ES2543364B1 - PHARMACEUTICAL COMPOSITION UNDERSTANDING THE COMBINATION OF AN NON-STEROID ANTI-INFLAMMATORY AGENT, AN ADJUSING AGENT AND AN ANTI-NURETIC ANALGESIC, WITH ANTI-BIOCEPTIVE EFFECT - Google Patents

Abstract

The present invention relates to the technical field of the pharmaceutical industry, since it is intended to provide a pharmaceutical composition composed of the synergistic combination of a non-steroidal anti-inflammatory agent, such as the active ingredient: MELOXICAM, an adjuvant agent, such as The active substance: MELATONIN and an antineuritic analgesic, such as: B vitamins (B1, B6 and B12), which are formulated in a single dosage unit, which is indicated for the treatment of pain caused by various etiologies , pain of inflammatory origin, lumbar neuropathy, diabetic neuropathy, trigeminal neuralgia, sciatic neuralgia. # The combination of the agents mentioned above produce a greater effect when they are administered together in a single dose unit unlike when they are administered from independently, generating benefits such as: lower doses administered, faster of the therapeutic effect and minor side effects, which may occur when administered independently.

Description

PHARMACEUTICAL COMPOSITION UNDERSTANDING THE COMBINATION OF AN NON-STEROID ANTI-INFLAMMATORY AGENT. AN ADJUSING AGENT AND AN ANTINEURYTIC ANALGESIC. WITH ANTI-EFFECTIVE EFFECT

FIELD OF THE INVENTION The present invention relates to the technical field of the pharmaceutical industry, since it is intended to provide a pharmaceutical composition composed of the synergistic combination of a non-steroidal anti-inflammatory agent, such as the active ingredient: MELOXICAM, an agent adjuvant, such as the active substance: MELATONINE and an antineuritic analgesic, such as: VITAMINS OF COMPLEX B (81, 86 AND 812), which are formulated in a single dosage unit, which is indicated for the treatment of pain caused by various etiologies, pain of inflammatory origin, lumbar neuropathy, diabetic neuropathy, trigeminal neuralgia, sciatic neuralgia. The combination of the agents mentioned above produce a greater effect when they are administered together in a single dose unit unlike when they are administered independently, generating benefits such as: lower doses administered, faster therapeutic effect and lower side effects , which can occur when administered independently.

BACKGROUND OF THE INVENTION Pain is an unpleasant sensory and emotional experience, as such, personal and non-transferable, although communicable. This experience is unique, unrepeatable, and transcendent. It combines neurophysiological, psychological, behavioral and cultural mechanisms. Defined in this way, pain is a multidimensional, psychophysical and sociocultural problem that transcends the patient, the family and the whole society. In 1979, the International Organization for the Study of Pain (IASP) defines it as an unpleasant sensory and emotional experience associated with actual or potential tissue damage that can be described in terms of the magnitude of the damage. To date, this definition of pain is considered the most appropriate, since it presents a change with respect to the previous ones when introducing two new concepts.

•

He considers that pain is not only a sensory response to tissue damage, but is also composed of emotional and subjective components.

•

It can occur without a somatic cause that justifies it.

The pain begins in the special receptors or nociceptors, which are spread throughout the body. These receptors transmit information in the form of electrical nerve impulses that are sent to the spinal cord along the nerve pathways and then to the brain. Sometimes the signal causes a reflex response upon reaching the spinal cord, and is immediately forwarded by the motor nerves to the original point of pain, causing muscle contraction. The pain signal reaches the brain is processed and interpreted as such and the conscious perception is carried.

The pain can be acute or chronic, neoplastic or non-neoplastic. This division has implication around the etiology, pathophysiology and symptomatology. However, perhaps of greater importance are the diagnostic and therapeutic aspects.

There are different pain classifications that differ according to the author, but basically we can define the following modalities:

•

Acute pain: it is caused by harmful stimuli triggered by wounds or skin diseases, deep somatic structures or viscera, acute pain is perceived 0.1 seconds after contact with the painful stimulus; The generated nerve impulse travels to the central nervous system through high conduction velocity fibers (Aó). It lasts seconds, minutes or even days; but it usually disappears when the condition that originates it comes to an end.

•

Chronic pain: differs from the previous one in that it persists beyond the reasonable time for the cure of an acute disease, so it is associated with a chronic pathological process that causes continuous pain; it is related to the deep structures of the body; It is not well located and is capable of producing continuous and unbearable suffering.

•

Somatic pain: is the one that occurs when a potentially damaging stimulus for physical integrity excites nociceptive receptors. Strictly should include pain originating in any part of the body other than nerves or central nervous system, this term is used to refer to pain

originated by the receptors found in the skin, muscles and joints, where the pain is well located and specific.

•

Neuropathic pain: results from chronic lesion or alteration in peripheral or central nerve pathways, and may develop and persist in the absence of an obvious harmful stimulus. It is characterized because the symptom is presented as a basal or burning sensation (dysesthesia), with hyperalgesia or allodynia (perception of any stimulus as painful).

•

Psychogenic pain: is what occurs when the individual describes psychological problems such as anxiety or depression in terms of tissue damage, verbally or due to their behavior. While the damage may or may not exist, the central problem is the amplification and distortion of these peripheral impulses by the psychological state.

For pain relief there are currently a wide variety of agents capable of producing a powerful and selective effect of inhibition of painful neurotransmission, both at the preclinical level in animals, and at the clinical level in man.

Drugs that produce analgesia can act at a peripheral and / or central level, either by modulating or inhibiting the synthesis of inflammation-mediating substances. Among the analgesic drugs are non-steroidal anti-inflammatory analgesics (NSAIDs), which in addition to being analgesics, share anti-inflammatory and antipyretic properties. The genesis of its analgesia is mainly due to the inhibition of the biosynthesis of prostaglandins (PG's). Some NSAIDs such as ketoprofen, indomethacin, aspirin, naproxen and ibuprofen are selective inhibitors of type 1 cyclooxygenase (COX-1), while nimesulide, meloxicam, celecoxib and rofecoxib are selective inhibitors of type 2 cyclooxygenase (COX-2). Another important and main mechanism in the generation of analgesia is that performed by opioids, specifically morphine and its analogues. These analgesics interact with IJ (mu) and K (Kapa) receptors primarily, and in which certain endogenous peptides, such as enkephalin, endortins and dinorphins, also act. These receptors would be responsible for all the effects produced by opioid drugs, and are located in certain sites of the central nervous system and also in peripheral organs. Analgesia can also be obtained by blocking the transmission of the nerve impulse, through local anesthetics, or irreversibly by infiltrating the phenolic alcohol into the neural pathway. Finally, other drugs that, without being analgesics themselves, reduce pain as a result of a symptomatic action on it; This is the case of some coronary vasodilators that suppress anginal pain and some anticonvulsants that relieve pain caused by neural damage. With this perspective, antidepressant drugs began to be used in patients with chronic pain associated with depression. They were subsequently used in patients with chronic pain, but without a depressive illness, with therapeutic results.

excellent. Clinical and experimental data support the potential of combining opioids with other analgesics such as NSAIDs, steroid drugs with NSAIDs, these with muscle relaxants (paracetamol-metocarbamol) or the combination of these three: NSAIDs, steroids and muscle relaxants. These combinations have demonstrated analgesic efficacy and in less profile of adverse effects than any of the drugs administered separately. Combining drugs that act at different levels with different pharmacological mechanisms of action can provide potential benefits such as:

•

Increase analgesic efficacy, through synergistic or additive interaction.

•

Expand the analgesic spectrum: opioids reduce selectivity to pain-independent stimuli while adjuvant drugs decrease selectivity to pain-evoked stimuli.

So the combination allows:

•

Decrease the dose of the drug (opioid, NSAIDs, muscle relaxant, etc.)

•

Reduce adverse effects.

Given the multiple pathways involved in pain perception, the Organization World Health and the American Pain Society have recommended the therapeutic combination Thus, reducing the dose of analgesics achieves a Better tolerance on the part of the patient.

When two drugs are administered together, their effects can be: a) Additives, which corresponds to the simple sum of the effects produced by each drug individually. b) Subadditive, also called antagonistic and corresponding to an effect less than

the simple sum of each agent separately.

e) Synergistic or supra-additive, which is a greater effect, than the sum of the effects

separated from each drug.

d) Empowerment. It results from the use of an analgesic with another non-analgesic drug and

5

whose combination results in greater effect than observed when only the

analgesic.

In the articles of Dodick D, Capobianco D of 2001 entitled "Treatment and

management of cluster headache "and Gagnier J of the same year called" The

therapeutic potential of melalonin in migraines and other headache types "you can

1 o

deduce that melatonin has a potential for effect if not analgesic, if for

control headache and migraine, due to its antioxidant agent potential.

International patent application WOJ1997 / 012612 with the title "Compositions of

melatonin and analgesic agents and their methods of use "describes a

fifteen

composition comprising melatonin and one or more analgesic agents for

relieve pain and induce sleep, however it does not speak of a synergistic effect

analgesic with an antineuritic analgesic to improve pain management.

US Patent 7799,817 "Compositions and methods for regulating sleep" speaks of

twenty

compositions and methods for the regulation of sleep and circadian rhythms, where

the compositions are nutritional supplements that contain melatonin and one or

more vitamins that improve the effectiveness of melatonin. The compositions of

beneficial and advantageous way to regulate sleep when administered to an individual and

are administered to human or animal suffering from irregular sleep or rhythm

25

circadian or are administered in anticipation of the evolution of said irregularity.

The disadvantages presented by the technologies described above lie in the fact that

deals with inventions do not achieve a synergistic or additive effect in a treatment

pain-specific, with a non-steroidal anti-inflammatory agent, such as the

active substance: MELOXICAM, an adjuvant agent, such as the active substance:

30

MELATONINE and an antineuritic analgesic, such as: VITAMINS OF THE COMPLEX

B (81, 86 and 812), which are formulated in a single unit of

dosage.

JUSTIFICATION OF THE INVENTION

The characteristic details of the present invention are clearly shown in the following description, in the accompanying figures and examples, which are mentioned by way of examples and should not be considered as limiting.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a graph showing the time course after the 1% formalin injection. Figure 2 shows a graph showing the antinociceptive effect of oral administration of increasing doses of meloxicam, evaluated during the second phase of the formalin test. Figure 3 shows a graph showing the antinociceptive effect of oral administration of increasing doses of melatonin, evaluated during the second phase of the formalin test. Figure 4 shows a graph showing the antinociceptive effect of oral administration of increasing doses of B complex, evaluated during the second phase of the formalin test. Figure 5 shows a graph showing the antinociceptive effect of oral administration of increasing doses of the meloxicam and melatonin mixture, evaluated during the second phase of the formalin test. Figure 6 shows a graph of the isobolographic analysis of the oral administration of the meloxicam-melatonin mixture. Figure 7 shows a graph showing the antinociceptive effect of oral administration of increasing doses of the meloxicam and B-complex mixture, evaluated during the second phase of the formalin test. Figure 8 shows a graph of the isobolographic analysis of the oral administration of the meloxicam-vitamin B complex mixture. Figure 9 shows a graph showing the antinociceptive effect of oral administration of increasing doses of the melatonin and B complex mixture, evaluated during the second phase of the formalin test. Figure 10 shows a graph of the isobolographic analysis of the oral administration of the melatonin -vitamin B complex mixture. Figure 11 shows a graph showing the antinociceptive effect of oral administration of increasing doses of the meloxicam, melatonin and complex mixture B, evaluated during the second phase of the formalin test.

Figure 12 shows a graph of the isobolographic analysis of the oral administration of the meloxicam-melatonin-vitamin B complex mixture.

DETAILED DESCRIPTION OF THE INVENTION The vitamins of the B complex have antinociceptive and anti-inflammatory activity. This complex, composed of thiamine (vitamin 81), pyridoxine (vitamin 86) and cyanocobalamin (vitamin 812) are essential for the synthesis of neurotransmitters, for Myelin production in the central nervous system and peripheral nervous system. Thiamine (vitamin B1) Thiamine is the first vitamin of the B complex. Deficiency of this vitamin causes polyneuropathy, accompanied by axonal degeneration. High doses of thiamine produce nodal block and suppression of neural stimulus transmission. The relationship between vitamin B 1 and the nervous system was the basis for extending the use of high doses of thiamine by various routes in order to relieve neuropathic pain, since thiamine practically lacks pharmacological actions at low doses in humans. Pharmacokinetics Thiamine is an essential coenzyme for carbohydrate metabolism, it is involved in the oxidative decarboxylation of acetylcoenzyme A pyruvate and in the synthesis of acetylcholine (neuronal chemical mediator). This vitamin has a high degree of turnover in the body and is not stored in any organ or tissue for prolonged times, so it is essential a continuous intake. Thiamine and its derivatives that enter by natural digestive route or parenterally, are rapidly deposited in the liver, muscle, brain and to a lesser extent in other tissues, its absorption is in the proximal portion of the small intestine, stored in Small deposits in the muscle with a brief biological life. Excess thiamine is stored and deposited in its 3 types of esters, after a certain limit the rest is eliminated in urine.

Pyridoxine (vitamin S6)

Vitamin B6 is a coenzyme of lysiloxidase, essential for the formation of fibroblast, since they help the synthesis and release of collagen by the influence of ascorbic acid. There is evidence that collagen is essential for joint formation, which is the site where many pain conditions originate. The concentration of pyridoxine in blood is low in rheumatoid arthritis, although it is not well known if the decrease in this vitamin is a cause or a consequence of rheumatic processes. Recent studies show that the administration of pyridoxine can directly suppress the response of nociceptive stimuli, suggesting that this suppression may cause an analgesic response. Finally, the influence of pyridoxine on serotonin metabolism indicates that it can prevent manifestations of pain.

Pharmacokinetics Pyridoxine is rapidly absorbed by the gastrointestinal tract after oral administration; However, gastrointestinal absorption may be lower in patients with malabsorption syndrome. The normal serum pyridoxine concentration is 30-80 IJg / mL. It is mainly stored in the liver and to a lesser extent in muscle and brain. The biological half-life of pyridoxine is 15 to 20 days, in liver the main meta bolito pyridoxal is oxidized to pyridoxic acid, which is excreted in the urine.

Cyanocobalamin (vitamin 812)

Vitamin 81 2 increases RNA in neurons and is an essential factor for the formation of propionyl-CoA within the Krebs cycle and provides metamalonyl-CoA to neurons. Metamalonil-CoA, is the last important goal ball for the synthesis of neuronal cerebrosides and phospholipids for the production of myelin. One of the most important roles of cyanocobalamin is the transformation of polyglutamate to tetrahydrofolate, necessary for the synthesis of hemoglobin and red blood cells in the formation of blood. The deficiency of this vitamin causes the neuro-anemic syndrome causing pain. Recent studies in rats confirm that the administration of vitamin 812 reduces the pain caused by various substances such as carrageenan, kaolin, calcium, etc., observing a preventive activity and a therapeutic activity. The preventive activity is obtained by administering vitamin

812 half an hour before the provocation of pain and therapeutic activity is observed when administered 2 hours after the provocation of pain. Vitamin 812, in addition to preventing anemia, helps reduce pain caused by substances that induce inflammation.

Pharmacokinetics Vitamin 812 is regularly absorbed by the distal small intestine, when supplied orally. In the stomach, free vitamin B 12 binds to the intrinsic factor, which is a glycoprotein excreted by the gastric mucosa that is necessary for an active absorption of the vitamin by the gastrointestinal tract. The complex is temporarily stopped at specific receptors in the wall of the distal ileum, before the vitamin is absorbed and enters the systemic circulation. The intrinsic factor transport mechanism is saturated with 1.5-3 mg of vitamin 812; however, additional amounts of vitamins can be absorbed independently of the intrinsic factor, by passive diffusion through the intestinal wall. This passive diffusion mechanism is important only in the presence of much larger amounts of vitamin (minimum 1 mg). In oral administration of vitamin 812 in doses less than 3 mg, the peak plasma concentration is not reached until after 8-12 hours, because the vitamin is temporarily retained in the wall of the distal ileum. In the cells of the intestinal mucosa, vitamin 812 is released from the intrinsic factor, and rapidly binds to plasma proteins in the blood, mainly to a transcobalamin 111 storage protein. Blood concentrations of transcobalamin 11 are withdrawn after the Vitamin 812 is absorbed. In fasting state most of the circulating vitamin binds to transcobalamin 1. Vitamin 812 is distributed in the liver and bone marrow and other tissues, including the placenta. The total body storage of vitamin 812 in healthy subjects is estimated in a range of 1-11 mg with an average of 5 mg of 50-90% being stored in the liver. When vitamin 812 is administered in amounts that exceed the binding capacity in plasma, liver and other tissues, it is free in blood and available for urinary excretion. Approximately 10-15% is synthesized daily by bacteria in the large intestine, but is excreted by feces, without being absorbed.

Meloxicam The selective inhibition of COX-2 in relation to COX-1 has been consistently demonstrated for meloxicam in various in vitro test systems, in in vivo experimental models and in ex vivo humans. Inhibition of thromboxane in human platelets is incomplete and dose dependent; Selective inhibition of platelet aggregation has not been observed with meloxicam at the recommended daily doses of 7.5 or 15 mg.

Aniinflammatory, analgesic and antipyretic properties have been demonstrated in classic models of inflammation, pain and fever. With a dosage of a single daily dose, meloxicam has shown efficacy in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Clinically, meloxicam offers efficacy similar to that of existing nonsteroidal anti-inflammatory drugs at established doses, including diclofenac, piroxicam and naproxen, and at the same time is associated with less gastrointestinal side effects, measured through symptoms such as dyspepsia, abdominal pain, diarrhea nausea and vomiting In large-scale clinical studies, meloxicam is associated with lower rates of gastrointestinal perforations, ulcers and hemorrhages (PUBs) and their complications than conventional non-steroidal anti-inflammatory drugs, although the studies did not have sufficient power to detect these differences as statistically significant. Combined analyzes of clinical studies and controlled, large-scale, comparative epidemiological drug studies support the above and indicate a low risk of PUBs and serious gastrointestinal complications at the recommended doses. Chemical properties Meloxicam, like other NSAIDs that include celecoxib and rofecoxib, is classified by the World Health Organization (WHO) based on its chemical structure, rather than its pharmacological or clinical properties. Meloxicam is an enolcarboxamide described since 1994 as a selective COX-2 inhibitor in relation to COX-1. Minimal changes in its chemical structure can alter affinity and selectivity for its white enzyme, COX-2. The 5-methyl group in the meloxicam thiazolyl ring can interact efficiently with its white enzyme. The low water solubility of meloxicam at an acidic pH and its amphiphilic protonation behavior are responsible for tissue kinetics that prevents a high concentration of the substance in certain tissues of the digestive tract. Therefore, meloxicam does not show the typical "ion trapping" behavior of NSAIDs of the carbonic acid class, which may contribute to the favorable penile of gastrointestinal tolerability observed clinically.

Pharmacokinetics Meloxicam is well absorbed orally by up to 89% without its absorption being modified with food. There is high binding to plasma proteins up to 99.5%, it has a high penetration in synovial fluid reaching up to half equivalent to its plasma concentrations. The metabolism is based on oxidation of the methyl group of its thiazolyl molecule. About half of the medicine is eliminated in the urine and the rest in the stool, in urine only traces of the unmodified drug are found and in feces only 5% of the administered dose is found. The elimination half-life is approximately 20 hours. When there is mild hepatic or renal impairment, your metabolism is not altered; at 40-50 minutes after administration, concentrations of 1.6 ~ g! mL are detected.

Pharmacodynamics

Meloxicam acts by inhibiting cyclooxygenase 2, which it does selectively, this fact has been proven in cell groups in vivo, this inhibition is responsible for its therapeutic action as a non-steroidal anti-inflammatory. Given its selectivity of inhibition of cyclooxygenase 2 (COX-2) and its low inhibitory influence on cyclooxygenase 1 (COX-1) which is responsible for gastric irritation and decreased renal flow, its therapeutic action is the same but with less Side effects than other anti-inflammatories, experimental studies have shown that the anti-inflammatory effects of meloxicam are greater than other non-steroidal anti-inflammatories, without the gastric and renal lesion being greater. This has the advantage not only of secondary reaction but also of economic benefit for the patient. With a COX-2 / COX-1 ratio of 0.33 less than 33.0 of piroxicam or 30.0 of indomethacin, meloxicam exerts its action by inhibiting prostaglandins, which are chemical mediators known in all inflammatory processes.

Melatonin The hormone melatonin is synthesized in pinealocytes (pineal gland cells) from serotonin (5-HT), through two steps controlled by as many enzymes. The synthesis and release of melatonin shows a marked circadian rhythm, producing the maximum peak of secretion during the night (although there are a few examples of an increase in secretion during the day). This circadian rhythm in the production of melatonin provides the body with valuable information about the time of day and the time of the year and, as a result, this hormonal cycle leads to other circadian rhythms. This rhythmicity in melatonin secretion can be explained by its relationship with suprachiasmatic nucleus neurons. In mammals, the enzyme limiting the synthesis of melatonin (N-acetyltransferase) is under the control of norepinephrine

released by axons from neurons of the upper cervical ganglion (a ganglion of the sympathetic nervous system). The action of norepinephrine on pinealocytes results in an increase in cAMP that leads to the induction of N

acetyltransferase and melatonin synthesis.

Melatonin is a hormone that has numerous actions. In addition to the functions related to the regulation of seasonal and circadian variations of other hormones and the synchronization of many different aspects of rhythmicity associated with the light / dark cycle. Melalonin is, above all, a powerful antioxidant, and therefore acts to protect cells and tissues from damage caused by reactive radicals. In addition, compared to other antioxidants such as vitamin E, ascorbic acid or glutathione, melatonin seems to be more effective in protecting cells from oxidative stress. Melatonin preserves macromolecules such as DNA, proteins or lipids from oxidative damage in numerous experimental conditions harmful to the cell. It also has an effect inhibiting the synthesis of DNA (antiproliferative effect) in certain tumor cells in vitro, and has been shown to inhibit cell death (apoptosis) in the thymus. In the human species there are large variations in the production of melatonin throughout life (in addition to the daily variations already noted), being the highest levels in childhood, then declining at puberty. Therefore, a possible relationship of melatonin with aging has been raised.

Experiments with animals and cell cultures suggest that melatonin may have beneficial effects on certain aspects of aging and associated diseases. Of special interest are the possible effects of melatonin on the central nervous system. Given its high lipophilicity (easily crosses the blood brain barrier) and its non-toxic nature, melatonin can be an effective and important molecule in the antioxidant defense system in the brain. Whether or not the natural decrease in melatonin production associated with age is responsible for some of the symptoms of aging is still to be demonstrated, although significant improvements in the quality of life of the elderly have been reported after exogenous administration. of this hormone. In any case, more experimental data are needed to clarify the possible places and mechanisms of action, as well as clinical studies to identify the possible side effects that could result in prolonged treatment with melatonin, especially in the elderly and sick people.

The pharmaceutical composition of the present invention is composed of the pharmaceutically acceptable combination of a non-steroidal anti-inflammatory agent, such as the active substance: MELOXICAM, an adjuvant agent, such as the active substance: MELATONIN and an antineuritic analgesic, such as: VITAMINS OF COMPLEX B (B1, B6 AND 812), in addition to pharmaceutically acceptable excipients, which are formulated in a single dosage unit, said composition potentiates orally (po) the analgesic effect and produces an effective synergistic effect, with better tolerance and lower manifestations of side effects, using lower concentrations of the above-mentioned agents, compared to the doses that are normally used when the active substances are administered separately.

To evaluate the efficiency and tolerance of the pharmaceutical composition motive of the present invention; as well as the synergistic effect of the active ingredients Melatonin, Meloxicam and vitamins of the B complex (81, B6 and 812) combined in a single dosage unit, was analyzed by the isobolographic method, in the experimental pain model in the rat induced by formalin, where the aforementioned active ingredients were administered separately, as well as the combination between them.

Materials and Methods Female Wistar rats, 7 to 9 weeks old, weighing 175-199 grams are used. The rats had free access to food and water before the experiments. All experiments will be performed according to the Guidelines on Ethical Aspects for the Investigation of Experimental Pain (ED) in animals. Each rat is used only once and they are sacrificed in a chamber saturated with CO2.

The test consists of subcutaneous administration of formalin (formaldehyde in a range of concentrations ranging from 1 to 5%), in a volume of 20-25 IlL in mice, and 30-100) .IL in rats. The injection is usually given on the dorsal surface of the right hind leg and the animals are usually sacrificed shortly after the test is over. The formalin test describes different behaviors, including biting, licking and shaking the injected leg, the latter being the most used parameter to quantify the degree of pain.

The formalin test in rodents is biphasic. The first phase (acute or neurogenic) begins after the injection and lasts between 3 and 5 minutes and is due to the direct stimulation of nociceptors, mainly C fibers. The second phase (tonic

or inflammatory) starts 15-20 minutes after the injection and lasts between 20 and 40 minutes.

Subcutaneous injection of 1% formalin produced the typical shaking conduit, characterized by brief and rapid withdrawal or flexion of the injected leg. The number of shakes will be plotted as a function of time, graphs such as the one shown in figure 1 will be obtained. In this figure the time course after the 1% formalin injection is observed and the biphasic conduit is distinguished (phase 1 and 2) feature of this model. Twelve hours before starting the experiments, the food was suspended, but the free access of water was maintained. Dose response curves were performed at increasing doses of B vitamins (10.0, 31 .6, 56.2 and 100.0 mg / kg p.o.)

(100: 100: 1); Meloxieam (3.1, 5.6, 10.0 and 17.7 mg / kg, p.o.), and melatonin (31 .6, 56.2

100.0 and 177.8 mg / kg, p.o.) applied 60 minutes before the formalin injection. The effective doses thirty (LEFT) of each curve were obtained, to perform the isobolographic analysis of the combination of complex B and meloxicam. The ratio of 1: 1 among these drugs was tentatively established and the best ratio for the combination with melatonin was sought since it is desired that the maximum dose in the combination of this be 5.0 mg / kg

The results are expressed as the mean ± standard error (e.e.) of at least 6 rats per group. Curves of the number of shakes / minute were performed as a function of time. The area under the curve (ABC) of the temporary courses, is a global expression of the intensity and duration of the effect, and was calculated by the trapezoid method. The% antinociception was determined by the following formula:

% Antinociception = «Vehicle-Compound) Nehicle) X 100.

The area under the curve (ABC) and% antinociception was evaluated by analysis of variance (ANOVA) followed by the Tukey test and the results with a P <0.05 were considered significant.

Intraplantar injection of formalin produced the typical shaking conduit characterized by brief and rapid withdrawal or flexion of the injected leg. When the number of shocks was plotted as a function of time, graphs were obtained where the biphasic behavior characteristic of this model is distinguished.

EFFECT OF ORAL ADMINISTRATION OF MELOXICAM ON PAINFUL CONDUCT INDICATED BY FORMALlNA The administration of oral meloxicam reduced dose-dependent number of shakes in phases 2 of the formalin test, reaching a significant difference at a dose of 3.1 mgfKg and a maximum antinociception effect at a dose of 17.8 mg / Kg in both phases. A linear regression analysis was performed to calculate the effective dose 30 (SD30), being 4.3 mg / kg. As seen in Figure 2.

EFFECT OF ORAL ADMINISTRATION OF MELATONIN ON PAINFUL CONDUCT INDUCED BY FORMALlNA The administration of oral melatonin reduced dose-dependent number of shakes in phases 2 of the formalin test, reaching a significant difference at a dose of 100 mg / kg and a maximum effect of antinociception at a dose of 177.8 mg / kg in both phases. The antinociceptive effect of oral administration of melatonin was observed in the regression graph to calculate the ED30 that resulted in 69.5 mg / kg. As it looked in figure 3.

EFFECT OF ORAL ADMINISTRATION OF COMPLEX B ON PAINFUL BEHAVIOR INDUCED BY FORMAL

The administration of complex 8 (81, 86 and 812) 100: 100: 1 ratio. Oral route reduced the number of shakes in phase 2 of the formalin test in a dose-dependent manner, reaching a significant difference at a dose of 31.6 mg / kg. and a maximum effect of antinociception at a dose of 100.0 mg / kg. Regression analysis was performed to calculate the ED30, which is 33.6 mg / kg. As seen in Figure 4.

DE ", ESTIMATED AFTER THE ORAL ADMINISTRATION OF MELOXICAM, MELATONINA and COMPLEX B.

I LEFT it and its respective standard errors that were estimated from the dose-effect curves (dose-% antinociception) that were obtained after oral administration of increasing doses of meloxicam, melatonin and B complex.

PHARMACO Meloxicam Melatonin Complex B

DE "(rng / Kg) 4.3 69.5 33.6 and. e. DE30 0.38 8.04 5.13

EFFECT OF THE ORAL COADMINISTRATION OF THE MELOXICAMMELATONINE MIXTURE ON THE PAINFUL CONDUCT INDUCED BY FORMAL PROPORTION (0.92: 0.8)

10 Combinations designed for the study of the interaction of the meloxicammelatonin mixture, it is worth mentioning that this proportion was used in the combination to adjust the maximum dose of melatonin to 5.6 mg. From the value of the DE30 of meloxicam.

Meloxicam combination (rng / Kg, p.o.)

Melatonin combination (rng / Kg, p.o.) Total dose in the combination (rng / Kg, p.o.)

1.0

1.4 2.4

2.0

2.8 4.8

4.0

5.6 9.6

15 Co-administration of the meloxicam-melatonin mixture, dose-dependently reduced the number of shakes in phase 2 of the formalin test, reaching a significant difference and a maximum effect of antinociception at a total dose of 9.6 mg / kg. in phase 2, as seen in figure 5.

The statistical analysis and the isobologram of the oral co-administration of the meloxicam-melatonin mixture suggests the type of synergistic interaction between both drugs. Since the interaction rate is less than one and evaluated by a t test

states that there are statistically significant differences. As can be seen in figure 6.

Statistic analysis

DE30 (mg / Kg)

DE30 (mg / Kg) index of

combination

combination

interaction

experimental

theoretical

7.4 ± 0.6

9.51 ± 0.51 0.778 ± 0.06

EFFECT OF THE ORAL COADMINISTRATION OF THE MELOXICAM MIX

COMPLEX B ON PAINFUL BEHAVIOR INDUCED BY FORMAL

Combinations designed to study the interaction of the meloxicam mixture

complex 8 based on the ED30 values of both drugs.

Meloxicam combination (mg / Kg, p .o.)

Complex B combination (mg / Kg, p .o.) Total dose in the combination (mg / kg, p.o.)

0.5

4.2 4.7

1.1

8.4 9.5

2.1

16.8 18.9

4.3

33.6 37.9

Co-administration of the meloxicam-B complex mixture reduced the number of shakes in phase 2 of the formalin test in a dose-dependent manner, reaching a significant difference at 9.5 mg / kg p.o. and a maximum effect of

15 antinociception at a total dose of 37.9 mg / kg. in phase 2, as seen in figure 7.

The statistical analysis and the isobologram of the oral co-administration of the meloxicam-B complex mixture suggests the existence of some type of synergistic interaction

20 between both drugs. Since the interaction rate is less than one and evaluated by a t-test, it states that there are statistically significant differences with P <0.005, as shown in Figure 8.

Statistic analysis

FROM "(rng / Kg) in

DE30 (rng / Kg) Index of

the combination

combination interaction

experimental

theoretical

7.09 ± 0.06

18.9 ± 2.57 0.374 ± 0.06

5 EFFECT OF THE ORAL COADMINISTRATION OF THE MELATONINACOMPLEJO MIXTURE ON THE PAINFUL CONDUCT INDICATED BY FORMALlNA Combinations designed for the study of the interaction of the melatonin complex B mixture with a ratio of 0.92: 0.08 respectively, trying that the maximum dose of melatonin used was 5.6 mg from the values of the DE30 of the

10 combination of vitamins.

Melatonin in the combination (rng / Kg, p.o.)

Complex B in the combination (rng / Kg, p.o.) Total dose of the combination (rng / Kg, p.o.)

0.7

3.9 4.6

1.4

7.7 9.1

2.8

15.5 18.2

5.6

30.9 36.5

The co-administration of the melatonin-B complex mixture, dose-dependently reduced the number of shakes in phase 2 of the formalin test, reaching a significant difference 18.2 mg / kg, p.o. and a maximum effect of antinociception at a total dose of 36.5 mg / kg, as shown in Figure 9.

The statistical analysis and the isobologram of the oral co-administration of the Melatonin mixture: B vitamins suggest the existence of some kind of interaction

20 synergistic between both drugs. Since the interaction rate is less than one and evaluated by a t-test, it states that there are statistically significant differences, as shown in Figure 10.

Meloxicam (mgIKg, p.o.)

Melatonin (mgIKg, p.o.) Complex B (mgIKg, p.o.) Total dose in the combination (mg / kg, p.o.)

0.45

0.45

4.2 5.1

0.95

0.95

8.4 10.2

1.85

1.85

16.8 20.5

3.7

3.7

33.6 41.0

Statistical analysis Statistical analysis of the co-administration of the Melatonin B complex vitamin mixture.

DE "(mg / Kg) in

DE30 (mg / Kg) Interaction Index

the combination

combination

experimental

theoretical

8.9 ± 2.27

36.5 ± 4.8 0.243 ± 0.08

MELOXICAM-MELATONINE-COMPLEX B INTERACTION

Combinations designed for the study of the interaction of the meloxicammelatonin mixture in (ratio 0.92: 0.8) and complex B based on the ED30 values of both drugs. As can be seen in figure 11.

. .

..

The statistical anahsls and the Isobologram of the oral coadmlnlstraclon of the meloxicam-melatonin mixture with the B complex suggest the existence of some type of synergistic interaction between both drugs, but when applying the statistic to the analysis

15 isobolographic with a t-test establishes that there are no significant differences in the combination, so the result is an additive type synergy. As seen in figure 12.

Statistic analysis

DE30 (mgIKg)

DE30 (mgIKg)

Index of

experimental

theoretical interaction

115.7 ± 2.07 120.5 ± 2.6 1 0.765 ± 0.14

According to the results, the synergistic interactions of Melatonin, Meloxicam and Vitamins of complex B (81, 86 and 812) are demonstrated, are reflected with an increase in the potency and efficiency of the combination. The main advantage of this combination is the ability to administer lower doses of the active ingredients contained in it. This has a therapeutic advantage for pain management caused by various etiologies, pain of inflammatory origin, lumbar neuropathy, diabetic neuropathy, trigeminal neuralgia, sciatic neuralgia.

The pharmaceutical composition of the present invention has the following concentration ranges:

•

MELOX1CAM, from 3 mg to 8 mg, preferably 5 mg per dose;

•

MELATONIN, from 3mg to 10 mg, preferably 5 mg (sub-analgesic dose) per dose unit;

•

VITAMINS OF COMPLEX B, specifically:

or Vitamin B1 (Thiamine) from 50 mg to 150 mg, preferably 100 mg per dose,

or Vitamin B6 (Pyridoxine) from 50 mg to 150 mg, preferably 50 mg per dose; Y,

or Vitamin B12 (Cyanocobalamin) from 0.005 mg to 0.015 mg, preferably 0.010 mg per dose; Y,

Said pharmaceutical composition is formulated in a single dosage unit MELOXICAM, MELATONIN and VITAMINS B1 (Thiamine), B6 (Pyridoxine) and B12 (Cyanocobalamin), to be administered orally in the form of tablets, capsules or solutions.

The pharmaceutical composition composed of the synergistic combination of a non-steroidal anti-inflammatory agent, such as the active substance: MELOXICAM, an adjuvant agent, such as the active substance: MELATONIN and an antineuritic analgesic, such as: VITAM INAS OF COMPLEX B (B1 , B6 and B12), is used for the preparation of a medication for the treatment of pain; lumbar neuropathy; diabetic neuropathy; trigeminal neuralgia; and, sciatic neuralgia.

Claims (9)

one.

A pharmaceutical composition comprising: the synergistic combination of,

2.

The pharmaceutical composition of the preceding claim, characterized in that: MELOXICAM, MELATONIN and VITAMINS B1 (Thiamine), B6 (Pyridoxine) and 812 (Cyanocobalamin), are formulated in a single dosage unit.

3.

The pharmaceutical composition of the preceding claims, characterized in that: the preferred concentration of MELOXICAM is 5 mg per unit dose.

Four.

The pharmaceutical composition of the preceding claims, characterized in that: the preferred concentration of MELATONIN used is 5 mg (sub-analgesic dose) per dose unit.

5.

The pharmaceutical composition of the preceding claims, characterized in that: the preferred concentration of Vitamin 81 (Thiamine) is 100 mg per unit dose.

8.

a non-steroidal anti-inflammatory agent, where the active substance is

MELOXICAM, which is in a concentration range of 3

mg to 8 mg per dose;

b.

a adjuvant agent, where the active substance is MELATONINA, the

which is in a concentration range of 3mg to 10mg per

dose;

C.

an antineuritic analgesic, which is VITAMINS OF THE COMPLEX

B, specifically VITAMINS B1

(Thiamine), B6 (Pyridoxine) and B12

(Cyanocobalamin) and they are found

in a concentration range of

Vitamin 81

(Thiamine) 50 mg to 150 mg per dose, Vitamin 86

(Pyridoxine)

from fifty mg to 150 mg by dose Y Vitamin 812

(Cyanocobalamin) from 0.005 mg to 0.015 mg per dose; Y,

d.

At least one acceptable pharmaceutical excipient.

The pharmaceutical composition of the preceding claims, characterized in that: the preferred concentration of Vitamin B6 (Pyridoxine) is 50 mg per unit dose. 7. The pharmaceutical composition of the preceding claims, characterized 10 because: the preferred concentration of Vitamin B12 (Cyanocobalamin) is 0.010 mg per unit dose. 8. The pharmaceutical composition of the preceding claims, characterized because: it is formulated in a single dosage unit to be administered orally in the form of tablets, capsules or solutions. 9. The use of the pharmaceutical composition according to claims 1 to 13 for the preparation of a medicament for the treatment of pain; pain of inflammatory origin; lumbar neuropathy; diabetic neuropathy; neuralgia 20 of the trigeminal; and, sciatic neuralgia.