WO2005023306A2

WO2005023306A2 - Combination of medicaments comprising lansoprazole and domperidone

Info

Publication number: WO2005023306A2
Application number: PCT/BR2004/000166
Authority: WO
Inventors: Alexandre FUNARI NEGRÃO
Original assignee: Medley S.A. Indústria Farmacêutica
Priority date: 2003-09-05
Filing date: 2004-09-03
Publication date: 2005-03-17
Also published as: WO2005023306A3; BR0303794A

Abstract

The present invention is dealing about a combination of medicaments, medicinal association, medicament and medicament of facilitating presentation type, comprising in an individualized form yet combined at the same time: - one or more medicinal units containing the active principle lansoprazole, its derivatives or pharmaceutically acceptable salts; - one or more medicinal units containing the active principle domperidone, its derivatives and pharmaceutically acceptable salts; and at option other additives or drugs known by the man of the technique in vehicle or carrier also pharmaceutically acceptable.

Description

MEDICAMENT, KIT OF MEDICAMENTS, COMBINATION OF MEDICAMENTS, MEDICINAL ASSOCIATION AND MEDICAMENT OF FACILITATING PRESENTATION TYPE. The present invention is dealing about a medicament for facilitating the treatment of gastro-esophagus disfunctions, like functional dyspepsia, with application in the pharmaceutical industry. The functional dyspepsia represents a clinical condition quite common, characterized, for the most part, by epigastrical pain, without any ulcerous structural morbid changes or any other illness possibly related to it. Other symptoms also present, include abdominal discomfort or dilatation, retrostemum burning, nauseas, vomits and precocious satiety. Exactly because of that diversity of clinical symptoms the choice of the most appropriate treatment turns out to be of fundamental importance. Among the commonly prescribed treatments for functional dyspepsia, figure the anti-secretory compounds and the prokinetic compounds, generally used during periods of two to four weeks ( Finney JS et al. Meta-Analysis of Antisecretory and Gastrokinetic Compounds in Functional Dyspepsia. J Clin Gastroenterol 1998; 26 (4): 312-320 and AUescher HD et al. Treatment of Non-Ulcer Dyspepsia: a Meta-Analysis of Placebo-Controlled Prospective Studies. Scand J Gastroenterol 2001 (9): 934-941 ). In relation to the prokinetic compounds, 60% to 90% of the results have been considered to be good or excellent, in placebo-controlled studies. Literature based data show world-wide predominant rates of dyspepsia, varying from 7% to 41% among the population. In different studies, realized in the United Kingdom, in Scandinavia, in Germany and in the United States, the predomination varies from 20% to 40%. The dyspepsia is being considered as a problem of social importance, with significant economical consequences, because of the elevated number of medical consultations, the costs of medicaments, the absence at work and the repercussions in social and family life. To this situation is being aggregated the fact that a typical dyspeptic patient is the one who presents symptoms for a prolonged period. The functions of the digestive tube are basically coordenated by:

• Neuro-endocrines mediators;

• Fibers originating in the Central Nervous System (CNS); • Brain cells present in the submucous membrane and between the muscular fibers, that are constituting the Intestinal Nervous System, as it is called (INS). The digestive tube also presents innumerable recipients for acetylcholine, noradrenaline, dopamine and opiates. Although the INS exercises many functions in an independent way, it is suffering a strong influence from the sympathetic vagal system and of CNS. Recent studies show, that the various alterations that may occur in the axis brain-intestines have, in reality, two significations: the CNS influences the functioning of INS, which on its part, influences the perception of the symptoms by CNS. Considerig the alterations to be related especifically to the digestive tube, some elements have been described to explain the physiopathology of functional dyspepsia. Among those are: ^■ Elevated acid secretion ■ Alterations in the gastrical-intestinal motility and in the visceral sensibility Findings of clinical studies showed that the acid secretion in patients with functional dyspepsia has not been different from asymptomatic individuals, selected for control purposes. That fact, however, does not exclude that a subgroup of patients with functional dyspepsia shows a higher sensibility of the mucous membrane to acid, normally produced, fact that increases relativelv the role of the acid secretion. As a proof of this affirmation, we have the fact that dyspeptical patients with predominant epigastrical pain, showed recovery when using inhibitors of proton bomb (IPB), compared with placebo ( Magalhaes AF. Dispepsia funcional: tratamento. In Dispepsias e Gastrites: 45-54 ) [Functional Dyspepsia: treatment. In Dyspepsia and Gastritis: 45-54] In case of functional dyspepsia, the gastrical sensation is being altered in about 50% of the patients ("irritable stomach"): the dilatation of the stomach causes symptoms even at lower pressures and with smaller volumes, than in asymptomatic individuals. A delay of the gastrical evacuation can be noted in about half of the patients with functional dyspepsia. The evacuation of liquids is quite variable, however, in 50% of the dyspeptic patients, a slow evacuation of solids had been observed. A certain percentage of the patients with functional disturbances of the digestive tube presents visceral hypersensivity, with diminution of the nociceptive entrance. Over many years, research scientists got to meet periodically for up-dating the conceptions about dyspepsia. From 1994 onwards until now, various meetings had been realized until it was possible to come to the most recent consensus about dyspepsia, published in 1999 and known as Consensus Rome II. Among the various conceptual up-datings, it had been established that the sub- types of functional dyspepsia "must be based just on the dominant symptom", that means, the one that most incommodes the patient. It had been defined, therefore, that the dyspepsias can be of three types: ^■ of dismotility type ■ of ulcer type ^■ mixed or not specific. There does not exist the promise of a definit cure for patients with functional dyspepsia. The treatment aims to ameliorate the symptoms or prevent the relapses.

The evolution of the dyspeptical patients is generally characterized by continuous symptoms or by periods of remission and exacerbation. For being a very common condition among the population in general and because of the diversity of clinical symptoms, it is use to recommend that the patients are being treated even the empiric way, without previous diagnostic proceedings. In a schematic way, the treatment of functional dyspepsia has always to be approached by using a close relation doctor-patient, with advices regarding the habits for guaranteeing a healthy life. Still, some therapeutic complementary measures have always to be taken into consideration. Depending on each case, there could be indicated: the use of kinetic compounds the use of acid inhibitors ■ the use of antidepressive agents the use of medicaments with INS the elimination of Helicobacter pylori the psychotherapy

Lets analyse more profoundly the first two medicinal indications, the most specific ones for the remission of the dyspeptic symptoms: the use of kinetic compounds and acid inhibitors. During a meta-analysis realized by Dobrilla et al, in 1989, both the use of antisecretory agents and of gastrokinetic compounds showed to be efficient in the short term treatment of the functional dyspepsias. Nearly 10 years later, new medicaments came up, which were the reason for realizing a new meta-analysis, showing again positive results of those two classes of medicaments: compared with placebo, the therapeutic successes have been 20% superior when using antisecretory agents and 46% with the use of gastrokinetic compounds (Finney JS et al. Meta-Analysis of Antisecretory and Gastrokinetic Compounds in Functional Dyspepsia. J Clin Gastroenterol 1998; 26 (4): 312-320). A meta-analysis of all the Works published until 1998 showed that the kinetic compounds have been 20% superior in relation with placebo when treating functional dyspepsias. Among the kinetic compounds used in the majority of the cases in clinical practice, the domperidone distinguishes itself. Domperidone is a peripheral antagonist of dopamine, with its primary action to be effected on the floor of the fourth ventricle and in the intestinal dopamine receptors. Although it possesses gastroprokinetic properties and antiemetic agents, similar to the metoclopramide, it does not penetrate straight away the blood-nerve- barrier. The domperidone increases the tonus of the lower oesophageal sphincter and stimulates the gastric emptying. Experimental studies demonstrated that the medicament is a specific antagonist of the cerebral dopamine receptors, suggesting further more a specificity by the receptors D-2, preferentially to D-l. In spite of this cerebral action in vitro, domperidone has no specifically central effects in vivo, due to the fact that it does not penetrate straight away the blood-nerve barrier. Its antiemetic effect is probably caused by the blocking of the dopamine receptors in a zone of chemoreceptors, situated outside the blood-nerve barrier. Various studies suggest that the intestine possesses specific dopamine receptors, exercising inhibitive actions, activation of which would reduce the gastrointestinal motility. The domperidone is then able to stimulate the motility by blocking those dopamine receptors. From the clinical point of view, the domperidone increases significally the pressure in the lower oesophageal sphincter, both in healthy patients as well as in patients with gastro-eosophageal reflux, though in less magnitude in this latter group. Notwithstanding, in a controlled study involving patients with oesophagitis of reflux, the results of domperidone had been significantly superior compared with placebo, during a treatment over five weeks. Domperidone also increases the amplitude of the oesophageal and duodenal peristole. In a study with healthy individuals, the domperidone increased significantly the antral peristole and the gastric emptying ⁽¹¹⁾. Consequently, the effects of domperidone in the motility of the oesophagus, stomach and duodenum seem to be similar to the ones of the metoclopramide. Both are promoting proximal motor propulsive activity in the gastrointestinal treatment. Results of placebo controlled studies indicate the utility of domperidone in the treatment of the gastro- oesophageal and gastrointestinal reflux (Sander JO et al. Efficacy of Cisapride and Domperidone in Functional (Nonulcer) Dyspepsia: A Meta-Analysis. Am J Gastroenterol 2001; 96: 689-696 ). The clinical effects of domperidone in patients with dyspepsia had been evaluated through double-blind studies, involving more than 800 patients. The results of those studies, in general, showed positive effects of the domperidone alleviating the dyspeptic symptoms, over the period of two to eight weeks of evaluation, be it when compared with the effects of metoclopramide, be it when compared with placebo. In five comparative studies between domperidone and metoclopramide, equivalent doses of domperidone caused alleviation of the symptoms in a similar form or significantly superior than the metoclopramide. In some of those studies, the adverse effects of central origin have been more frequent in patients receiving metoclopramide, generally resulting in a termination of the treatment. The general incidence of adverse occurrences showed to be low, with only rare reports of effects on CNS, suggesting advantages in situations, where the preoccupation with adverse effects restricts the use of metoclopramide ( Kilbinger H and Weihrauch TR. Drugs Increasing Gastrointestinal Motility. Pharmacology 25: 61-72 (1982) ). Duan et al. realized a study demonstrating that the use of domperidone alleviated gastric emptying, beside other symptoms, in patients with non-functional dyspepsia ( Duan L P et al. A Study of Gastric Emptying in Non-Ulcer Dyspepsia Using a New Ultrasonographic Method. Scand. J Gastroenterol 1993; 28: 355-360 ). A study involving domperidone and cisapride in patients with dyspepsia, both administered three times a day, in standard doses, during three weeks, showed a general amelioration of the symptoms with both medicaments, fact confirmed by a meta-analysis realized by Sander et al ( Sander J O et al. Efficacy of Cisapride and Domperidone in Functional ( Nonulcer ) Dyspesia: A Meta-Analysis. Am J Gastroenterol 2001; 96: 689-696 ). Another study evaluated the addition of domperidone (10 mg, three times a day) to cisapride in the treatment of patients with chronic dyspepsia, resulting in a significant amelioration (p<0,05) of the dyspeptic symptoms in relation to the associated use of cisapride with placebo (Spencer C. M. and Faulds D. A Reappraisal of its Pharmacodynamic and Pharmacokinetic Properties, and its Therapeutic Efficacy in Acid-Related Disorders. Drugs 1994; 48 (3): 404-430 ). A meta-analysis comparing the therapeutic effect of the inhibitors of the proton bomb (IPB) with the antagonists H₂ (AH2) showed amelioration of the symptoms in 55% of the patients with IPB against 33% of the patients with AH2. A double-blind work and controlled by placebo, evaluated more than 1.200 dyspeptic individuals and showed that the use of IPBs, in different doses, has been superior, compared with placebo, from the statistical point of view (8% to 10% of superiority) in patients with ulcer-type dyspepsia. An interesting fact has been that the IPB, by itself, did not show superiority in comparison with placebo in cases of dismotility type dyspepsia, demonstrating on the other hand an apparent efficacy of the IPB in cases of ulcer-type dyspepsia. Other Works showed the superiority of IPB in specific groups of patients, like those with pain during the night or H. pylori positive. Specifically the lansoprazole is a substituted benzimidazole, a category of anti-secretory substances that suppress the gastric secretion by specific inhibition of the system of the enzyme (H+, K+) ATPase, on the secretory surface of the gastric parietal cells. As this enzymetic system is being known as proton bomb, the lansoprazole is being denominated inhibitor of proton bomb, blocking the final step of acid secretion. This effect is dose-dependent and causes the inhibition of the acid gastric secretion, both, basal as well as stimulated, independent of the stimulus. Double-blind and randomized studies evaluated the efficacy of lansoprazole, in doses of 15 mg and 30 mg, once a day, in relation to ranitidine (150 mg, twice a day) and to omeprazole (10 and 20 mg, once a day), in the alleviation of the epigastric burning and pain in more than 800 dyspeptic patients. Another study, comparing the effects of lansoprazole, omeprazole and ranitidine, demonstrated that the lansoprazole has significantly been superior in suppressing the acid secretion ( Blum RA et al. The Comparative Effects of Lansoprazole, Omeprazole and Ranitidine in Suppressing Gastric Acid Secretion, Clinical Therapeutics 1997: 19: 1013-23 ). The main objectives of the invention have been:

• facilitating the treatment (for doctors and patients), because of the diversity of

medicaments, having each one various posologies, presentations and formulations, fact that may lead to administering inadequate doses of one or both products, beside a possible lessening of adherence to the treatment by the patient, due to a scheme of posology, by using multiple medicaments with different administering timetables;

• developing a product that contemplates at least two different types of active

principles, lansoprazole and domperidone, associated in one single presentation, with indication for patients with functional dyspepsia, that facilitates the adherence of the patient, being able to produce clinical results, measurable and satisfactory. Aiming to achieve this object, a medicament has been developed containing drugs of synergistic effect, presenting at least two types of active principles: lansoprazole and domperidone. The present invention refers to a medicament that comprises in a facilitating, individualized way and yet combined at the same time: - one or more medicinal units containg the active principle lansoprazole, its derivatives or pharmaceutically acceptable salts; - one or more medicinal units containing the active principle domperidone, its derivatives or pharmaceutically acceptable salts; and optionally other additives or drugs, kown by the man of the technique in vehicle or carrier, also pharmaceutically acceptable. The medicament, according to the invention, employs the active principles lansoprazole, its derivatives or pharmaceutically acceptable salts and domperidone, its derivatives or pharmaceutically acceptable salts, in different possible dosages . Preferentially the lansoprazole is being employed in the dosages of 15 mg or 30 mg, per medicinal unit and the domperidone is being employed preferentially in the dose of 10 mg per medicinal unit. The kit of medicaments, according to the invention comprises preferentially a total of 07, 14 or 28 medicinal units on lansoprazole basis and 14, 21, 28, 42, 56 or

84 medicinal units on domperidone basis, corresponding to a treatment period of 07, 14 or 28 days, respectively. The kit, according to the invention comprises 01, 02 or

04 cartridges, blisters or similai-, or still another quantity, depending on the period of treatment, containing the units to be taken. The medicinal association, according to the invention comprises: - one or more medicinal units of the active principle lansoprazole, its salts or derivatives pharmaceutically acceptable, and; one or more medicinal units of the active principle domperidone, its salts or derivatives pharmaceutically acceptable; and at option other additives or drugs known by the man of the technique in vehicle or carrier, also pharmaceutically acceptable. The medicinal association employs the active principles lansoprazole, its derivatives or salts pharmaceutically acceptable and domperidone, its derivatives or salts pharmaceutically acceptable, in different possible dosages. Preferentially the lansoprazole is being employed in doses of 15 mg or 30 mg, per medicinal unit and the domperidone is being employed preferentially in the dose of 10 mg per medicinal unit. The invention is also dealing with the assembly of medicaments, comprising one or more medicinal units containg the active principle lansoprazole, or derivatives and salts pharmaceutically acceptable and one or more medicinal units containing the active principle domperidone, or derivatives and salts pharmaceutically acceptable, beside other additives and carriers known by the man of the technique, in the dosages of 15 mg or 30 mg for the medicinal units of lansoprazole and dosage of 10 mg for the medicinal units of domperidone. The invention is dealing in particular with the assembly of medicaments, containing 07, 14 or 28 medicinal units on lansoprazole basis and 14, 21, 28, 42, 56 or 84 medicinal units on domperidone basis. The medicament, showing a facilitating presentation type, according to invention, comprises one or more medicinal units of lansoprazole 15 mg or 30 mg to be administered at least once a day, preferentially on empty stomach and one or more medicinal units of domperidone 10 mg to be administered twice or three times a day, preferentially before the main meals (lunch and dinner or breakfast, lunch and dinner), beside other additives and carriers known by the man of the technique and pharmaceutically acceptable, comprising 07, 14 or 28 medicinal units on lansoprazole basis and 14, 21, 28, 42, 56 or 84 medicinal units on domperidone basis. The examples to follow hereafter are of pure illustrative character and should not be taken for limitating effects of the invention. FAamp ..1 ; A patient of 26 years of age, sex masculine, complaining about pyrosis for 1 year, mainly after the meals, started to present for approximately 60 days a dry cough. He also claimed about frequent flatulence and the feeling of "fullness". He denied dysphagia, vomiting and epigastric pain. 6 months ago, on occasion of a physical examination, no abnormalities had been detected. In that case it had been decided to realize a "therapeutic test" with the medicine Lansoprazole in the dose of 30 mg/day in the morning during 2 weeks. After this period, the patient returned, reporting an amelioration of just the pyrosis. The "therapeutic test" with this patient has been an excellent alternative to alleviate the symptom associated to the Illness of the Gastrooesophageal Reflux (IGOR). This treatment, however, just alleviated the pyrosis and did not contribute to the amelioration of the chronic cough and the feeling of gastric fullness. When returning to the surgery, it was decided to maintain the treatment with lansoprazole associated with a medical treatment of prokinetic compounds, in that case, domperidone 10 mg, 3 times a day before the main meals (breakfast, lunch and dinner). This treatment has been kept up over 3 months. At the end of this period, the patient showed an overall amelioration of the symptoms: pyrosis, cough and gastric fullness. After having obtained the mentioned results, the applicant improved the development of a medicament that would be able to contemplate the desired active principles, in the ideal therapeutic dosages, in a facilitating kit for improving administering of the medicament on the part of the patients. Example 2: A patient of 40 years, sex feminine, presented "stomachache" and superabundance after the meals and the feeling of "burning in the chest" when laying down. Lanzoprazole 15 mg, had been administered, 1 pill in the morning during 7 days, beside a nutritional orientation and repose with elevated headrest. After 1 week the patient showed amelioration of the epigastric pain and retrosternal burning, however, the feeling of superabundance remained. She has been submitted to an upper digestive endoscopy, exposing a slight pangastritis, whereupon domperidone 10 mg has then been administered, 1 pill after lunch and dinner, associated with lansoprazole, 1 pill in the morning over a 2 weeks periode. After the combined use of those pharmaceutical products the patient developed a general amelioration of the clinical symptoms. Example 3: A patient of the age of 50 , sex masculine, referred to superabundance postprandial since aproximately 1 year. The patient has been advised that the symptom most likely is being related to the so-called diabetic gastro-paresis, because of his diabetic background for more than 20 years. Furthermore the patient claimed also about frequent regurgitations, accompanied by burning in the chest. A revision of previous treatments exposed that the patient followed correctly the given measures of dietetic hygiene (lifting of the headrest of the bed, not to lay down before three hours after the meals, avoid copious meals, fatty or acid food, smoking and alcohol) and that he had used already antiacid agents (magnesium hydroxide and aluminum) and blocking agents H2 (ranitidine), without therapeutic success. After that, diagnostic exams have been solicited: oesophageal pH monitoring of 24 hours and radiological study of gastric emptying. The conclusion of the exams showed clearly an abnormal acid exposition of the oesophagus and decrease of the gastric motility. At that point had been administered the medicaments lansoprazole 15 mg o empty stomach plus domperidone 10 mg before breakfast, lunch and dinner during a period of 28 days. On his return, the patient reported a significant amelioration of the superabundance postprandial and of the oesophagitis of reflux.

Claims

CLAIMS 1. Medicament characterized for comprising in a facilitating, individualized way and yet combined at the same time: - one or more medicinal units containg the active principle lansoprazole, its derivatives or pharmaceutically acceptable salts; one or more medicinal units containing the active principle domperidone, its derivatives or pharmaceutically acceptable salts; and optionally other additives or drags, kown by the man of the technique in vehicle or carrier also pharmaceutically acceptable.

2. Medicament according to claim 1, characterized by the fact of employing lansoprazole or its derivatives or pharmaceutically acceptable salts in different dosages.

3. Medicament according to claims 1 and 2, characterized by the fact of employing lansoprazole, preferentially in the doses of 15 mg and 30 mg, per medicinal unit.

4. Medicament according to claim 1, characterized by the fact of employing domperidone or its derivatives or pharmaceutically acceptable salts in different dosages.

5. Medicament according to claims 1 and 4, characterized by the fact of employing domperidone, preferentially in the dose of 10 mg per medicinal unit.

6. Kit of medicaments according to claim 1, characterized by the fact of containing preferentially a total of 07, 14 or 28 medicinal units on basis of the active principle lansoprazole and 14, 21, 28, 42, 56 or 84 medicinal units on the basis of the active principle domperidone, characterizing the period of treatment of 07. 14 or 28 days, respectively.

7. Kit of medicaments according to claim 1, characterized by the fact of comprizing a total of 01, 02 or 04 cartridges, blisters or similar, or even another quantity, depending of the treatment period, containing the medicinal units to be taken.

8. Medicinal association characterized for comprising: - one or more medicinal units of the active principle lansoprazole, its salts or pharmaceutically acceptable derivatives, and; - one or more medicinal units of the active principle domperidone, its salts or pharmaceutically acceptable derivatives; and at option other additives or drags known by the man of the technique, in vehicle or carrier also pharmaceutically acceptable.

9. Medicinal association according to claim 8, characterized by the preferential employment of lansoprazole in the doses of 15 mg and 30 mg, per medicinal unit.

10. Medicinal association according to claim 8, characterized by the fact of employing domperidone in the dose of 10 mg, per medicinal unit.

11. Assembly of medicaments characterized for comprising one or more medicinal units, containing the active principle lansoprazole, or derivatives and pharmaceutically acceptable salts and one or more medicinal units containing the active principle domperidone, or derivatives and pharmaceutically acceptable salts, beside other additives and carriers known by the man of the technique, in the dosages of 15 mg or 30 mg for the medicinal units of lansoprazole and dosage of 10 mg for the medicinal units of domperidone.

12. Assembly of medicaments characterized for comprising one or more medicinal units of lansoprazole, and one or more medicinal units of domperidone, beside other additives and carriers known by the man of the technique and pharmaceutically acceptable, in a combined form yet individual, in the dosages of 15 mg or 30 mg for the medicinal units of lansoprazole and dosages of 10 mg for the medicinal units of domperidone, containing 07, 14 or 28 medicinal units on the basis of the active principle lansoprazole and 14, 21, 28, 42, 56 or 84 medicinal units on the active principle domperidone.

13. Medicament exposing a facilitating form of presentation, characterizes for comprising one or more medicinal units of lansoprazole 15 mg or 30 mg to be administered at least once a day, preferentially on empty stomach, and one or more medicinal units of domperidone 10 mg to be administered at least twice or three times a day, preferentially before the main meals (lunch and dinner or breakfast, lunch and dinner ), beside other additives and carriers known by the man of the technique and pharmaceutically acceptable.

14. Medicament exposing a facilitating form of presentation according to claim 13, characterized for comprising 07, 14 or 28 medicinal units on basis of the active principle lansoprazole and 14, 21, 28, 42, 56 or 84 medicinal units on basis of the active principle domperidone.