WO2009069993A1 - Pharmaceutical composition combining various antispasmodic agents and a non-steroidal anti-inflammatory agent, which can be used to control and treat renal colic and inflammation - Google Patents

Abstract

The invention relates to a pharmaceutical composition comprising the snyergic combination of various antispasmodic agents, such as the active principles phloroglucinol and trimetylphloroglucinol, and a non-steroidal anti-inflammatory agent, such as the active principle meloxicam, as well as pharmaceutically acceptable excipients, which are formulated in a single dosage unit to be administered orally. The composition, which is used to control and treat renal colic and inflammation caused by litiasis, provides effective pain control as well as ensuring that renal function remains healthy and suppressing and alleviating the effects of urethral obstruction.

Description

PHARMACEUTICAL COMPOSITION COMPOSED BY THE COMBINATION OF VARIOUS ANTI-SPASMODIC AGENTS AND AN AGENT

NON-STEROID ANTiiNFLAMATORY, USEFUL FOR CONTROL AND

TREATMENT OF RENAL CHOLIC AND INFLAMMATION.

FIELD OF THE INVENTION

The invention that is required below has application in the pharmaceutical industry and describes a pharmaceutical composition composed of the synergistic combination of various antispasmodic agents, such as the active ingredients: Floroglucinol and Trimethylfloroglucinol and a non-steroidal anti-inflammatory agent, such as the active ingredient : Meloxicam, in addition to pharmaceutically acceptable excipients; which are formulated in a single dosage unit to be administered orally, which is indicated for the control and treatment of renal colic and inflammation caused by lithiasis.

The combination of the aforementioned active ingredients produces a greater synergistic effect when they are administered in combination in a single dosage unit unlike when they are administered independently, generating Benefits such as: lower doses administered, faster pharmacological action, maximization of the therapeutic effect and lower risks of presenting side effects. BACKGROUND OF THE INVENTION

Renal colic (CR) is a frequent urological emergency, which presents one of the most distressing forms of pain in humans, so it requires rapid diagnosis and treatment. More than 12% of the population will suffer a CR during their lifetime, with the recurrence rate being around 50%. CR is caused by an acute, partial or complete ureteral obstruction, which in the vast majority of cases is usually due to a calculus, causing acute distension of the collecting system.

The frequency is higher in the morning and during hot seasons, due to lower nocturnal urinary production and situations with greater insensitive losses, such as intense sweating. These circumstances significantly increase urinary concentration, acting as a clear predisposing factor to develop an attack, which affects older men more. American epidemiological studies show that Caucasian men have the highest incidence, followed in order by black women and men. In epidemiological studies that include the North American Hispanic population, no differences are observed compared to the Caucasian population, but a greater number of urological interventions due to symptomatic lithiasis are detected in Hispanic women. 25% of patients with recurrent renal colic have a family history of urolithiasis, and with a family history, the lithiasic risk is multiplied by three.

The sharp increase in intraluminal pressure due to acute ureteral obstruction extends from the nociceptor nerve endings - (chemoreceptors and mechanoreceptors) located in the submucosa and in the lamina lamina of the peripielic renal capsule

(responsible for renal pain), the renal pelvis (responsible for reno-ureteral pain), and in lower density, in the proximal ureter.

In addition, the smooth musculature of the ureteral wall contracts trying to expel the obstruction, and if not He does it, he spasms. Prolonged isotonic contraction leads to increased production of lactic acid that will irritate slow type A (myelinated) and fast type C (unmyelinated) fibers. These generated nerve impulses travel to the medullary segments DI-12, reaching the central nervous system, where they are specified by location, character and intensity, which will enhance the crisis. It is believed that local mucosal irritation plays a minor role. The distribution of renal pain by dematomas is the result of a somato-visceral convergence of the neural information received from the spinal cord, so that pain can be perceived in each organ that shares innervation with the urinary tract.

This explains the typical irradiation of pain from spinal fibers to renal and ureteral afferent fibers, and sensory fibers from the skin, corresponding to those areas innervated by the genitofemoral, ilioinguinal and iliohypogastric nerves. The rest of visceral symptoms that are frequently associated with renal colic (nausea, vomiting, tachycardia, decrease in intestinal peristalsis) are due to multiple connections between the renal, celiac and mesenteric plexuses that reach the spinal cord at the same level causing neighborhood irritation.

Three successive phases have been described in acute ureteral obstruction: the first, which can last from 0 to 1.5 hours, where renal blood flow (FSR) and ureteral pressure (PU) increase, in the second continues to increase, and finally we find a third phase, beyond 5 hours, where the FSR and PU decrease together.

The initial increase in FSR is due to a preglomerular vasodilation, which many studies show is secondary to an increase in local production of eicosanoids, mainly prostaglandins E2 (PGE2) and prostacyclines (PGI2), and where the increase in nitric oxide (NO) It also has a relevant role. On the other hand, PGE2 inhibit the secretion of antidiuretic hormone (ADH) during acute obstruction, a fact that increases PU more, due to increased urinary flow. Subsequently, the FSR and PU decrease in a mechanism of self-defense due to the subsequent preglomerular vasoconstriction that will increase intrarenal resistances, being a reaction established by different mediators, angiotensin II, thromboxane A2, ADH and endothelin.

The decrease in PU is secondary to a very important decrease in glomerular filtration that always persists within the minimum levels in a phenomenon that manifests itself because the urine accumulated in the renal pelvis can escape due to pyelovenous and pyellophoretic reflux, among others.

This whole process would explain, in part, the clinical observation of a spontaneous improvement in pain intensity a few hours after its onset in most patients.

It is important to highlight that renal colic pain is not directly caused by spasmodic contractions of the clogged ureter, and therefore, the use of spasmolytic drugs will be of little use, and in addition, they could be counterproductive by inhibiting ureteral physiological peristalsis, making it difficult and delaying Elimination of the obstructive cause. In some cases, prolonged and intense hyperpressure within the collecting system could imply a very severe annulment of the glomerular filtration, but before this happens, a rupture of the urinary tract can occur at the level of the calix fornix, with significant extravasation of urine at perirenal level.

Said urine can be reabsorbed by the venous and lymphatic systems of the interstitial space, being another defense mechanism to decrease intraluminal tension, and pielic and ureteral pressures, and that even starts before the rupture of the urinary tract.

Fortunately, the risk of definitive renal failure is not established until several weeks after a complete obstruction has been established with maximum annulment of the glomerular filtration rate, without the literature having precisely established the time necessary to cause irreversible renal lesions (2 to 6 weeks). according to the authors and in experimental animal models).

In the vast majority of patients, up to 90%, colic is due to acute ureteral obstruction caused by a lithiasis. From 5 to 10%, colic is due to alterations of the non-lithiasic urinary tract, such as pyeloureteral junction syndrome, presence of clots due to renal tumors, ureteral atony due to pyelonephritis, papillary necrosis or urothelial neoplastic processes.

Some patients with renal colic may present with extrinsic ureteral obstruction secondary to other processes, such as intestinal diseases (appendicitis, diverticulitis, Crohn's disease), gynecological, retroperitoneal, vascular (aortoiliac aneurysms, retrocave ureter), oncological and hematological or post-surgical complications . The pain of renal colic is usually sudden onset, unilateral and very intense. It is located in the lumbar fossa and the angle costovertebral resiguiendo the lower margin of the 12th rib.

This pain characteristically radiates along the antero-descending urethral path to the bladder, external genitalia, and even the inner thigh. Sometimes, the patient refers to the pain It begins in areas where it typically radiates, subsequently presenting typical low back pain.

The patient has great agitation, looking for an anti-allergic position impossible to find and characteristically, holding the renal fossa. It is possible for the doctor to determine the position of a ureteral stone by the irradiation zone.

If the stone is lodged in the upper part of the ureter, the pain radiates to the testicle, since the innervation of this organ is similar to that of the kidney and the upper portion of the ureter.

When the stone is in the middle portion of the right ureter, the pain radiates to the point of

McBurney, being able to simulate appendicitis. On the left side it may resemble diverticulitis or other diseases of the descending colon or sigma.

As the calculation approaches the bladder, inflammation and edema of the ureteral orifice occurs, symptoms of bladder irritability appear (polaquiuria and tenesmus).

The most frequently associated non-urinary symptoms are usually digestive, in the form of nausea, vomiting and constipation due to reflex ileus. Fever not It is part of the symptomatology of uncomplicated renal calculus, although there may be a fever.

When exploring the patient, we will feel a soft abdomen, with no signs of peritonism, and with some tympanism due to the ileum reflex. The mild renal percussion of the affected side will be positive, even with lumbar muscle contracture.

In man, the testicle is often retracted and elevated, but not painful on palpation. In women, the pelvic exam will be normal.

In the history, in addition to the clinical characteristics of our own, to further guide the picture, we can look for personal and family history of renal colic, exertion hematuria, spontaneous expulsion of small lithiasis, etc., as well as a family history of urinary lithiasis, which Observe in 3 to 10% of cases.

In addition, there may be predisposing factors for urolithiasis such as: prolonged immobilization, diseases with bone manifestations

(hyperthyroidism, Paget, sarcoidosis, myeloma, etc.) and digestive diseases (hemorrhagic rectocolitis, ileitis, ileum resections, inflammatory bowel diseases).

Certain treatments may also be responsible for metabolic stones (oncological chemotherapy of uric lithiasis; vitamin D, calcium and furosemide of calcium lithiasis; carbonic lithiasis anhydrase inhibitors of calcium phosphate) or calculations of drug origin (triamterene, sulfa drugs, nitrofurantoins, indinavir ). In clinical practice it is very important to establish the differential diagnosis between febrile renal colic or acute obstructive pyelonephritis and simple acute pyelonephritis.

Conservative management is considered the first line of treatment of simple renal colic, since two thirds of ureteral stones are expelled spontaneously within 4 weeks of the onset of symptoms.

A ureteral lithiasis that has not been expelled after 1 to 2 months is highly unlikely to be expelled spontaneously.

There are multiple strategies at different pathophysiological levels for the treatment of renal colic. It would seem reasonable to think that for a patient with acute renal colic, those measures aimed at increasing urinary production, such as the use of diuretics or increasing the volume of fluids administered, could theoretically favor the passage of lithiasis by increasing the pressure hydrostatic inside the ureter, reducing the duration and intensity of symptoms.

Meta-analysis studies have not been able to establish scientific evidence in this area, and if we add the potential risk of pathway rupture and renal failure, we could conclude that these measures would not be recommended.

On the other hand, it seems clear the recommendation to avoid excessive overhydration during the acute phase of renal colic, which would cause an exacerbation of the symptoms and a potential risk of rupture of the pathway, with no evidence to reduce expulsion times. There are multiple studies that show the efficacy of local heat to reduce pain and distress in minor trauma, including pain cardiac origin and menstrual pains in young women.

The mechanism of analgesic action is manifested because the local heat acts by distorting the stimuli of the peripheral nociceptors and their processing in the dorsal cord, causing a reduction of sympathetic activity caused by colic pain, and achieving a decrease in the perception of this pain . Some studies show that the application of local heat in renal colic is an effective and easy measure to relieve pain, useful as a complementary treatment in the acute condition.

Anticholinergic drugs such as hyoscine N-butylbromide have been used classically as analgesics in renal colic by inducing a relaxation of smooth muscles with decreased ureteral spasm, which has been the classic pathophysiological explanation of pain. Currently, it is sufficiently known that the pathophysiological mechanism of pain is the distention of the renal capsule due to the obstruction, the spasm resulting ureteral, a response that contributes less to the picture.

Despite this, the use of analgesics as an adjuvant treatment of NSAIDs and opiates in acute crises is still widespread. Although there are studies that show that the use of antimuscarinics decreases pain compared to placebo, no study has shown that they are as effective as opiates, NSAIDs or other analgesics when used as a single drug.

Multiple studies show that NSAIDs provide significant pain relief in renal colic. Apart from its potent analgesic and anti-inflammatory effect, they have the theoretical benefit of acting directly on the synthesis of prostaglandins, and therefore, decrease the FSR, reduce urinary production and intraluminal pressure.

Meta-analysis studies have shown that NSAIDs are at least as effective as opiates in the treatment of renal colic. The most frequent side effects are well defined: gastrointestinal bleeding and renal failure, although with proper gastric protection During treatment and in patients without prior renal failure, no serious adverse effects have been detected in extensive meta-analysis studies. They should only be avoided in allergic patients or with previous renal insufficiency, so as not to aggravate it.

At present, most of the drugs found in the market for the treatment of renal colic, whether they are analgesic or non-steroidal anti-inflammatory drugs, are composed of active ingredients that are formulated independently, which comply with a specific therapeutic activity; However, these medications, especially NSAIDs, have a large number of adverse effects when administered at high and repeated doses.

SUMMARY OF THE INVENTION

With the purpose of offering a pharmaceutical alternative that manages to reduce symptoms more quickly in patients suffering from acute renal colic and inflammation, with a greater therapeutic effect and that also reduces the risk of side effects manifesting, it is that they carried out the development of the present invention, by means of the which describes a pharmaceutical composition composed of the combination of various antispasmodic agents and a non-steroidal anti-inflammatory agent, which act synergistically and are formulated in a single dosage unit to be administered orally, which provides important benefits such as they are: lower doses administered, maximization of the therapeutic effect, greater rapidity of pharmacological action, reduction of the risk of severe complications and the reduction of the risk of manifesting side effects.

The objectives of the present pharmaceutical composition are to establish effective pain control and preserve renal function as much as possible by suppressing or relieving the effects caused by ureteral obstruction.

DETAILED DESCRIPTION OF THE INVENTION The antispasmodic agents used in the present invention, such as the active ingredients: Floroglucinol and Trimethylfloroglucinol, also known as Triphenoles, belong to. a group of synthetic antimuscarinics whose pharmacological action is to exert a direct or selective relaxation on smooth muscle fibers, without inducing antagonism on acetylcholine. This mechanism of action is manifested by a therapeutic analgesic effect useful for the relief of colic or spastic pain in the urinary tract.

Antispasmodics are drugs that, due to the manifestation of an acute colic, produce the relaxation of the smooth muscle that is present in the wall of the hollow viscera, such as: the intestines, the gallbladder, the ureters (renal duct) and the tubes of fallopian (uterine duct).

These hollow viscera come to present irritation, which causes the presence of acute pain caused by: the intake of food in poor condition (by the toxins they produce), the passage of a kidney or gallbladder and inflammation of the tubes of Fallopian caused by a foreign body (ectopic pregnancy) or hormonal stimulation.

Antispasmodics have selective therapeutic activity at the biliary, urinary, genital and digestive levels. In bile ducts they act favoring the muscle relaxant action and dilation, both of the sphincter of Oddi, which causes an effective emptying of the bile fluid, as well as bile ducts, where they allow the descent and, in large proportion, the expulsion of the calculus present in conditions such as cholelithiasis and choledocholithiasis. In the urinary tract they help the descent and eviction of kidney stones in most cases, - in others, they help in the migration of these stones to the urinary meatus, thereby providing the probability of removing them surgically. At the level of genital organs, antispasmodics act in cases of dysmenorrhea when spasm and pain occur. Given the affinity for the uterine musculature, these produce an analgesic-spasmolytic action very useful during this condition. In digestive tract, the direct or specific relaxing action of antispasmodics on smooth muscle translates into a therapeutic action in colic or spastic pain without antagonizing acetylcholine, with clinical improvement in 96.5% of cases, concluding With this, antispasmodics are effective drugs in the relief of gastrointestinal pain. Triphenols lack anticholinergic effects, which usually occur secondarily after the decrease in smooth muscle reactivity. Some of these effects are: dryness of the mucous membranes (buccal: due to decreased salivation and ocular: due to the decrease in tear production), tachycardia, urinary retention and gastrointestinal disturbances, such as nausea, vomiting, constipation. Frequently, triphenols are administered with very good results in the relief of colic pain, secondary to various pathologies, such as: dysmenorrhea, urolithiasis, cholelithiasis, choledocholithiasis, cholecystitis and colic of intestinal origin without occlusion or intestinal suboclusion.

Floroglucinol has been shown to have a muscle relaxant action on smooth muscles, with special selectivity on the sphincter of Oddi, in fact it is considered that Floroglucinol is the most active of the triphenols and its therapeutic effect is considered long-lasting.

After oral administration of Floroglucinol, a plasma profile is obtained coinciding with a rapid and total absorption of the administered dose with an absorption Tmax of 50 minutes and a plasma half-life apparently close to 30 minutes. Its volume of distribution is 3.31 L./kg with a high total clearance rate (72.5 mL./min./kg) and its plasma half-life is 6 to 8 hours.

The area under the curve of the conjugated metabolites of Floroglucinol is higher than that of free Floroglucinol and its concentrations are estimated to be around 160.9 μg / h / mL. for their conjugated glucuro and sulfo metabolites, respectively.

The systemic bioavailability in the case of Floroglucinol conjugated metabolites is about 32% of the free Floroglucinol plasma concentration which ensures its pharmacological effect.

Triphenols are eliminated mainly by the renal route in the form of their conjugated metabolites (unchanged Floroglucinol + conjugated metabolites after hydrolysis), practically the entire dose administered is recovered by urine during the first 24 hours after administration.

Trimethylchloroglucinol is an antispasmodic agent, whose effect is considered immediate due to its rapid biotransformation. Both substances united in one only exert a very effective antispasmodic effect, which is desirable because they quickly eliminate or reduce spasm of smooth muscle fibers and eliminate or significantly reduce the pain produced by said muscle spasm.

Nonsteroidal anti-inflammatory agents

(NSAIDs) encompass a broad group of drugs that have an important analgesic, anti-inflammatory and antipyretic activity, as well as other therapeutic effects.

Within the classification of NSAIDs are Enolic Acids, which in turn are subdivided into: Pyrazolones [Metamizol), Pyrazolidinediones (Phenylbutazone), Oxicams {Piroxicam and Meloxicam). Also, in this classification we can find another group of drugs called Coxibs, to which they belong: Celecoxib, Parecoxib, Lumiracoxib, Etoricoxib, Rofecoxib (retired) and

Valdecoxib (retired).

Non-steroidal anti-inflammatories manifest their analgesic action by relieving pain associated with inflammation or tissue injury by decreasing the production of prostanoids that sensitize nociceptors to mediators, such as bradykinin. They are effective in pain of mild or moderate intensity. Its antipyretic effect is presented by inhibition of prostaglandin production in the hypothalamus and interference in temperature regulation mechanisms.

Its anti-inflammatory activity is produced by reducing the components of the inflammatory response in which COX products play an important role such as vasodilation, edema and pain.

All non-steroidal anti-inflammatories are analgesic and antipyretic, some {Indomethacin, Piroxicam) are more anti-inflammatory, most are moderately anti-inflammatory (Ibuprofen,

Nabumetone) and others [Paracetamol) have a minimal anti-inflammatory effect. Some non-steroidal anti-inflammatory agents have platelet antiaggregant activity, which is of special interest in the case of Acetylsalicylic Acid because of its irreversible inhibitory effect on platelet COX. This NSAID is very useful in the prevention of coronary and cerebral thromboembolic accidents.

Also, some NSAIDs have uricosuric action as a result of the inhibition of uric acid transport from the lumen of the renal tubule to the interstitial space. It can only be seen with some NSAIDs at high doses, such as phenylbutazone, sulfinpyrazone or salicylates.

In the mechanism of action of NSAIDs, all their effects are related to the inhibition of cyclooxygenase (COX) and the inhibition of prostaglandin production. The ASA is the only one that produces an irreversible inhibition of COX-I. The anti-inflammatory effect of NSAIDs is clearly related to COX-2 inhibition and many of the undesirable effects are related to COX-I inhibition. Meloxicam was characterized as a potent anti-inflammatory agent in various conventional models of inflammation. In addition, it proved to have a weak gastric ulcerogenicity in the stomach of rats, despite its potent anti-inflammatory activity.

When these results were initially obtained, there was no explanation of the best pharmacological profile of Meloxicam compared to conventional NSAIDs. At that time, only one COX was known

(cyclooxygenase), the enzyme responsible for the synthesis of prostaglandins, and it was thought that the inhibition of the activity of this enzyme was responsible for both the therapeutic effects and the side effects of NSAIDs.

The inhibition of COX, and therefore the prevention of the formation of prostaglandins, provided a unifying explanation of the action of NSAIDs regarding their therapeutic actions as well as their gastrotoxicity, nephrotoxicity and their antithrombotic effects.

From the discovery of a second COX enzyme, COX-2, the hypothesis that Anti-inflammatory effects of NSAIDs are achieved through a different mechanism than the frequently observed side effects of these compounds, including the alteration of cytoprotection in the stomach, renal function and inhibition of platelet aggregation. COX-I is the constitutive isoenzyme that is found under physiological conditions in most tissues, a "maintenance" enzyme, so to speak, while COX-2 expression is mostly induced, particularly during inflammatory processes. . However, recent evidence indicates that COX-2 expression is also constitutive in some tissues, such as in the CNS and kidney. Most of the available NSAIDs inhibit both enzymes in a non-selective manner, which causes anti-inflammatory effects (related to COX-I inhibition), typically of a gastrointestinal nature.

Since then it has been shown that Meloxicam inhibits the COX-2 enzyme more potently than the COX-I enzyme at the recommended anti-inflammatory doses, which explains the initial experimental results: Meloxicam showed in the range of the relevant pharmacological models a selective inhibition of COX-2 in relation to COX-I in a dose-dependent manner; While COX-I inhibition was incomplete, at the recommended doses of Meloxicam, inhibition of platelet aggregation could not be demonstrated.

Meloxicam is an enolcarboxyamide derivative that belongs to the enolic acid group. It performs a potent inhibitory activity on cyclooxygenase-2 (COX-2), with a selectivity 75 times higher for COX-2 compared with COX-I, acting as an inhibitor in the synthesis of prostaglandins that have the function of being responsible mediators of inflammatory processes. Meloxicam was described as of 1994 as a selective COX-2 inhibitor in relation to COX-I. The 5-methyl group present in the Meliaxicam thiazolyl ring can enter the additional space at the active COX-2 site, which explains part of its selectivity. Effective intracellular access is determined by its unique lipophilic and amphiphilic properties. In its acid form, Meloxicam has a membrane solubility 10 times greater than that of Piroxicatn, comparable to that of other NSAIDs.

Meloxicam leaves membranes approximately twice as fast as Diclofenac. In general, Meloxicam is rapidly transported through membranes, but within a range that allows it to efficiently interact 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 this drug in certain tissues of the digestive tract.

Therefore, Meloxicam does not show the typical "ion trapping" behavior that characterizes NSAIDs of the carbonic acid class, which may contribute to the favorable profile of gastrointestinal tolerability observed clinically.

Meloxicam has a good digestive absorption and optimal bioavailability (89%), after having been administered a single dose by mouth. Some of the main pharmacokinetic characteristics are: its prolonged absorption, its sustained serum concentrations and its long elimination half-life (20 hours), which allows a single daily dose to be administered. Once its absorption in the digestive tract, Meloxicam easily diffuses into the blood and inflamed tissues, having a high adherence with plasma proteins (> 99%) and its metabolites are excreted both in the urine and feces .

Currently, there are different pharmaceutical products on the market that are intended for the treatment of renal colic caused by lithiasis. In these products we can find various active ingredients that are formulated independently; nevertheless, in this type of pathologies it is of vital importance to avoid severe complications, as well as to quickly reduce the symptoms of patients suffering from said pathology; Therefore, the activity of a group of drugs that act in different ways is essential to achieve the recovery of patients who are suffering from this condition.

The pharmaceutical composition of the present invention is composed of the synergistic combination of various antispasmodic agents, such as active ingredients: Floroglucinol and Trimethylfloroglucinol, and a non-steroidal anti-inflammatory agent (NSAID), as is the active substance: Meloxicara, in addition to pharmaceutically acceptable excipients, which are formulated in a single dosage unit to be administered orally, the which is indicated for the control and treatment of renal colic and inflammation caused by lithiasis, in addition to other related pathologies.

Said pharmaceutical composition has been developed taking into account that the aforementioned active ingredients have a great efficacy and capacity for the control and treatment of renal colic caused by lithiasis, and because these drugs act synergistically, they reduce the symptoms that It characterizes this pathology, such as inflammation and pain, in addition to increasing the speed of pharmacological action, maximizing the therapeutic effect with lower doses administered, reducing the risk of severe complications and reducing the risk of manifesting side effects. One of the antispasmodic agents used in the pharmaceutical composition object of the present invention, such as the active ingredient: Floroglucinol, is present in the formulation in a concentration range from 40.0 mg to 320.0 mg per dose unit.

Another of the antispasmodic agents used in the pharmaceutical composition object of the present invention, such as the active ingredient: Trimethylfloroglucinol, is present in the formulation in a concentration range from 40.0 mg to 320.0 mg per dose unit.

The non-steroidal anti-inflammatory agent (NSAID) used in the pharmaceutical composition object of the present invention, as is the active ingredient: Meloxicam, is present in the formulation in a concentration range from 3.0 mg to 30.0 mg per dose unit.

To evaluate the effectiveness of the pharmaceutical composition that is the subject of the present invention, as well as the synergistic effect that results from combining the active ingredients: Floroglucinol,

Trimethylfloroglucinol and Meloxicam in a single unit of Dosage, a comparative clinical study was conducted in which the aforementioned active ingredients were administered separately, as well as the combination thereof. COMPARATIVE CLINICAL STUDY BETWEEN THE MOST TRIMETHYLFLOROGLUCINOL COMBINATIONS MORE MELOXICAM VS. FLOROGLUCINOL MORE TRIMETHYLFLOROGLUCINOL VS. MELOXICAM ADMINISTERED ONLY. Material and methods .

Patients with clinical and radiological diagnosis of distal ureteral lithiasis seen in the Urology Department were included in the study. These patients were treated with the combinations of Floroglucinol + Trimethylfloroglucinol + Meloxicam vs. Floroglucinol + Trimethylfloroglucinol vs. Meloxicam administered independently.

Patients with persistent pain, patients with clinical, laboratory and imaging data for urinary infection, patients with systemic sepsis data and patients with recurrent lithiasis were excluded from the study. Patients who did not follow the treatment were also excluded. properly or that it was not possible to follow up properly.

Patients seen between May of the

2005 and March 2006 treated with the combination of: Floroglucinol + Trimethylfloroglucinol + Meloxicam in the

Group I, those treated with Floroglucinol +

Trimethylfloroglucinol in Group II and those treated with

Meloxicam administered independently in the

Group III The clinical diagnosis of ureteral lithiasis was made and the presence of stones in the lower third with a size smaller than one centimeter was confirmed by imaging studies. In patients, adequate initial pain control was achieved and they were given the combination of: Floroglucinol 80 mg +

Trimethylfloroglucinol 80 mg + Meloxicam 7.5 mg vs.

Floroglucinol 80 mg + Trimethylfloroglucinol 80 mg vs.

Meloxicam 7.5 mg, all administered every 12 hours.

The patients were periodically monitored through medical consultation until the problem was resolved, whether it was the expulsion of the stone or its extraction. Results

At the end of the study, there were a total of 42 patients in Group I with a distribution of 30 men and 12 women with an average age of 29.7 years with a range of 15 to 58 years, in which the clinical diagnosis of lithiasis was made ureteral, the location of the stones in the distal portion was confirmed and it was determined that they were smaller than one centimeter by imaging methods.

In 35 patients, simple abdominal plaque and renal ultrasound were performed as diagnostic methods, 7 patients also underwent excretory urography and in 2 cases a non-contrasted helical CT was requested due to a history of iodine allergy. The treatment of this group was administered based on the size of the calculation, which ranged from 2 to 10 mm. , dividing the patients into two subgroups, in the first with a size between 2 and 5 mm. there were 30 cases and in the second with a size between 5 and 10 mm. There were the remaining 12 patients. All were asked for a general urine test and in 22 cases urinal culture was initially requested. In Group II there were 19 patients, 11 male and 8 female, in 17 patients the diagnosis was made by simple abdominal plaque and renal ultrasound, while in the remaining 2 the diagnosis was made by excretory urography. The size of the calculations varied from 3 to 10 mm. , dividing the patients into two subgroups, 13 cases with dimensions between 3 and 5 mm. and the remaining 6 cases with dimensions greater than 5 mm. and less than 10 mm. In all 19 cases a general urine test was performed and in 9 cases urinal culture was requested at the beginning.

In Group III there were 20 patients, 10 male and 10 female, in 18 patients the diagnosis was made by simple abdominal plaque and renal ultrasound, while in the remaining 2 the diagnosis was made by excretory urography. The size of the calculations varied from 3 to 10 mm. , dividing the patients into two subgroups, 14 cases with dimensions between 3 and 5 mm. and the remaining 6 cases with dimensions greater than 5 mm. and less than 10 mm. In all 20 cases a general urine test was performed and in 10 cases urinal culture was requested at the beginning. In all patients, treatment was initiated once the initial renal colic pain was controlled. 18 patients of Group I, 7 patients of Group II and 10 patients of Group III were hospitalized for more than 6 hours. In the same way, 5 patients of Group I and 2 patients of Group II were hospitalized for more than 24 hours. These patients with persistent symptoms were those who underwent mostly contrasted studies. There were no adverse effects in any of the groups.

In total, 35 patients in Group I threw the calculation within one week (80.9%), compared with 11 patients in Group II that accounted for 52.66% and 9 patients in Group III representing 47.5%, in the Same period of time.

The results according to the size of the calculation were: that in 30 patients of Group I with calculations of dimensions between 2 and 5 mm. these managed to be expelled mostly in a total of 30 patients (100%), while only 10 of the 13 patients in Group II with dimension calculations less than 5 mm. they were able to expel them within the aforementioned period of time (69.23%) and 10 of the 14 patients of Group III with calculations of dimensions smaller than 5 mm. they were able to expel them in the same period of time (54.3%).

With respect to calculations of dimensions larger than 5 mm. and less than 10 mm. , these managed to be expelled in their entirety in 12 of the 12 remaining patients corresponding to Group I (100%), 1 of the 6 remaining patients in Group II expelled the calculus greater than 5 mm. and less than 10 mm. and 1 of the remaining 6 patients in Group III expelled the calculation during the second week of follow-up.

For patients in Groups II and III who did not expel the stones, endoscopic ureterolithotripsy was performed for extraction.

Conclusions

With the study described above we can verify that there is a significant difference in the outcome of patients treated with the combination of Floroglucinol + Trimethylfloroglucinol + Meloxicam compared to Floroglucinol + Trimethylfloroglucinol and Meloxicam administered only independently to the indicated doses and for established periods. The objective of the study was to confirm that the proposed treatment reduces the period of time for the expulsion of the stones lodged in the urinary tract smaller than one centimeter and that with this scheme the requirements of analgesics and rehospitalizations due to the potent anti-inflammatory and relaxing effect of the Ureteral smooth muscle of the motif combination of the present invention.

Claims

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, what is contained in the following CLAIMS is claimed as property

1.- Pharmaceutical composition characterized in that it is composed of the synergistic combination of various antispasmodic agents, such as the active ingredients: Floroglucinol and Trimethylfloroglucinol and a non-steroidal anti-inflammatory agent, such as the active substance: Meloxicam, in addition to pharmaceutically acceptable excipients; which are formulated in a single dosage unit to be administered orally, which is indicated for the control and treatment of renal colic and inflammation caused by lithiasis.

2. - Pharmaceutical composition according to claim 1, characterized in that one of the antispasmodic agents, such as the active ingredient: Floroglucinol, is present in the formulation in a concentration range from 40.0 mg to 320.0 mg, preferably being used in the formulation a concentration of 80.0 mg per dose unit.

3. - Pharmaceutical composition according to claims 1 and 2, characterized in that another of the antispasmodic agents, such as the active ingredient: Trimethylfloroglucinol, is present in the formulation in a concentration range from 40.0 mg to 320.0 mg, being preferably a concentration of 80.0 mg per unit dose is used in the formulation.

4. - Pharmaceutical composition according to claims 1 to 3, characterized in that the non-steroidal anti-inflammatory agent, such as the active ingredient: Meloxicam, is present in the formulation in a concentration range from 3.0 mg to 30.0 mg, being preferably used in the formulation a concentration of 7.5 mg and 15.0 mg per unit dose.

5. Pharmaceutical composition according to claims 1 to 4, characterized in that it is formulated in a single dosage unit to be administered orally in the form of capsules or tablets.

6. - Pharmaceutical composition according to claims 1 to 5, characterized in that it is used for the treatment of renal colic and inflammation caused by lithiasis, which achieves effective pain control in addition to ensuring that renal function is preserved by suppressing renal function. or relieving the effects caused by ureteral obstruction.