hyperactivity, in this model is evaluated the loss of normal motor muscle function, so it is considered a model of muscle weakness, which may well be considered a side effect. This model consists of placing the animal by its front ends on a rope suspended between two poles at a height of 20 cm. The animals are administered with the test drugs and 60 minutes later the number of them is counted, out of a total of 10, that are not able to hold on the rope for at least 60 seconds, considering negative if the animal is sustained with only one leg, or when it exhibits weak behavior in the hind legs that prevents straightening compared to control animals.

Different groups of animals (n = 10) were used to characterize the dose-response curves of CAR, CL and CLON in both experimental models. Based on the doses that were previously effective in an inflammatory pain model, the CAR and CL were administered in doses of 1, 10, 100 and 150 mg / kg po, and 0.5, 5.0 and 50.0 mg / kg po. respectively. Clonazepam (CLON) was used in pharmaceutical presentation as a positive control of the muscle relaxant effect. The evaluated doses of CLON were 0.01, 0.1 and 1 mg / kg po. Saline was administered as control of each experimental game.

The treatment with CAR and CLON produced a decrease in the Straub-tail effect that was dose dependent, in figure 15 the dose-response curve in scale is shown semilogarithmic, measured as percentage of responders. The differences between the control group and the treatments to construct the dose-response curve were analyzed by means of the? 2 test. The dose-response curves were evaluated to obtain the power indicators (DE5o) by means of the Probit method according to Tallarida (2000).

Figure 16 shows the same relationships as in Fig. 15, with the transformation to Probit units. From the latter, the necessary doses were obtained to reach 50% (DE5o) of the maximum possible effect of each drug. It is worth mentioning that CLON was used as a positive control to verify the proper functioning of the experimental models and was only used in this experimental phase.

On the other hand, as discussed below, in the case of LC no relaxing effect was presented in any of the tests, so the subsequent experiments only apply to the evaluation of the relaxing effect of carisoprodol alone and in combination with fixed doses of CL . As expected, the CLON has a relaxing power much higher than that of CAR (more than 700 times). On the other hand, it was possible to demonstrate that CL does not have a relaxing effect in this experimental model even at doses as high as 50 mg / kg po.

Analogously to what was observed in the previous model, both CAR and CLON produced a decrease in the clamping capacity of the mice to the tight string (muscle weakness), which was dependent on the dose, as can be seen in the figures 17 and 18. These figures show the dose-response curves, measured as a percentage of responders, as well as using the Probit-derived scale, for both drugs. In this case, it was evident that the ED 50 of the drugs were superior to those found in the previous model, however, CLON maintains a relaxing power much higher than that of CAR. CL did not present a relaxing effect in this experimental model even at doses as high as 50 mg / kg po, so the evaluation of the interaction of the relaxing effect of the CLC combination could not be evaluated by means of isobolographic analysis.

Farkas et al. (2005) suggested that a more predictive form of the potential as a muscle relaxant of drugs is the establishment of the quotient of the collateral effect / DE5 or muscle relaxation.

This quotient was estimated at 1.43 for the CAR case and 0.66 for the CLON case.

Evaluation of combinations To evaluate the potential as a muscle relaxant of the CLC combination, the quotient was used; DE50 collateral effect / DE5o muscle relaxation, so these quotients were calculated for the experimental models proposed (Farkas et al., 2005). Considering that the ED50 value of carisoprodol obtained in the Straub-tail inhibition model should correspond to the relaxing effect rather than the one producing muscle weakness (traction model), such DE5o (65.1 mg / kg po. ) and was tested in combination with fixed or increasing doses of CL (0.05, 0.5 and 5 kg / mg po.) to determine if the latter was able to enhance the effect of CAR. The treatment with the ED50 of CAR produces in 50% of the cases, a failure in the inhibition of Straub-tail induced by morphine, whereas when administering increasing doses of CL, 0.5 mg / kg, 5 mg / kg and 50 mg / kg such opioid effect is gradually inhibited until reaching the maximum with the highest dose of CL. The differences between the DE5o of carisoprodol alone and combined with CL were compared with a test? 2. Values of p < 0.05 indicated statistically significant changes. Quantitatively the previous experiment is illustrated in Figure 19 in which it is shown how the presence of LC produces an increase from 10 to 20% in the proportion of mice that respond to the relaxing effect in both the Straub-tail inhibition model (Fig. 19) as in that of the tight string (Fig. 20).

Evaluation of adverse effects It is well known that muscle relaxants can induce different adverse effects due to their action on the central nervous system. During the development of all The aforementioned experiments were performed an evaluation of the neurological profile, which consists in the qualification of changes in behavior / indicator with respect to the control of the following parameters: 1. excitation: urine / excrement, alarm response, agitation, allodynia and general shaking . 2. motor function: exploratory walk, righting reflex, asymmetric spinal posture, asymmetrical walk, circle walk, loin arch. 3. Others: reflex of ear, corneal reflex and serpentine tail. The results of that evaluation are shown in table 3.

Table3.

On the other hand, other changes related to the normal vegetative function were also evaluated in comparison with the different treatments (Table 4). From these tables it could be seen that only the administration of CLON at high doses is associated with the appearance of important adverse effects of the central type.

Table 4 In order to study the effect of drugs at the gastrointestinal level, a study was made using 5 experimental groups of 10 mice each, to which they were administered systemically (intraperitoneally) the highest doses of both individual drugs as of the combinations (CAR: 100 mg / kg; LC: 50 mg / kg, CAR-CL (1: 10): 35.55 mg / kg; CAR-CL (1: 1): 13.68 mg / kg), comparing the observations with respect to a control administered with saline. This administration was done every 24 hours, 2 times per day for three days. At the end of the study, the mice were sacrificed by cervical dislocation and the stomachs were obtained to undergo a histological study, where the possible damage or appearance of ulcers or bleeding was evaluated. In this study it was observed that there were no significant differences in the gastrointestinal tract (GI) in control mice compared to mice treated with CAR at the highest dose. The macroscopic observation of the GI tissue did not indicate the presence of abnormalities even in those treated with CAR 100 mg / kg and not in the other treatments.

In conclusion, according to the evidence presented, it was demonstrated that the combination of CAR and CL administered systemically produces the enhancement of the individual analgesic effects of the drugs, and the magnitude of synergism depends on the type of pain to be fought, ie the combination CLC is equally effective but more potent in the treatment of inflammatory pain than in visceral pain. On the other hand, synergism also depends on the composition of the combination, although in both cases more CL than CAR is required in the combination.

Indeed, the combination containing CAR and CL in a 1: 1 ratio is suitable for the treatment of inflammatory pain with a reduction in the need of each agent close to 6.6 times with respect to the individual use of each drug. On the other hand, the CAR-CL combination in a 1: 10 ratio is effective to treat visceral pain, generating a reduction of around 6.1 times compared to the need for individual drugs.

Regarding the relaxing effect of the CLC combination, the relaxing potential of CL was evaluated and it was found that even at doses as high as 50 mg / kg po., It does not present relaxing effects in both experimental models.

For that reason, the isobolographic analysis approach (Tallarida, 2000) could not be used to evaluate the magnitude and nature of the interaction. In any case, using a different approach in which the effect of increasing doses of CL on the ED50 of CAR was evaluated. The experimental results showed that the combination of the ED50 of CAR (65.1 mg / kg) + a dose of 5 mg / kg of CL (a ratio 1: 13, CAR: CL) produced the enhancement of the muscle relaxing effect of CAR and only collateral effects were present with high doses of CL.

In conclusion, based on the analgesic and relaxing effect of the CLC combination, it can be suggested that this combination represents a good alternative for the control of muscle spasm and the pain associated with it.

The combination of lysine clonixinate and carisoprodol mentioned in the present invention can be formulated into different pharmaceutical forms for use as an analgesic. The dosage forms can be both solid forms such as; tablets, capsules, suspensions; semisolid such as suppositories and as oral and injectable solutions for intramuscular and intravenous administration.

The combination of lysine clonixinate and carisoprodol can be formulated in mixtures with conventional excipients, ie, organic or inorganic substances which act as appropriate vehicles for the modes of oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other mode of administration. appropriate administration that is described in the state of the art.

Suitable pharmaceutically acceptable vehicles include but are not limited to: water, saline solutions, alcohols, gum arabic, vegetable oils, benzyl alcohol, polyethylene glycols, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, paraffin, perfumed oils, monoglyceride and diglyceride fatty acids, fatty acid esters of pentaerythritol, hydroxymethylcellulose, polyvinylpyrrolidone, etc.

The pharmaceutical compositions can be sterilized and if required can be mixed with auxiliary agents, eg, lubricants, preservatives, stabilizers, humectants, emulsifiers, salts to modify the osmolarity, pH buffers, substances to give color, flavor and / or aromatic substances and similar.

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Claims (1)

1. CLAIMS 1. An analgesic pharmaceutical composition characterized in that it comprises: a combination of carisoprodol its enantiomers or mixture thereof or any of its pharmaceutically acceptable salts in all its crystalline forms and of lysine clonixinate as well as its hydrates, or any of its pharmaceutically acceptable salts in all its crystalline forms, in a carisoprodolxlonixinate lysine ratio that can vary from 1: 0.5 to 1: 100 (w / w) respectively. 2. The composition according to claim 1, characterized in that it also comprises pharmaceutically acceptable excipients. 3. The composition according to claim 2, characterized in that it has a pharmaceutical dosage form that is selected from the group consisting of: tablets, capsules, oral solutions, injectable solutions, oral suspensions and suppositories. 4. The composition according to claims 1 to 3, characterized in that the carisoprodol is: [2-methyl-2- (l-methylethylcarbamoyloxymethyl) pentyl] aminomethanoate or any of its pharmaceutically acceptable salts. 5. The composition according to claim 4, characterized in that the carisoprodol is preferably [2-methyl-2- (l-methylethylcarbamoyloxymethyl) pentyl] aminomethanoate. 6. The composition according to claims 1 to 3, characterized in that the lysine clonixinate is: the lysine salt of 2- (3-chloro-2-methyl-phenyl) aminopyridine-3-carboxylic acid. 7. - The composition according to claims 1 to 3, characterized in that the proportions of carisoprodol: lysine clonixinate are preferably 1: 1 and 1: 13. 8. The composition according to claim 7 characterized in that the ratio carisoprodolxlonixinato of lysine of 1: 1 .2 is suitable for relieving inflammatory pain 9. - The composition according to claim 7 characterized in that the ratio carisoprodolxlonixinato de lysine of 1: 10 is suitable for relieving pain visceral. 10. The composition according to claim 7, characterized in that the ratio carisoprodol lonixinate lysine of 1: 13 is adequate to cause muscle relaxation. 1. The use of the composition according to claim 1 as a muscle relaxant. 12. The use of the composition according to claim 1 as an analgesic. 13. - The use of the composition according to claim 1 for preparing a medicament for the treatment of pain. 14. The use according to claims 8, 9 10, 11 and 12 wherein the pain is pain caused by spasm or muscle contracture. 15. - The use of the composition according to claim 14 wherein the pain is associated with: sprains, fractures, muscle contractures (torticollis), lumbago, bursitis; musculoskeletal and odontological surgical processes, etc. SUMMARIZES The present invention relates to pharmaceutical compositions containing a muscle relaxant known as carisoprodol and the other a non-steroidal anti-inflammatory analgesic known as Usin clonixinate. When both drugs are combined in specific proportions the combination produces pharmacological effects that indicate synergy, so it is possible to use less of both drugs to achieve the same degree of analgesia and muscle relaxation as when used alone, with the advantage of having fewer adverse effects.