MX2013001354A

MX2013001354A - Oral pharmaceutical composition containing a combination of a visceral smooth muscle relaxant and an analgesic/anti-inflammato ry, and use thereof for treating irritable bowel syndrome of diverse etiology.

Info

Publication number: MX2013001354A
Application number: MX2013001354A
Authority: MX
Inventors: Gabriel Mercelín Jiménez; P Angeles Moreno Alionka Citlali
Original assignee: Mavi Farmaceutica S A De C V
Priority date: 2013-02-01
Filing date: 2013-02-01
Publication date: 2014-09-02
Also published as: MX347034B

Abstract

The present invention is related to the pharmaceutical technology and pharmacology of the gastro-intestinal tract, mainly detailing a pharmaceutical combination of a visceral smooth muscle relaxant and an analgesic/non-steroidal anti-inflammatory useful for treating the irritable bowel syndrome of diverse etiology. The preferred visceral smooth muscle relaxant is pinaverium bromide and the preferred analgesic/non-steroidal anti-inflammatory is the lysine clonixinate. Described are examples, without limitation, of the formulation in a solid oral pharmaceutical form, which contains the combination proposed in this invention.

Description

ORAL PHARMACEUTICAL COMPOSITION CONTAINING A COMBINATION OF A RELAXANT OF THE SMOOTH VISCERAL MUSCLE AND ANALGESIC / ANTI-INFLAMMATORY, AND ITS USE IN THE TREATMENT OF COLON SYNDROME IRRITABLE OF DIVERSE ETIOLOGY.

FIELD OF THE INVENTION The present invention relates to the pharmaceutical technology and pharmacology of the gastrointestinal tract, particularly, it details a pharmaceutical combination of a visceral smooth muscle relaxant and a non-steroidal anti-inflammatory analgesic that is useful for the treatment of irritable bowel syndrome of etiology diverse The visceral smooth muscle relaxant is the pinaverio and the non-steroidal anti-inflammatory analgesic is clonixinate. Preferably, the visceral smooth muscle relaxant is its bromide salt and the non-steroidal anti-inflammatory analgesic is its lysine salt.

BACKGROUND OF THE INVENTION Irritable bowel syndrome is a condition that affects more than 15% of the population in the United States of America, it is one of the most important non-fatal diseases to control (ertz 2003). . The patients can present a variety of symptoms, the most characteristic is the abdominal pain associated with alteration in the movements intestinal The pathophysiology of this condition is not clear, as it is the result of a combination of disturbances in the motor and sensory functions of the viscera.

The main disturbances in the intestine can be both constipation and diarrhea at different times, which is why this syndrome is classified as a disorder in intestinal motility; however, not only disturbances in motility can explain the pathology. Recently, a greater emphasis has been given to the pathogenesis of pain in these patients, and there is sufficient evidence to suggest an increase in visceral sensitivity. The etiology of this visceral hypersensitivity is probably multifactorial. It may be due to genetic factors, alterations in digestive motility, visceral hypersensitivity, psychological alterations and a history of physical and / or sexual abuse.

A tool for the diagnosis of Irritable Bowel Syndrome, has been defined as CRITERIA OF ROME II, which have been structured by a group of experts, who have been reviewing these criteria and updating them periodically. The diagnosis will be made through the evaluation of the following symptoms: • Less than 3 bowel movements per week • More than 3 stools per day • Hard or ball depositions • Soft or liquid stools • Excessive effort during defecation • Defecatory urgency • Feeling of incomplete evacuation • Presence of mucus during bowel movements • Feeling of bloating or abdominal distension. considered as a subtype with predominance of diarrhea when: • There are one or more of the symptoms listed as 2, 4 or 6, none of 1, 3 or 5.

Two or more of the symptoms listed as 2 4 or 6 or one of the 1 or 5 are present. considered as a subtype with predominance of constipation when There are one or more of the symptoms listed as 1, 3 or 5, none of 2, 4 or 6.

Two or more of the symptoms listed as 1 3 or 5 and one of 2, 4 or 6 are present.

It is considered as an alternating subtype when it does not meet any of the above combinations.

According to a review of the studies conducted to compare different treatments used for irritable bowel syndrome from 1966 to 2009, it was found that out of 56 studies analyzed (3725 patients) it is known that the bulking agents did not register a significant difference in The decrease in abdominal pain between these and the patients treated with placebo (186 patients), nor a significant generalized improvement was registered comparing them with the placebo group (565 patients).

Considering antispasmodics, improvement was observed in the group treated with these drugs compared to those treated with placebo (1392 patients), there was a generalized improvement in patients treated with antispasmodics vs those treated with placebo (1983 patients). The antispasmodics that presented these improvements were: cimetropio / diciclomina, pinaverio and trimebutina.

CALCIUM CHANNEL BLOCKERS Calcium channel blockers reduce motility and can promote absorption of electrolytes and water. Constipation is a side effect of the use of this type of drugs.

PINAVERIUM BROMIDE Pinaverium Bromide, FR 2,097,032 and US 3,845,048 in the name of Societe Berri-Balzac, responds to the IUPAC nomenclature as 4- [(2-bromo-4,5-dimethoxyphenyl) methyl] -4- [2- [2 - (6,6-dimethylbicyclo [3.1.1] hept-2-yl) ethoxy] ethyl] morpholino, of molecular formula C26H4iBr2N04 and molecular weight of 591.42. It was proposed for the first time by R. Baronnet et al., Eur. J. Med. Chem. 1974, 9, 182.

The pinaverio is an antispasmodic, anticholinergic and relaxant of the intestinal smooth muscle that acts as a local spasmolytic agent in the digestive tract. This mechanism of action is a product of the inhibition of calcium channels in the smooth muscle, inducing a relaxation of the digestive and biliary tracts. It facilitates gastric emptying and decreases intestinal transit time in patients with constipation. It is very effective in improving the symptoms of irritable bowel (abdominal pain, gas, diarrhea or constipation).

The pinaverium bromide has a low absorption (8-10%), combined with a marked hepatic-biliary excretion, so that most of the administered dose remains in the gastrointestinal tract. This represents an advantage, by reducing the adverse effects of calcium channel blocking drugs in the cardiovascular system, and increasing their usefulness in the treatment of irritable bowel syndrome.

A dose of pinaverium bromide of 50 mg every 8 hours, or 100 mg twice daily is suggested.

Among the adverse effects reported for pinaverio are: dry mouth, diarrhea, constipation, nausea, tachycardia, decreased blood pressure.

LYSINE CLONIXINATE The Lysine Clonixinate, US 3,973,027 and FR 74,07817 (Mar, 7, 1974) in the name of Roemmers Industrial, Commercial and Financial Corporation, responds to the IUPAC nomenclature as (2- (3-chloro-o-toluidin) lysine nicotinate It has a molecular formula of C HnCl ^ C ^. C6H14N202 and a molecular weight of 408.88 Lysine clonixinate is a dry amorphous powder, of white or light yellowish white color, with a characteristic and irritating, soluble odor. in methanol, slightly soluble in aqueous media and with a high tendency to dissolve in organic solvents.

Lysine clonixinate, an anthranilic derivative of nicotinic acid, is a drug belonging to the family of non-steroidal anti-inflammatory analgesics (NSAIDs), particularly the family of fenamates. Like the rest of the NSAIDs, it has side effects at the gastrointestinal level. It can be administered orally or parenterally. Its pharmacological characteristics that distinguish it for its power, efficiency and speed of action, as well as its good tolerance and adequate margin of safety.

Its mechanism of action is through the inhibition of the enzyme cyclooxygenase, responsible for the synthesis of prostaglandins. Prostaglandins PGE2 and PGF2a / are directly responsible for the stimulation of pain neuroreceptors. Clonixinate lysine, by blocking its production, prevents hyperalgesia, regardless of the cause, intensity and location.

It has also been shown that lysine clonixinate inhibits already produced bradykinin and PGF2a, which is why it is considered as a direct antagonist of pain mediators.

It stands out from the group of acid anti-inflammatories due to its high analgesic potency demonstrated in experimental models and through its clinical use, destined to the treatment of painful processes of different intensity and origin; it does not cause depression of the Central Nervous System, nor dependency.

It is indicated as an analgesic and anti-inflammatory in somatic and visceral pain.

Lysine clonixinate administered orally in single or multiple doses, is rapidly absorbed in the gastrointestinal tract reaching maximum serum concentrations 1 hour after administration. It is widely distributed in all tissues and does not interfere with coagulation at the platelet level.

It is metabolized in the liver and eliminated in the urine. In the rat at a dose of 40 mg / kg orally, the maximum concentration is 131.3 pg / mL at 15 minutes.

Its elimination half-life is approximately 1.38 h, eliminated by urine.

SUMMARY OF THE INVENTION It is proposed the development of a solid oral pharmaceutical form for the treatment of symptoms associated with irritable bowel syndrome, containing a combination of pinaverium (antispasmodic) and clonixinate (non-steroidal anti-inflammatory analgesic), preferably a combination of its pharmaceutically salts acceptable as bromide, and lysine and sodium, respectively; more preferably, a combination of pinaverium bromide and lysine clonixinate, which generates a synergy between the active ingredients and allows a greater adherence to the treatment.

The invention consists of a formulation combining a non-steroidal anti-inflammatory and a visceral smooth muscle relaxant together with pharmaceutically acceptable excipients in an appropriate concentration for the manufacture of a medicament, useful in the treatment of irritable bowel syndrome of various etiology.

In another embodiment of the invention, the pharmaceutical formulation of interest contains lysine clonixinate and pinaverium bromide as active substances for the treatment of irritable bowel syndrome, in combination with pharmaceutically acceptable excipients and appropriate to the pharmaceutical form of convenience.

In another embodiment of the invention, the pharmaceutical formulation of interest is orally administered and has a preferred pharmaceutical form of tablet or capsule.

In another embodiment of the invention, the present invention details the manufacturing methods of the pharmaceutical form of interest.

DESCRIPTION OF THE INVENTION The combination of products from two or more drugs in a single dose unit is acceptable only when the dose of each ingredient meets the requirements for a particular population and when the combination has demonstrated a real advantage in its therapeutic effect, safety and compliance over that obtained through the independent administration of the compounds (Br. J. Clin Pharmacol., 2008; 65 (5): 795-796).

The manufacture of such combinations should preferably obey: • The drugs in the combination must act through different mechanisms • The pharmacokinetics should not be very different • The combination should not generate additive toxicity of the ingredients • Decrease in the dose of drugs to be combined The use of the pinaverium in combination with clonixinate, preferably the pharmaceutically acceptable salts pinaverium bromide in combination with lysine clonixinate thus provide a particularly effective pharmaceutical composition of simultaneous and localized action in the treatment of irritable bowel syndrome of diverse etiology, by reducing the first, the adverse effects of calcium channel blockers in the cardiovascular system and increase their usefulness in the specific and localized treatment of irritable bowel syndrome, while the second in turn, with a preferred distribution of soft tissue pharmacokinetics, provides analgesia and anti-inflammatory effect in somatic and visceral pain present.

According to the above, the association of pinaverium bromide and lysine clonixinate together with pharmaceutically acceptable excipients in a drug, will allow a highly targeted treatment of the intestinal smooth muscle by the distribution and sites of action of the active, resulting in a treatment of greater effectiveness because the antispasmodic mechanisms of action of pinaverio and analgesics / anti-inflammatory of lysine clonixinate are complementary. The combined presentation in a single dosage unit together with pharmaceutically acceptable excipients, avoids the intake and repeated taking of two different drugs, resulting in better adherence rates to the treatment, offering a new treatment alternative for the population suffering from these symptoms and decreasing the associated effects of administering the drugs separately.

The various dosage forms according to the present invention can comprise excipients and / or vehicles suitable for the formulation thereof. Thus, the pharmaceutical composition to which the present invention refers can be administered in the form of tablets, pellets, granules and / or capsules.

The term "pharmaceutically acceptable excipient" as used herein includes any physiologically inert and pharmacologically inactive material known to anyone of ordinary skill in the art, and which is compatible with the physical and chemical characteristics of the pinaverium and clonixinate selected as active ingredients of the present invention, preferably, a pharmaceutically acceptable salt of pinaverium and clonixinate, more preferably bromide of pinaverio and lysine clonixinate. The pharmaceutically acceptable excipients used in the pharmaceutical composition of the invention are in a total concentration ranging from 5 to 50% by weight and comprise, but are not limited to, diluents, binders, disintegrants, surfactants, lubricants and glidants. The pharmaceutically acceptable excipients suitable for the administration of the oral solid dosage forms according to the present invention can be selected from suitable vehicles which comprise, but are not limited to, sugars such as glucose, sucrose, lactose and fructose, starches or derivatives of starch, croscarmellose sodium, oligosaccharides, such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, polyvidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (for example cellulose ether), sugar alcohols such as mannitol or sorbitol , calcium carbonate, calcium phosphate, lactose, lactitol, dextrates, dextrose, maltodextrin, saccharides including monosaccharides, disaccharides, polysaccharides, sugar alcohols such as arabinose, ribose, mannose, sucrose, trehalose, maltose and dextran.

At least one of the excipient is a diluent selected from the group consisting of starch, such as, but not limited to corn starch, microcrystalline cellulose, calcium phosphate, lactose, maltodextrin mannitol, sorbitol, cross-linked polyvinylpyrrolidone and sodium carboxymethylcellulose, preferably starch and microcrystalline cellulose. When the starch is the diluent, then its concentration is selected from the group consisting of 150 mg to 450 mg per tablet, preferably 150 to 300 mg, 160 to 290 mg, 170 to 280 mg, 170 to 270 mg, 180 to 260 mg, 170 to 250 mg, 190 mg to 240, 200 to 240 mg, 210 mg to 240, 220 to 240 mg and 230 to 240 mg per tablet, more preferably 235.0 mg per tablet. Another preferred concentration is selected from the group consisting of 200 to 450 mg, 210 to 440 mg, 220 to 430 mg, 230 to 420 mg, 240 to 410 mg, 250 to 400 mg, 260 to 390 mg, 270 to 380 mg, 280 to 370 mg, 290 to 360, 300 mg to 360, 310 to 360 mg, 320 mg to 360, 330 to 360 mg, 340 mg to 360 and 350 to 360 mg per tablet.

The tablet also contains a flow regulator selected from the group consisting of talc, anhydrous silicon dioxide and a lubricant, preferably anhydrous silicon dioxide. The concentration of a flow regulator is in the range of 2 to 8 mg, the preferred concentrations of the flow regulator are selected from the group consisting of 2 to 6 mg, 3 to 6 mg, 3 to 5 mg, 3 to 4 mg, 2 to 5 mg and 2 to 4 mg per tablet, and even more preferred 4 mg. Another preferred concentration is selected from the group consisting of 4 to 8 mg, 5 to 8 mg, 6 to 8 mg, 6 to 7 mg, 5 to 7 mg, 4 to 7 mg, 4 to 6 mg, 5 to 6 mg per tablet, and 6 mg per tablet.

The tablet further contains lubricants selected from the group consisting of polyethylene glycols, stearic acid, aluminum stearate, calcium arachidonate and magnesium stearate, preferably stearic acid, aluminum stearate, calcium arachidonate and magnesium stearate., more preferred is magnesium stearate. The concentration of the lubricant is in the range of 5 to 15 mg per tablet, the preferred concentrations of the lubricant are selected from the group consisting of 5 to 10 mg, 5 to 9 mg, 5 to 8 mg, 6 to 10 mg, to 9, 6 to 8 mg, 7 to 10 mg, 7 to 9 mg, 7 to 8 mg per tablet and 8 mg per tablet. Another preferred concentration of the lubricant is selected from the group consisting of 8 to 15 mg, 8 to 14, 8 mg to 13 mg of 8 to 12 mg 9 to 15, mg 9 to 14, mg 9 to 13, 9 to 12 mg , 10 to 15 mg, 10 mg to 14, 10 to 13 mg, 10 mg to 12, 11 to 15 mg, 11 mg to 14, 11 to 13 mg, 1 1 to 12 mg per tablet and 12 mg per tablet.

In the following, examples are described, without limitation, of the formulation in solid oral pharmaceutical form containing the combination proposed in this invention: Tablets Maximum dose of Clonixinate: 750 mg.

It is also suggested a dose of 1 tablet c / 8 hours after the food, for a period no longer than 5 days, or sooner if the symptomatology of the irritable bowel is reversed.

Capsules These doses of clonixinate and pinaveria are those that have been reported as safe and effective in the corresponding clinical studies. Being the most effective therapeutic combination, the time of consumption of the assets is less, which can reduce the incidence of adverse events.

Claims

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following claims is claimed as a priority. CLAIMS

1. - A pharmaceutical composition characterized in that it contains a visceral smooth muscle relaxant in an amount of 10 to 100 mg, an anti-inflammatory analgesic in an amount of 50 to 250 mg and pharmaceutically acceptable excipients.

2. - A pharmaceutical composition according to claim 1, characterized in that the anti-inflammatory analgesic is clonixinate or a pharmaceutically acceptable salt thereof.

3. - A pharmaceutical composition according to claim 2, characterized in that the pharmaceutically acceptable salt of the clonixinate is lysine clonixinate.

4. - A pharmaceutical composition according to claim 2, characterized in that the pharmaceutically acceptable salt of the clonixinate is sodium clonixinate.

5. - A pharmaceutical composition according to claim 1, characterized in that the visceral smooth muscle relaxant is pinaverium or a pharmaceutically acceptable salt thereof.

6. - A pharmaceutical composition according to claim 5, characterized in that the pharmaceutically acceptable salt of the pinaverium is pinaverium bromide.

7. - A pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable excipients are in a concentration of 5 to 50% by weight of said composition.

8. - A pharmaceutical composition according to claim 1, characterized in that the amount of the visceral smooth muscle relaxant is preferably from 50 to 100 mg.

9. - A pharmaceutical composition according to claim 1, characterized in that the amount of the anti-inflammatory analgesic is preferably from 125 to 250 mg.

10. - A pharmaceutical composition according to claim 1, characterized in that the visceral smooth muscle relaxant and the anti-inflammatory analgesic are in a single solid oral dosage unit in combination with pharmaceutically acceptable excipients.

11. - A pharmaceutical composition according to claim 10, characterized in that the visceral smooth muscle relaxant is pinaverium bromide.

12. - A pharmaceutical composition according to claim 10, characterized in that the antiinflammatory analgesic is lysine clonixinate.

13. - A pharmaceutical composition according to claim 10, characterized in that the solid oral dosage unit is a tablet.

14. - A pharmaceutical composition according to claim 10, characterized in that the solid oral dosage unit is a capsule.

15. The use of a pharmaceutical composition containing a visceral smooth muscle relaxant in combination with an anti-inflammatory analgesic and pharmaceutically acceptable excipients, for the manufacture of a medicament useful in the treatment of irritable bowel syndrome of diverse etiology.