Aripiprazole and tramadol compositions with potentiation effects and high analgesic efficacy useful for the treatment of neuropathic pain

Abstract

. The present invention describes pharmaceutical compositions comprising the synergistic combination of aripiprazole (ARI) and tramadol (TRA), compounds with different mechanisms of action, wherein one of them is a compound not classified as an analgesic and the other is a classical analgesic, which exhibit analgesic potentiation effects (anti-allodynic and anti-hyperalgesic) and maximum analgesic efficacy effects (anti-allodynic and anti-hyperalgesic), which are effective against allodynia and hyperalgesia occurring in neuropathic pain, making them useful for the treatment of pain.

Description

[0001] Aripiprazole and tramadol compositions with potentiation effects and high analgesic efficacy useful for the treatment of neuropathic pain

[0002] Field of the invention.

[0003] The present invention relates to the field of compositions useful for the treatment of pain, particularly to compositions comprising synergistic combinations of various drugs for the treatment of pain, more particularly to pharmaceutical compositions comprising combinations of aripiprazole (ARI) and tramadol (TRA) with potentiation effects and high analgesic efficacy, wherein said combinations show activity as anti-hyperalgesics and anti-allodynics in neuropathic type pain, thus remaining very useful for the treatment of neuropathic pain.

[0004] Background of the invention.

[0005] Pain is an experience that people have experienced at least once and has a great impact on the quality of life, it is considered to be one of the main reasons why people need medical treatment (1). Although it can be classified in different ways, all are correct as they describe it from very different points of view. Within a general classification, pain can be divided mainly into 3 types, nociceptive pain, inflammatory pain and pathological pain. The latter is characterized by an abnormal functioning of the nervous system, it does not have a protective role, on the contrary, it is maladaptive. Furthermore, it can be subclassified into two categories, dysfunctional pain and neuropathic pain (NPD) (2).

[0006] In 2017 representatives of the International Society for the Study of Pain (IASP) defined NPD as "Pain caused by injury or disease of the somatosensory nervous system"(3). Epidemiological studies estimate that 7 to 8% of the population suffers from this condition (4). NPD is characterized by sensory loss in the affected area, generation of continuous or intermittent spontaneous pain, dysesthesia, paresthesia and the development of hypersensitivity, presenting hyperalgesia and allodynia (5).

[0007] Today there is no pharmacological therapeutic tool that covers and minimizes 100% the repercussions of the different types of NPD. The IASP published a series of recommendations for their treatment. Tricyclic antidepressants (amitriptyline, desipramine or imipramine), anticonvulsants (gabapentin or pregabalin) and some latest generation antidepressants (duloxetine or venlafaxine) are suggested as the first line of treatment (6-7). On the other hand, opioid-type drugs such as tramadol are used in second instance (6,8).

[0008] Opioid compounds are a group of drugs that interact with opioid receptors (OR) in a similar way as endogenous opioid peptides (such as endorphins), and are used in therapeutics for the treatment of different stages of pain, mainly for moderate to severe chronic pain and DNP (9). In addition to the analgesic effect of opioids, there is the possibility of undesirable effects such as sedation, euphoria, dysphoria, fatigue, nausea, vomiting, hypotension, gastrointestinal hypomotility (constipation), respiratory depression, pruritus and urinary retention among others (10). Likewise, repeated or chronic opioid treatments can develop different degrees of pharmacological tolerance and physical dependence (9). One of the main reasons why opioid-based treatments have been studied is to improve their effectiveness in different aspects, such as, for example, obtaining a greater degree of relief (efficacy), minimizing the doses administered, reducing the appearance of adverse effects and trying to avoid or delay the development of tolerance, among others.

[0009] For these reasons, it is extremely necessary to find new pharmacological treatments for pain relief, since there is no completely effective therapeutic strategy and, to top it off, their use can bring with it a series of adverse effects (11). As a result of this problem, new alternatives have arisen to find molecular entities that can enter the market quickly and without high investment. A novel strategy is drug repositioning (also known as therapeutic switching, drug reuse, drug reassignment or drug reprofiling), where this alternative avoids some of the most important challenges in classical drug development, thus optimizing the entry of drugs into the clinical phases (12). This tool consists of identifying new therapeutic indications for known drugs or drug candidates that failed in their initial purpose, i.e., those entities that were discarded for a certain condition due to their low efficacy (12- 13). For example, it has been shown that drugs designed to treat other pathological conditions also have analgesic properties, as is the case of some antibiotics (ceftriaxone) (14), antidepressants (amitriptyline, duloxetine and venlafaxine) (7), anesthetics (lidocaine and ketamine) (15) and anticonvulsants (carbamazepine, gabapentin, pregabalin and lamotrigine) (16) among other groups of drugs. Finally, the new application of antipsychotics, as drugs that modulate nociceptive behaviors, stands out (17).

[0010] Another tool for the optimization of therapeutic treatments are combination strategies, where the aim is to ensure that the individual components generate a synergistic interaction, i.e. that the resulting effect of the combination, i.e. of the pharmacological interaction, is greater than a simple addition of effects (18-20). Drug combinations have different advantages compared to the administration of a single compound, including the ability to act on multiple pharmacological targets by having different mechanisms of action, making the treatment more effective, they can reduce the doses used, avoiding toxicity and in repeated or chronic use, where they can minimize or delay the development of pharmacological tolerance (18).

[0011] On the other hand, various solutions for the treatment of DNP have been reported, such as compositions comprising pregabalin and meloxicam (21), metamizole and morphine (22), sibutramine optionally in combination with phosphodiesterase or lipase inhibitors (23), phenoxymethyl piperidine derivatives and sodium channel blockers (24), as well as non-racemic mixtures of d- and I- methadone (25); However, these solutions are insufficient for the treatment of DNP.

[0012] Therefore, it is necessary to have more and better solutions for the treatment of NPD.

[0013] Brief description of the figures.

[0014] Figure 1. Time course (TC) of the evaluation of control groups (SHAM and CCI) for the anti-allodynic effect in the experimental model of chronic sciatic nerve constriction injury (CCI) in rat.

[0015] Figure 2. CT of the evaluation of control groups (SHAM and CCI) for the anti-hyperalgesic effect in the experimental model of chronic sciatic nerve constriction injury (CCI) in rats. Figure 3. CT of the anti-allodynic (analgesic or antinociceptive) effect of 4 doses of ARI (0.1-10.0 mg / kg) imp. in DNP rats in the rat CCI experimental model.

[0016] Figure 4. CT of the anti-allodynic (analgesic or antinociceptive) effect of 7 doses of TRA (0.1-31.6 mg / kg) i.p. in DNP rats in the CCI experimental model.

[0017] Figure 5. CT of the anti-hyperalgesic effect (analgesic or antinociceptive) of 4 doses of ARI (0.1-10.0 mg / kg) i.p. in DNP rats in the CCI experimental model.

[0018] Figure 6. Dose-response curves (DRC) of the antiallodynic (analgesic or antinociceptive) effect produced by individual administration of ARI and TRA in DNP rats in the CCI experimental model. The total effect is expressed as area under the curve (ABC) of the corresponding TCs in Figure 3 and 4. Figure 7. CDR of the antiallodynic (analgesic or antinociceptive) effect of ARI and TRA administered individually, as well as the combination of ARI 10 mg / kg + TRA in rats with DNP in the CCI experimental model.

[0019] Figure 8. Overall analgesic (anti-allodynic) effects produced by the combination that generated potentiation and that used small doses of both drugs in combination (ARI 10 mg / kg with TRA 0.1 mg / kg) compared to the effect of the individual components and the theoretical sum of the treatments. Figure 9. CT obtained during 3 hours of evaluation of the antiallodynic effect produced by the individual administration of ARI 10.0 mg / kg, TRA 0.1 mg / kg, and the combination of ARI + TRA in these same doses, being this the combination that generated supra-additive effect (potentiation) and that used the lowest individual doses. The antiallodynic effect was increased by 18.84% over the sum of individual effects.

[0020] Figure 10. Overall analgesic effects from evaluation of the ARI + ART combination with doses generating high antiallodynic efficacy compared to an individual ART dose required to achieve the same % antiallodynia. It is also compared with the individual effects that make up the combination. The same antiallodynic effect produced individually by the most effective dose of TRA (31.6 mg / kg), but using 10 times less dose, can be achieved by using TRA (3.1 mg / kg) in combination with a dose of ARI (10 mg / kg).

[0021] Figure 11. CT of the evaluation of the antiallodynic effect produced by single administration of ARI 10 mg / kg, TRA 3.1 and 31.6 mg / kg and the combination of AR1 10 mg / kg + TRA 3.1 mg / kg that generated high analgesic efficacy in the CCI model of DNP. The components of the combination (in small doses) interacted to produce an overall effect equal to that produced by TRA, but with 10 times the individual dose of TRA.

[0022] Figure 12. Overall effect analysis of the combination ARI 10 mg / kg + TRA 17.8 mg / kg that generated the maximum anti-allodynic efficacy, compared to the individual components of the association, the theoretical sum and the combination that generated high anti-allodynic efficacy (ARI 10 mg / kg + TRA 3.1 mg / kg).

[0023] Figure 13. CDR of the effect anti-hyperalgesic (analgesic or antinociceptive) produced by individual administration of ARI and TRA in DNP rats in the CCI experimental model. The total effect is expressed as ABC of the corresponding TCs. Figure 14. CDR of the anti-hyperalgesic (analgesic or antinociceptive) effect of the compounds administered individually, as of the combination of ARI 10 mg / kg with different doses of ART.

[0024] Figure 15. Global analgesic anti-hyperalgesic global analgesic effects of the combination ARI 10 mg / kg with TRA 0.1 mg / kg, doses that produce maximum anti-hyperalgesic potentiation, compared with the theoretical sum of the individual effects generated by each compound, and compared with the individual effects of ARI 10.0 mg / kg and TRA 0.1 mg / kg, same doses that form the combination. There was a greater effect than the theoretical sum (43.65% increase), so that a supra-additive interaction (potentiation) in the anti-hyperalgesic effect is evident.

[0025] Figure 16. CT of the evaluation of the antihyperalgesic (analgesic or antinociceptive) effect produced by single administration of maximally potentiated AR1 10.0 mg / kg, TRA 0.1 mg / kg, and the combination of ARI + TRA (at the same doses administered individually). The antihyperalgesic effect was increased beyond the sum of individual effects.

[0026] Figure 17. Anti-hyperalgesic evaluation in the CCI model of the combination ARI 10 mg / kg + TRA 10 mg / kg, compared with the individual effects of ARI and TRA at the same doses of the combination, and with the highest evaluated dose of TRA (31 .6 mg / kg) and with the theoretical sum. It is evident that the combination ARI + TRA at optimal doses generates a highly effective anti-hyperalgesic effect similar to that produced by the most effective dose of TRA (31.6 mg / kg), reducing 3.16 times the opioid dose when co-administered with the antipsychotic.

[0027] Figure 18. Evaluation of the motor coordination of the individual and combined treatments through the Rota-Rod test. Evidencing that with the combination of greater potentiation and greater efficacy, no greater motor incoordination is produced than that already produced by the individual compounds in their most effective doses.

[0028] Figure 19. Evaluation of the gastrointestinal transit of the individual treatments and in combination to determine the degree of constipation through the activated charcoal test. Evidencing that with the combination of greater potency and greater efficacy, the gastrointestinal transit is not affected compared to control, and that TRA in its more effective dose produces greater alteration of the gastrointestinal transit than that produced by the combinations.

[0029] Detailed description of the invention.

[0030] The present invention provides pharmaceutical compositions comprising synergistic combinations of aripiprazole (ARI) and tramadol (TRA) which, when administered in reduced and precise doses together, produce synergistic analgesic effects, thus optimizing current strategies for the treatment of pain, particularly neuropathic pain (NPD). As described in the present invention, by combining aripiprazole (ARI) and tramadol (TRA) in different proportions, synergistic interactions of interest of additive and supra-additive (potentiation) type in the anti-allodynic and anti-hyperalgesic effect are obtained, i.e. they better relieve, for example, neuropathic pain, consequently the compositions of the invention turn out to be very useful and with great therapeutic potential for the treatment of DNP.

[0031] The combination of some drugs has a very important potential in therapeutics. In the field of pain pharmacology, it is intended that the combinations present a potentiated analgesic effect, maximizing efficacy and minimizing the incidence of adverse effects (26) which is highly related to safety. Based on this and in accordance with the present invention, the possibility of generating a new innovative therapeutic alternative arises, which involves the use of an opioid drug such as TRA, used for the treatment of DNP, in conjunction with a drug that interacts with dopamine receptors subtype 2 (RD2), for example, ARI, an antipsychotic, of which there are some reports of antinociceptive activity in DNP. For the purposes of the present invention, the first component of the pharmaceutical compositions described herein is TRA, a drug approved for the management, treatment and relief of moderate to severe pain (27). Its mechanism of action is based on the activation of mu (p) and kappa (K) receptors, whose affinity toward these receptor subtypes is low. In addition, it presents a second mechanism of action based on the modulation of monoaminergic systems. TRA is a blocker of noradrenaline (NA) and serotonin (5-HT) reuptake, giving it properties as an inhibitor of pain transmission in the spinal cord (28-29). Compared to other members of its pharmacological family, ART has a therapeutic profile with a greater number of advantages due to its duality in pain modulation, a lower incidence of adverse effects and a lower potential for abuse (27). However, the use of ART, depending on its dose, is limited by the occurrence of some adverse effects such as dizziness, vomiting, nausea, drowsiness and constipation, as well as seizures and serotonin syndrome due to the inhibition of 5-HT and NA reuptake (30). In order to improve the therapeutic profile and reduce the occurrence of adverse effects, TRA has been combined with drugs with different mechanisms of action to obtain additive or preferably synergistic effects. TRA has been combined with clonidine (a2-adrenergic agonist), acetaminophen, ketorolac, metamizole, gabapentin, amlodipine, dexketoprofen, among others (26,29,31-34).

[0032] The second component of the pharmaceutical compositions described herein is ARI, an atypical antipsychotic. This group of drugs is primarily used for the treatment of schizophrenia and bipolar disorder (35), and has also been recognized as an adjuvant analgesic (36). In clinical practice, atypical antipsychotics such as risperidone, olanzapine, quetiapine, ziprasidone and ARI have been used for the treatment of various stages of chronic pain such as diabetic neuropathy, post-herpetic neuralgia, headache, facial pain, musculoskeletal pain, cancer-associated pain and fibromyalgia (37). ARI is a drug that exerts its pharmacological effects through partial activation (agonism) of RD2 and 5-HTIA (17), it is also a 5-HT2A receptor antagonist (38). In addition to its antipsychotic activity, it has properties for the treatment of mood disorders and for the treatment of disorders related to substance abuse (17). Compared to other drugs of the same family, ARI has a lower incidence of adverse effects, e.g., low extrapyramidal disturbances, minimal increases in the subject's weight, and does not generate elevation in serum prolactin level or complications related to the cardiovascular system (39).

[0033] ARI is of great importance for several reasons; one of them is the antinociceptive (analgesic) potential in various preclinical pain models such as the formalin model (inflammatory-type pain) (17), the Randall Sellito model (mechanical hyperalgesia) (17,40), in the von Frey filament assay (tactile allodynia) (14,41) and in the hot plate test (41) in animals with peripheral neuropathy. Additionally, ARI is able to reduce some of the undesirable effects generated with the use of opioids (42), and in addition, it can increase the duration of the antinociceptive effect of opioids such as morphine (36) and reverse, to a certain degree, the pharmacological tolerance generated by the acute administration of this same opioid (36). In addition to preclinical evaluations, information about its possible analgesic potential in patients has been obtained due to some clinical observations. There are clinical data of patients with chronic pain who improved after administration of low doses of ARI, in a range of 2 to 6 mg / day; globally, people presented a reduction of pain and an increase in their motivation (43). Subsequently, another clinical study found that people with psychiatric disorders and some pain comorbidities were treated with ARI to improve their psychopathological condition. Unexpectedly, they presented a moderate improvement in their painful condition after 2 weeks of treatment and by the fourth week, the relief was significant (44).

[0034] Additionally, different reports show that low doses of ARI (1 mg / day) generate relief of burning mouth syndrome or glossodynia (45), where the treatment of this condition usually includes antidepressants or benzodiazepines. For example, amitriptyline (antidepressant) is frequently used, but the development of pharmacological tolerance has been observed and even if the dose is increased, it is not possible to obtain total relief and the adverse effects begin to become noticeable. The combination of amitriptyline with ARI (20 or 30 mg / day + 1 mg / day, respectively) has been reported, obtaining almost complete pain relief (46). Furthermore, if both treatments are compared, monotherapy with ARI presented a lower incidence of adverse effects (47). This is a clear example of how the combination with ARI improved the overall analgesic effect and how the compound can present synergistic interactions with different types of drugs. These clinical observations provide evidence of the possible analgesic potential of ARI administration in DNP.

[0035] Based on this background, in the present invention we proceeded to detect and optimize a therapeutic strategy by generating synergism between TRA and ARI , in order to obtain with low doses, potentiation antiallodynic and anti-hyperalgesic effects and high analgesic efficacy to treat DNP. Until before the present invention, there were no previous studies showing or suggesting that the combination of TRA with ARI produces synergism of potentiation of analgesic effects (anti-allodynia and anti-hyperalgesia) which are very useful for the treatment of DNP.

[0036] The present invention is intended to provide pharmaceutical compositions comprising appropriate (optimal) combinations of ARI and TRA that produce high antinociceptive efficacy or greater analgesic effects (synergism) with lower doses (less likely to cause adverse effects), which are extremely useful for the treatment of pain, e.g., neuropathic pain (NPD).

[0037] It is one of the modalities of the invention to provide pharmaceutical compositions comprising the unit ratio of 100:1 and 3.2:1 times by weight of ARI and TRA respectively, to obtain anti-allodynic or anti- hyperalgesic effects of high or maximum efficacy, thus significantly reducing the necessary doses of the opioid in combination, since to obtain the same efficacy with the opioid in single administration it is necessary to administer 316 and 10 times higher doses of the single opioid. The treating physician can adjust the unit dose, as well as the maximum daily dose, which has an optimized anti-allodynic and / or anti-hyperalgesic effect described, and which he / she considers to be the best, depending on the circumstances of each patient.

[0038] It is another mode of the invention, the possibility of using the pharmaceutical compositions described herein, comprising 100:1 times, 3.2:1 times by weight of ARI:TRA, and pharmaceutically acceptable derivative salts thereof, to prepare a medicament for the effective and efficient treatment of DNP with the lowest possible doses.

[0039] It is another embodiment of the invention to use pharmaceutical compositions comprising synergistic combinations of ARI and TRA suitable to be administered subcutaneously, orally, intraperitoneally, intramuscularly, intravenously or topically, in doses that are synergistically effective for the relief of allodynia and / or hyperalgesia occurring in neuropathies.

[0040] It is another of the modalities of the invention, the possibility of formulating pharmaceutical forms comprising as active principles ARI and TRA or their pharmaceutically acceptable salts to make them administrable by different routes to the patient who requires it, being able to be a mammal including the human, and being able to be adapted to carry the unitary doses that allow exerting the analgesic effect described in the treatment of allodynia or hyperalgesia in the DNP, where the pharmaceutical forms are obtained by a person from the technical field of pharmacology without being limited to any specific one, and seeking to preserve the efficacy of the drugs in terms of the synergistic effect described, either by releasing the active ingredient quickly or slowly, or instead seeking the highest efficiency in the target tissue, avoiding damage to the patient by chemical interaction, solubilizing insoluble substances, improving flavors, improving aspects and facilitating the doctor the posology to perform the treatment, being the different existing pharmaceutical forms solid, semisolid or liquid, for example: powders (which may be encapsulated), granules and tablets or tablets, pills, and suppositories. Also its administration in patches and in semi-solid pharmaceutical forms: ointments, pastes, gels, or liquid pharmaceutical forms: solutions, injections, syrups, suspensions or eye drops. Examples of pharmaceutically acceptable excipients accompanying the active principles of the invention are for example, for oral administration as tablets or tablets, agents comprising for example, diluents, binders, stabilizers, bulking agents, thickening agents, such as povidone, microcrystalline cellulose, lactose, etc., disintegrating agents such as for example cross-linked carboxymethyl cellulose, surfactants such as for example sodium lauryl sulfate, lubricating or sliding agents such as for example magnesium stearate, colloidal silicon dioxide, etc., wherein said excipients may be formulated for preferably slow or prolonged release for a systemic effect.

[0041] Solutions for intravenous or intraperitoneal administration can be prepared from the active ingredients dissolved first in an organic solvent such as DMSO, ethanol, or dimethylformamide and subsequently in aqueous buffers, such as PBS.

[0042] Particular preference is given to dosage forms designed for systemic administration, wherein liquid or solid compositions can be formulated, suitable for administration and whose excipients can be selected for example from components compatible with said dosage form, for example of a lipidic or peptidic nature, or peptidomimetics, known in the prior art as non-immunogenic, and which preferably can be bound to the active principles of the invention to improve their bioavailability; propellant agents such as, for example, propane, butane, or permissible chlorofluorocarbons; pH regulators such as, for example, sulfuric acid; chelating agents such as, for example, EDTA. The active ingredients can also be formed into micronized particles contained in gelatin capsules or other systems known in the technical field, which help release the active ingredient to its target site of action, for example, by means of solid dosage forms such as tablets or dragees, including those formulated for prolonged release.

[0043] According to the present invention, the synergistic compositions described herein may be obtained by combining ARI and TRA or their pharmaceutically acceptable salts with pharmaceutically compatible and / or acceptable vehicles known in the art, in the amounts and / or concentrations that correspond as described herein, and compounds known in the art may be included to obtain such compositions. Likewise, the administration of such compositions, may be made depending on the conditions of the patient, which will determine the doses and frequency of administration necessary to achieve an effective treatment of the ailment each particular case, although it is preferred to dose the compositions of the present invention according to the concentrations and dosage described herein.

[0044] As described here, male Wistar rats were used, on which the CCI model was replicated (48-50) in order to obtain allodynic and hyperalgesic behaviors, which are characteristic of neuropathic pain. The antinociceptive potential of ARI, TRA and various combinations of ARI and TRA was evaluated with these animals.

[0045] Different doses of ARI and TRA were evaluated, either administered individually, ARI (0.1 , 1.0, 3.1 and 10.0 mg / kg, i.p.) and TRA (0.1 , 1.0, 3.1 , 5.6, 10.0, 17.8 and 31.6 mg / kg, i.p.), or in combination, maintaining at all times the dose of ARI (10.0 mg / kg i.p.) plus TRA at different doses (0.1 , 1.0, 3.1 , 5.1 , 10.0, 17.8 and 31.6 mg / kg i.p.).), or also in combination, maintaining at all times the dose of ARI (10.0 mg / kg i.p.) plus TRA at different doses (0.1 , 1.0, 3.1 , 5.6, 10.0, 17.8 and 31.6 mg / kg, i.p.), thus obtaining different proportions. The analgesic potential (anti-allodynic and anti-hyperalgesic) of a total number of 7 combinations was evaluated. In addition, the individual treatments that generated the maximum antinociceptive efficacy (ARI 10 mg / kg and TRA 31.6 mg / kg) were selected, as well as the combinations ARI + TRA, 10 + 0.1 and 10 + 17.8 mg / kg correspondingly, to evaluate the possible incidence of adverse effects, such as alterations in motor coordination and decreased gastrointestinal transit (constipation).

[0046] From the proposed combinations in their different proportions, the type of synergism presented by coadministration was determined for both the anti-allodynic and anti-hyperalgesic effects by analyzing the overall antinociceptive effects of the compounds in TC and CDR. In this way, we demonstrated which proportions of both compounds exhibit therapeutically useful interactions, i.e. supra-additive (potentiation) and additive (summation) effects.

[0047] Male Wistar rats weighing between 60-70 grams (g) were used to replicate the ITC model (48-50). First, the animals were anesthetized i.p. with a mixture of ketamine 60 mg / kg and xylazine 5 mg / kg. The fur was removed from the right lower extremity, an antiseptic process was performed by applying iodopovidone in the working area and then an incision was made in the femoral biceps to expose the sciatic nerve. The trifurcation of this nerve was located and proximally, 4 ligatures were made (3-0 non absorbable silk suture Atramat) with at least 1 mm of separation between them. Afterwards, the nerve was positioned in the corresponding place and the muscle (3-0 chromic catgut suture absorbable Atramat) and skin (3-0 non absorbable silk suture Atramat) were sutured. Finally, gentian violet was placed in the suture area. It should be noted that the SHAM control group was manipulated and the surgical procedure was performed to generate the CCI model, but the 4 ligatures were not placed on the sciatic nerve as described in the methodology. On the day of the evaluation, the control group received the vehicle of the compounds, i.e., saline solution (NaCI 0.9%) i.p.

[0048] The behavioral evaluations were carried out once the characteristic behaviors of allodynia and hyperalgesia had developed, where for this point the weight of the animals ranged between 150-250 g. On the day of the experiment, each animal was placed for at least 20 minutes (min) in an observation chamber. First, a basal recording of the nociceptive response was performed. Subsequently, evaluation of the anti-allodynic and anti-hyperalgesic effect of the treatments was carried out using the acetone test and the von Frey filament test, respectively.

[0049] In the acetone test (cold allodynia), 100 pL of chemical agent were applied on the surface of the animal's right hind paw, where the total time that the animal used the limb to perform nociceptive behaviors (shaking, licking, etc.) during a period of 60 seconds (sec) was recorded, repeating this procedure 3 times (51). Measurements were taken at 30, 60, 90, 90, 120 and 180 min for the construction of the TC. On the other hand, in the test with von Frey filaments (tactile hyperalgesia), 10 stimulations were performed with the filament calibrated at 15 g on the animal's right hind paw and the number of times the animal presented limb withdrawal behavior was recorded (50). Similarly, information was collected for different periods of time to perform the TC.

[0050] The following experimental groups with n= 5 or 6 were performed: SHAM control (saline, i.p.), CCI control (saline, i.p.), ARI (0.1 , 1.0, 3.1 , and 10.0 mg / kg, i.p.) and TRA (0.1 , 1.0, 3.1 , 5.6, 10.0, 17.8 and 31.6 mg / kg, i.p.), and the combination of ARI (10 mg / kg i.p.) plus TRA (0.1 , 1.0, 3.1 , 5.6, 10.0, 17.8 and 31.6 mg / kg, i.p.).), and the combination of ARI (10 mg / kg i.p.) plus TRA (0.1 , 1.0, 3.1 , 5.6, 10.0, 17.8 and 31.6 mg / kg i.p.) in order to obtain different combinations with different proportions of the individual compounds and to detect those with remarkable therapeutic effects.

[0051] With the data obtained from each treatment, either individually or in combination, the TC was constructed from the percentage (%) of anti-allodynic or anti-hyperalgesic response. The ABC of the effect produced by each dose was determined and with these data the corresponding CDR was constructed for each group, plotting the effect produced by each dose. Each of the points in the graphs represents the mean ± standard error of the group (n= 5 or 6).

[0052] Two of the most representative adverse effects of conventional treatments were evaluated: alterations in motor coordination and constipation. The experimental groups were AR1 10 mg / kg, TRA 31.6 mg / kg, or the combinations ARI 10 mg / kg + TRA 0.1 mg / kg and ARI 10 mg / kg + TRA 17.8 mg / kg.

[0053] The evaluation of motor coordination was performed with Rota-Rod equipment. The evaluation protocol was performed on the same day with healthy animals. The experimental subjects were placed on the Rota-Rod equipment (Panlab Harvard Apparatus) for at least 10 min (habituation period), where once the required time was reached, they were subjected to two training periods (11 RPM) of 10 min with 5 min rest periods between each one of them. Subsequently, the first evaluation was carried out at time 0 (TO), where once finished, a single treatment was administered and after 60 min (T60) a second evaluation was carried out. In both evaluations, the number of falls presented by the animal in the 5 min of the test was recorded (52-53); the number of animals per group was 10 (n=10).

[0054] In addition, it was determined whether the experimental treatments produced constipation, for which the activated charcoal test was used to quantify gastrointestinal transit. The protocol was as follows: the animals were deprived of food 12 hr before the evaluation. On the day of the evaluation, a single treatment was administered to each animal and 30 min later an activated charcoal suspension (8 ml / kg, p.o.) was administered; the composition of this suspension was 5% activated charcoal, 5% gum arabic, 0.2% carboxymethylcellulose and saline solution as vehicle (54-55). Thirty minutes after the last administration, the animal was sacrificed (cervical dislocation) and the stomach and small intestine were extracted. The distance traveled by the activated charcoal suspension through the gastrointestinal tract was determined. In addition, the length of the small intestine from the pyloric sphincter to the ileocecal junction was recorded. With the data collected, the percentage of gastrointestinal transit (%GIT) was obtained. The number of animals per group was 5 or 6 (n=5 or 6). Figure 1 and 2 show the TC that summarize the nociceptive behavior over time of the control groups for the anti-allodynic and anti-hyperalgesic effect, respectively. The graphs show the SHAM group, where these animals were subjected to the surgical procedure, but the corresponding ligatures were not performed; this group of animals did not develop the allodynic or hyperalgesic behaviors characteristic of the model. In addition, the CCI groups are also presented, animals that underwent sciatic nerve ligation and developed allodynia and hyperalgesia for at least 3 hours. The administration of the vehicles corresponding to these groups did not generate any type of antinociceptive effect throughout the evaluation period. Thus, the sciatic nerve ligatures produced permanent states of allodynia and hyperalgesia for at least 3 h.

[0055] Figure 3 aggregates the TCs of the anti-allodynic (analgesic or antinociceptive) effect of 4 doses of ARI (0.1-10.0 mg / kg) i.p. in DNP rats in the experimental CCI model. The maximum effect was 53.2 ± 4.69% at 60 min with the 10 mg / kg dose. Although the effect of single administration was quite modest, this could generate some synergy when co-administered.

[0056] Figure 4 summarizes the TC of the anti-allodynic (analgesic or antinociceptive) effect produced by 7 doses of ART (0.1-31.6 mg / kg) i.p. A distinction is observed in the behavior of the TC at high (10 to 31.6 mg / kg) and low (0.1 to 3.16 mg / kg) doses. For high doses, these present a very rapid onset of the antinociceptive effect and with a high degree of relief, when the maximum effect is reached (30 min) the antinociceptive potential declines steadily, but is maintained at least in the time intended for evaluation (3 hr). For low doses of TRA, the antiallodynic effect occurred after 30 min and was maintained over time. The highest dose used (31 .6 mg / kg) obtained the highest overall effect or ABC. Figure 5 shows the TC of the anti-hyperalgesic (analgesic or antinociceptive) effect of 4 doses of ARI (0.1-10.0 mg / kg, i.p.) in DNP rats in the CCI experimental model. All the doses evaluated presented similar kinetics, starting with an onset of effect at 30 min and maintained throughout the evaluation period (3 hr). It is observed that as the dose is increased, the coverage of the TC (ABC or global effect) also increases and, therefore, the anti-hyperalgesic effect. The highest dose evaluated, 10.0 mg / kg, reached at min 120 its maximum effect with a value of 44±7.5%. Figure 6 shows the CDRs of the antiallodynic (analgesic or antinociceptive) effect produced by ARI and TRA in individual administration. The global effect is expressed as ABC (U2 / h) of the corresponding TC in figures 3 and 4. In the case of ARI, the dose-dependent relationship is observed, where all the doses evaluated present antiallodynic effect, from the lowest dose evaluated (0.1 mg / kg) to the highest (10.0 mg / kg), being that the last mentioned dose reaches the maximum efficacy (131 ±6.4 U2 / h) in these experimental conditions. For TRA, a classical sigmoid is observed, in which the drug presents a dose-dependent effect. The maximum efficacy obtained is 245.4±10.3 U2 / h at the highest dose evaluated, 31 .6 mg / kg.

[0057] To analyze the type of interaction or synergism of the combined administration of ARI and TRA, the analysis of the global antinociceptive effects of the compounds on TC and CDR was used for both the anti-allodynic and anti-hyperalgesic effects. In experimental animals (Wistar rats), each of the doses of TRA (0.1 , 1.0, 3.1 , 5.6, 10.0, 17.8 or 31.6 mg / kg) were evaluated in combination with a fixed dose of ARI, where the dose of 10.0 mg / kg was kept constant. In this way, the CDR of the combination of ARI 10 mg / kg + TRA (ARI 10 + TRA) was constructed, which consisted of a total of 7 different proportions of both compounds, with the purpose of detecting the combinations that generate the greatest antinociceptive efficacy, both antiallodynic and anti-hyperalgesic, as well as detecting which associations generate supra-additive interaction (potentiation).

[0058] Figure 7 shows the CDR family for the antiallodynic effect of both the compounds administered individually and all the combinations evaluated (7 different combinations). Unlike the evaluation of the individual drugs, the CDR for the ARI 10 + TRA combination did not present a classical behavior (sigmoid) in which the effect does not depend on the dose, since in the case of the evaluations of combinations the effect will depend on the proportion used of each of the molecular entities, this is due to the fact that changes in the ratio or proportions of the components generate different types of interactions leading to increases or decreases in the overall effect.

[0059] The comparative analysis between the 3 treatments (ARI, TRA and ARI 10 + TRA) in Figure 7 shows how the combined administration can present superiority with respect to the individual drugs. For example, the CDR of the combination ARI 10 + TRA showed a shift to the left on the X-axis indicating that with the combined administration lower doses are required to generate antiallodynic effects. In addition, it is very important that with the association in a low dose range of TRA (0.1 to 5.6 mg / kg) the amount of drug administered is optimized (reduced) and a good degree of relief is obtained. Of note from this figure are the combinations of ARI 10 mg / kg + TRA 0.1 mg / kg, that of ARI 10 mg / kg + TRA 3.1 mg / kg, and that of ARI 10 mg / kg + TRA 17.8 mg / kg. They are of interest because the first combination ratio presented a supra-additive type interaction (19% potentiation) in the anti-allodynic effect. The second is an equieffective combination with respect to the highest efficacy dose of individual ART (31.6 mg / kg), with the advantage of significantly reducing the doses that need to be administered. While the third ratio obtained in the evaluation the highest degree of anti-allodynic efficacy, which establishes that it is important to detect the best combination ratio, since only combining one drug with the other, in any ratio, would not guarantee obtaining the best desired effect. Therefore, and in accordance with the present invention, it is important to analyze and detect such adequate proportions of each drug.

[0060] Figure 8 shows an example of the proportion of the detected combination that using the lowest doses can generate high antiallodynic effects due to potentiation effects. On the Y-axis is placed the degree of anti-allodynic effect expressed in ABC (U2 / h) while on the X-axis the treatments, such as the individual components of the combination (TRA 0.1 mg / kg and ARI 10.0 mg / kg), the theoretical sum of the anti-allodynic effects of the drugs administered individually and finally, the result of the experimental evaluation of the combination (ARI 10 mg / kg + TRA 0.1 mg / kg). The Student's t-test was performed with the treatments "theoretical sum" and "combination", where for this particular case the combination "ARI 10 mg / kg + TRA 0.1 mg / kg" was used as an example. The statistical analysis detected that there is a significant difference between the two groups (P<0.05). This result expresses that the type of interaction of the combination in this ratio (ARI 10 mg / kg + TRA 0.1 mg / kg, 100:1) is of the supra-additive (potentiation) type.

[0061] Figure 9 shows the TC of the antiallodynic effect of the combination ARI 10 mg / kg + TRA 0.1 mg / kg, which generated a supra-additive interaction, indicating that the combination generated a greater effect than the simple addition of the effects of the individual drugs, obtaining an 18.84% potentiation for the antiallodynic effect. The TC shows how the treatment with the combination propitiates a rapid onset of the antiallodynic effect and is maintained for at least 3 hr of evaluation. The same graph shows the TC of the components of the combination administered individually, where they presented a lower ABC or global effect when compared to the combination ARI 10 mg / kg + TRA 0.1 mg / kg.

[0062] Figure 10 shows the graph that exemplifies the usefulness of using the combination of ARI 10 mg / kg + TRA 3.1 mg / kg (3.2:1 ratio) of the invention to generate an analgesic effect with great efficacy (antiallodynic) and significantly reducing the doses of the components of the combination. Employing this combination brings about an optimization in the amount of drug administered while maintaining a great anti-allodynic (antinociceptive or analgesic) effect. When comparing the effect obtained by the combination of the invention against the TRA dose with the highest efficacy (31 .6 mg / kg), no significant differences were obtained in the degree of relief. These results indicated that a 10-fold reduction of the TRA dose was achieved when co-administered with 10.0 mg / kg of ARI, and likewise, a similar anti-allodynic efficacy is achieved.

[0063] Figure 11 compares the anti-allodynic effect of the combination AR1 10 mg / kg + TRA 3.1 mg / kg against the most effective dose of TRA (31.6 mg / kg). The combination generated an overall effect that is similar to that produced by the TRA 31.6 mg / kg dose. However, a difference in the kinetics of antiallodynic effect is observed for both treatments. The maximum effect (Emax) achieved by the combination is lower than that of TRA 31 .6 mg / kg, but the effect remains constant, unlike the effect of single opioid administration which declines over time.

[0064] Figure 12 presents the comparison of the combination ARI 10 mg / kg + TRA 17.8 mg / kg (0.56:1 ratio) which presented the maximum anti-allodynic efficacy against its individual components (ARI 10.0 mg / kg and TRA 17.8 mg / kg), the combination ARI 10 + TRA 3.1 mg / kg (high anti-allodynic efficacy) and TRA 31.6 mg / kg. Treatment with the ARI + TRA combination (10 mg / kg + 17.8 mg / kg) of the invention generated the greatest degree of relief, being even greater than the effect of the highly effective combination (ARI 10 mg / kg + TRA 3.1 mg / kg). It is also important to note that it achieved similar efficacy to treatment with TRA 31.6 mg / kg, reducing almost 2-fold the amount of the opioid when co-administered with ARI 10 mg / kg. The dotted line crossing the Y-axis at 275 U2 / h indicates the ceiling limit of antinociceptive (anti-allodynic) effect detectable in the experimental model.

[0065] Figure 13 shows the CDRs for the anti-hyperalgesic effect of ARI and TRA administered individually. ARI shows a dose-dependent anti-hyperalgesic effect as does TRA. All evaluated doses of ARI (0.1- 10.0 mg / kg) generated a decrease in nociceptive behaviors. On the contrary, TRA in the evaluation of the dose of 0.1 mg / kg did not generate analgesia (anti-hyperalgesia), the effective range of TRA starts from doses higher than the aforementioned. The maximum efficacy of ARI was reached with the dose of 10.0 mg / kg and was 104.5±8.1 U2 / h, while TRA obtained a greater anti-hyperalgesic effect, 236±13.7 U2 / h with the dose of 31 .6 mg / kg under the experimental conditions of this research.

[0066] Subsequently, in Figure 14, the CDRs of the evaluations of the anti-hyperalgesic effect are compiled for both ARI and TRA administered individually and for the combination ARI 10 mg / kg + TRA (7 different combinations). It is important to mention the combinations of the invention that generated interactions of greater interest; ARI 10 mg / kg + TRA 0.1 mg / kg and ARI 10 mg / kg + TRA 10 mg / kg, where the first combination managed to generate an effect that went beyond the simple sum of its individual components, while the second combination generated analgesic (anti-hyperalgesic) effect of maximum efficacy.

[0067] Figure 15 shows the graph (bars) of the overall effect of the combination ARI 10 mg / kg + TRA 0.1 mg / kg of the invention which generated a potentiation anti-hyperalgesic effect. It should be noted that the anti-hyperalgesic effect of TRA 0.1 mg / kg administered individually is null, since no reduction in nociceptive behaviors is observed, therefore, when combined with ARI, TRA theoretically by simple addition should not contribute much in the antinociceptive effect (as observed in the anti-hyperalgesic effect of the "theoretical sum" group). However, when combined and evaluated experimentally, a significant increase in the analgesic (anti-hyperalgesic) effect was obtained. The analysis to determine the type of interaction between the two drugs indicates that there is an interaction of the supra-additive type, where the degree of potentiation was 43.65%. This suggests that ARI at its dose of 10.0 mg / kg functioned as a coadjuvant in the anti-hyperalgesic effect of TRA under our experimental conditions.

[0068] Figure 16 exposes the TC analysis of the anti-hyperalgesic effect produced by the single administration of 10.0 mg / kg ARI, 0.1 mg / kg TRA and the combination ARI 10 mg / kg + TRA 0.1 mg / kg of the invention that generated anti-hyperalgesic supra-addition (potentiation). The anti-hyperalgesic effect developed by TRA 0.1 mg / kg treatment is null, i.e. , administration of this dose does not promote a reduction of nociceptive behaviors. Treatment with ARI 10 mg / kg generated some degree of analgesia during the evaluation and interestingly, coadministration of ARI + TRA, 10 mg / kg + 0.1 mg / kg respectively, increased the anti-hyperalgesic effect beyond the simple addition of individual effects, thus proving the positive interaction between ARI + TRA in their 100:1 ratio. It should also not be forgotten that the combination ARI 10 mg / kg + TRA 3.1 mg / kg (3.2:1 ratio) generated 21.3% potentiation of anti-hyperalgesic effects. Figure 17 shows the usefulness of the combination ARI 10 mg / kg + TRA 10 mg / kg of the invention to generate an analgesic (anti-hyperalgesic) effect of maximum efficacy is compared to its individual components and TRA 31.6 mg / kg. For this ratio of ARI + TRA the determination of the interaction is limited by the individual maximum effects, i.e. , the theoretical sum effect is >275 U2Zh. Nevertheless, the experimental anti-hyperalgesic effect of the combination (238.25±8.8 U2Zh) is comparable with the effect of TRA 31.6 mg / kg (236±13.7 U2Zh) administered individually; mention that this dose was the highest dose evaluated in the TRA RDA and generated the maximum efficacy of the drug under our experimental conditions. Therefore, the same degree of relief will be obtained by administering a dose of 31.6 mg / kg of TRA or the ARI 10 mg / kg + TRA 10 mg / kg combination of the invention, where with the latter the dose of the opioid is reduced 3.2-fold when co-administered with the antipsychotic. The reduction of the doses of drugs used, especially opioids, is of great interest in the clinical setting since it could mean a decrease in the incidence of adverse effects, as well as in the development of pharmacological tolerance.

[0069] In accordance with the present invention, not only the evaluation of the beneficial potential of the treatments using the compositions described herein was included, but also the undesirable effects accompanying the individual pharmacological strategies, whereby the most representative side effects were considered, for example, the possible alteration of motor coordination and the possible decrease of gastrointestinal transit.

[0070] As a first step, the possible alteration of motor coordination was evaluated by means of the Rota-Rod test in healthy animals that received the individual treatments AR1 10 mg / kg, TRA 31 .6 mg / kg and also the combination treatments, ARI 10 mg / kg + TRA 0.1 mg / kg and ARI 10 mg / kg + TRA 17.8 mg / kg.

[0071] Figure 18 describes the evaluation of motor coordination through the quantification of the number of falls presented by the animal in the 5 min of the test. The control group corresponded to animals administered with saline solution and this did not generate any repercussion on motor coordination. The one-way ANOVA statistical test followed by Dunnett's post-hoc test determined that with respect to the control group there was no significant difference between the treatments (P>0.05), except for the group administered with the combination ARI 10 + TRA 17.8 mg / kg of the invention (P<0.05). However, the same statistical analysis was performed comparing against the TRA 31.6 mg / kg treatment, where this group represented the single TRA dose that generated the maximum effect under our experimental conditions. None of the treatments either individually or in combination were statistically different (P>0.05), in otherwords, the combination treatments did not increase the number of falls of the individual treatments.

[0072] Subsequently, the second adverse effect was evaluated which corresponded to the possible development of constipation from the administration of the individual treatments such as, ARI 10.0 mg / kg and TRA 31.6 mg / kg, and also the combinations ARI 10 + TRA 0.1 mg / kg and ARI 10 + TRA 17.8 mg / kg of the invention.

[0073] Figure 19 shows the analysis to determine the degree of constipation of each treatment through the quantification of the gastrointestinal transit (GIT) with the activated charcoal test. The value obtained in the evaluation of the control group who received saline solution as treatment was considered a TGI without alterations, where for this group the activated charcoal suspension traveled 67.3±4.1 % of the total length of the small intestine during the 30 min after administration. Statistical analysis with the one-way ANOVA multiple comparisons test followed by Dunnett's post-hoc test, determined that the only treatment that generated constipation was TRA 31.6 mg / kg (P<0.05), since the rest of the treatments evaluated did not propitiate the appearance of this adverse effect. Therefore, none of the associations analyzed between ARI + TRA of the invention produced constipation.

[0074] According to the results obtained in the present invention, it is evident that the combination of ARI + TRA generates different interactions depending on the proportions administered and in turn, these interactions change as different pain conditions such as allodynia or hyperalgesia are evaluated. For the antiallodynic effect, it was detected that the combination ARI + TRA can generate supra-additive or potentiation interactions and adequate efficacy by reducing the dose that needs to be administered. Regarding the anti-hyperalgesic effect, the combination ARI + TRA also showed to generate potentiation effects of up to 43.65%. Therefore, in order to obtain the greatest benefit, it is necessary to detect and administer the adequate proportions detected in this invention.

[0075] The antinociceptive response (anti-allodynic or anti-hyperalgesic) generated by the antipsychotic ARI is modest reaching with the dose of 10.0 mg / kg the maximum efficacy with a value of 131 ± 6.4 U2Zh and 104.5 ± 8.1 U2Zh for the anti-allodynic and anti-hyperalgesic effect respectively. On the other hand, the opioid TRA used a higher dose (31.6 mg / kg) to reach its maximal efficacy, but the antiallodynic and anti-hyperalgesic effect, 245.4 ± 10.3 U2 / h and 236 ± 13.7 U2 / h, is much higher with respect to ARI. The modest capacity of relief of nociceptive behaviors by the antipsychotic is well explained on the basis of classical pharmacology, which indicates that a partial agonist cannot generate 100% response by binding to its receptor, as would a full agonist such as TRA. The fact that single administration of ARI does not generate great relief does not mean that the compound is not useful in therapy, because when combined with another drug it could function as an adjuvant (14,36,56-57).

[0076] In the present invention it was determined that both for the anti-allodynic effect and for the anti- hyperalgesic effect the formation of the combinations of the invention composed by ARI 10 mg / kg + low doses of TRA (0.1 -5.6 mg / kg) propitiate pharmacological interactions with therapeutic utility. This finding is a clear example of an optimization of the therapeutic strategies for DNP since, according to the present invention, a significant reduction of the administered doses of opioids is obtained and, therefore, it could reduce or delay the appearance of some adverse effects associated with the use of opioid-type compounds, such as alterations in motor coordination or constipation. In short, ARI functioned as a coadjuvant in the antinociceptive (anti-allodynic and anti-hyperalgesic) effect of TRA. In summary, both for the anti-allodynic and anti-hyperalgesic effect, it can be established according to the present invention that with the combination of small doses of ARI and TRA, supra-additive or potentiation effects can be obtained, which are very useful for the therapy and management of neuropathic pain. Furthermore, the combinations do not generate constipation and do not increase the alterations in motor coordination beyond what is generated by the most effective single treatment (TRA 31.6 mg / kg). As described herein, the present invention provides an optimization of pain treatment for both anti- allodynic and anti-hyperalgesic effects when optimal combinations of ARI + TRA are employed in NPD compared to the effect that can be generated by the drugs (analgesics) alone. It is important to emphasize that the antinociceptive effects enhanced through the ARI + TRA combination strategy of the invention are only obtained when the appropriate proportions of each component, which were identified in the present invention, are respected.

[0077] References.

[0078] 1 . Yekkirala, A.S., et.al. 2017. Nature Reviews. Drug Discovery, 76(8), 545-564.

[0079] 2. Woolf, C. J . 2010. The Journal of Clinical Investigation, 120(11 ), 3742-3744.

[0080] 3. International Association for the Study of Pain. 2017. IASP Taxonomy. Pain terms. Neuropathic pain. https: / / www.iasp-pain.Org / resources / terminology / #Neuropathicpain

[0081] 4. Torrance, N., et.al. 2006. Journal of Pain, 7(4).

[0082] 5. Finnerup, N.B., et.al. 2021. Physiological Reviews, 101(1).

[0083] 6. Finnerup, N.B., et.al. 2015. The Lancet. Neurology, 14(2), 162.

[0084] 7. Rosenberger, D.C., et.al. 2020. Journal of Neural Transmission (Vol. 127, Issue 4, pp. 589-624).

[0085] 8. Busquets Julia, C., et.al. 2012. Seminarios de La Fundacion Espanola de Reumatologia, 13(3), 103-109.

[0086] 9. Nafziger, A.N., et.al. 2018. Journal of Clinical Pharmacology, 58(9), 1111-1122.

[0087] 10. Lam, L.H., et.al. 2016. Journal of Clinical Pharmacology, 56(7), 785-793.

[0088] 11 . Burgess, G., et.al. 2010. Journal of Clinical Investigation (Vol. 120, Issue 11).

[0089] 12. Gazerani, P. 2019. Pain Management, 9(4), 399-415.

[0090] 13. Montiel, & Aguirre. (2022). Montiel & Aguirre. Reposicionamiento Farmacologico; Nuevos Usos de Medicamentos Conocidos. https: / / www.inecol.mx / inecol / index.php / es / ct-menu-item-25 / ct- menu-item-27 / 17-ciencia-hoy / 1756-reposicionamiento-farmacologico-nuevos-usos-de- medicamentos-conoci

[0091] 14. Kinga, S., et.al. 2019. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 111, 882-890.

[0092] 15. Chong, C., et.al. 2009. Clinical Drug Investigation, 29(5).

[0093] 16. Waszkielewicz, M.A., et.al. 2011. Current Medicinal Chemistry, 18(28), 4344-4358.

[0094] 17. Almeida-Santos, A.F., et.al. 2015. European Journal of Pharmacology, 765, 300-306.

[0095] 18. Chou, T.C. 2006. Pharmacological Reviews, 58(3), 621-681.

[0096] 19. Lopez-Munoz, F.J., et.al. 1993. Drug Development Research, 29(4), 299-304.

[0097] 20. Tallarida, R.J., et.al. 2003. The Journal of Pharmacology and Experimental Therapeutics, 307(2), 699-704.

[0098] 21. Garcia Armenta, M.E., et.al. 2016. MX2014008336.

[0099] 22. Lopez Munoz, F.J., et.al. 2012. MX2010010372.

[0100] 23. Young James, W, et.al. 2002. US2002006963.

[0101] 24. Loughhead David, G., et.al. 2001. US6262078 (B1) 25. Somerville Judson, J., et.al. 2005. US6897242 (B1)

[0102] 26. Lopez-Munoz, F.J., 2004. European Journal of Pharmacology, 484(2-3), 157-165.

[0103] 27. Vazzana, M., et.al. 2015. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 70(C), 234-238.

[0104] 28. Stoops, W.W., et.al. 2012. Pharmacodynamic profile of tramadol in humans: influence of naltrexone pretreatment, https: / / doi.org / 10.1007 / s00213-012-2739-4

[0105] 29. Modi, H., et.al. 2013. Indian Journal of Pharmacology, 45(V), 76.

[0106] 30. Raiger, L.K., et.al. 2012. Indian Journal of Anaesthesia, 56(1), 55-57.

[0107] 31 . Lopez-Munoz, F.J., et.al. 2013. Archives of Medical Research, 44(7), 495-503.

[0108] 32. Cialdai, C., et.al. 2013. European Journal of Pharmacology, 714( -3), 346-351.

[0109] 33. Hyup Lee, J., et.al. 2013. Clinical Therapeutics, 35(11), 1830-1840.

[0110] 34. Corona-Ramos, J.N., et.al. 2016. Drug Development Research, 77(5), 217-226.

[0111] 35. Shin, S.W., et.al. 2019. The Korean Journal of Pain, 32(1), 3-11.

[0112] 36. Norouzi, M., et.al. 2017. Biomedical and Pharmacology Journal, 10(3), 1149-1157.

[0113] 37. Rico-Villademoros, F., et.al. 2014. Drugs of Today (Vol. 50, Issue 6).

[0114] 38. Mamo, D., et.al. 2007. The American Journal of Psychiatry, 164(9), 1411-1417.

[0115] 39. Naber, D., et.al. 2004. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 28(8), 1213-1219.

[0116] 40. Ferreira, R.C.M., et.al. 2017. BioMed Research International, 2017.

[0117] 41. Khalilzadeh, M., et.al. 2020. Cancer Chemotherapy and Pharmacology 2020 86:3, 86(3), 393- 404.

[0118] 42. Almeida-Santos, A.F., et.al. 2014. European Journal of Pharmacology, 742, 139-144.

[0119] 43. Kasahara, S., et.al. 2011 . The Primary Care Companion to CNS Disorders, 13(2).

[0120] 44. Fei, L., et.al. 2012. Therapeutic Advances in Psychopharmacology, 2(5), 211.

[0121] 45. Umezaki, Y., et.al. 2016. Neuropsychiatric Disease and Treatment, 12, 1229-1231 .

[0122] 46. Takenoshita, M., et.al. 2017. Pain Medicine: The Official Journal of the American Academy of Pain Medicine, 18(4), 814.

[0123] 47. Watanabe, M., et.al. 2022. Frontiers in Pain Research (Lausanne, Switzerland), 3.

[0124] 48. Bennett, G.J., et.al. 1988. Pain, 33(1), 87-107.

[0125] 49. De Vry, J., et.al. 2004. European Journal of Pharmacology, 491(2-3), 137-148.

[0126] 50. De la O-Arciniega, M., et.al. 2009. Pharmacology Biochemistry and Behavior, 92(3), 457-464.

[0127] 51. Dowdall, T., et.al. 2005. Pharmacology, Biochemistry, and Behavior, 80(1), 93-108.

[0128] 52. Dunham, N.W., et.al. 1957. Journal of the American Pharmaceutical Association. American Pharmaceutical Association, 46(3).

[0129] 53. Lopez-Rubalcava, C., et.al. 1994. Behavioural Pharmacology, 5(1), 42-51.

[0130] 54. Manara, L., et.al. 1986. Journal of Pharmacology and Experimental Therapeutics, 237(3).

[0131] 55. Schulz, R., et.al. 1979. Naunyn-Schmiedeberg’s Archives of Pharmacology, 308(3), 255-260.

[0132] 56. Aira, Z., et.al. 2014. Pain, 755(12), 2526-2533.

[0133] 57. Mercado-Reyes, J., et.al. 2019. European Journal of Pharmacology, 853, 56-64.

Claims

Claims.1 . A synergistic pharmaceutical composition useful for the treatment of pain, characterized in that it comprises combining a therapeutically effective amount of the compound aripiprazole (ARI) and a therapeutically effective amount of tramadol (TRA).

2. The pharmaceutical composition according to claim 1 , characterized in that the combination comprises a weight ratio of 100:1 times to 3.2:1 times of ARI:TRA.

3. The pharmaceutical composition according to claim 1 , characterized in that the combination comprises the effective dose of 0.1 to 10.0 mg / kg of ARI with the effective doses of 0.1 to 31.6 mg / kg of TRA.

4. The pharmaceutical composition according to claim 1 , characterized in that the combination comprises ARI and TRA dosages comprising 10 + 0.1 , and 10 + 3.1 mg / kg respectively.

5. The pharmaceutical composition according to claim 1 , characterized in that it is anti-allodynic and anti-hyperalgesic.

6. The pharmaceutical composition according to the preceding claims, characterized in that the pain is neuropathic pain.

7. The use of the pharmaceutical composition in accordance with the preceding claims for preparing a medicament for the treatment of pain.

8. The use of the pharmaceutical composition according to claim 7, wherein the pain is neuropathic pain.

9. The use of a pharmaceutical composition according to claim 7 to 8, which is suitable for subcutaneous, oral, intraperitoneal, intramuscular, intravenous or topical administration.

10. A synergistic pharmaceutical composition comprising a combination of a therapeutically effective amount of the compound ARI and a therapeutically effective amount of TRA, for use in the treatment of pain.

11. The pharmaceutical composition for use in accordance with claim 10, wherein the combination comprises a weight ratio of 100:1 times to 3.2:1 times of ARI:TRA.

12. The pharmaceutical composition for use in accordance with claim 10, wherein the combination comprises the effective dose of 0.1 to 10.0 mg / kg ARI with the effective doses of 0.1 to 31.6 mg / kg TRA.

13. The pharmaceutical composition for use according to claim 10, wherein the combination comprises ARI and TRA dosages comprising 10 + 0.1 , and 10 + 3.1 mg / kg respectively.

14. The pharmaceutical composition for use in accordance with claim 10, wherein said composition is anti-allodynic and anti-hyperalgesic.

15. The pharmaceutical composition for use in accordance with claims 10 to 14, wherein the pain is neuropathic pain.

Images