WO2004089414A2

WO2004089414A2 - Combinations of proton pump inhibitors or blockers with prokinetic agents

Info

Publication number: WO2004089414A2
Application number: PCT/BR2004/000046
Authority: WO
Inventors: Alexandre FUNARI NEGRÃO
Original assignee: Medley Farmaceutica Ltda
Current assignee: Medley Farmaceutica Ltda
Priority date: 2003-04-08
Filing date: 2004-03-31
Publication date: 2004-10-21
Anticipated expiration: 2005-10-08
Also published as: WO2004089414A3

Abstract

The present invention refers to a drug combination, drug association, a drug, and a drug presenting a facilitated presentation comprising, individually, and at the same time, jointly: one or more drug units containing on or more proton pump inhibitor agents; one or more drug units containing one or more prokinetic agents; and optionally, other additives or drugs which are well-known to those skilled in the art, within a medium or excipient, also pharmaceutically acceptable, preferably used for the treatment of functional dyspepsia and gastroesophageal reflux disease.

Description

DRUG COMBINATION, DRUG ASSOCIATION AND DRUG. The present invention refers to a drug to facilitate the treatment of gastroesophageal dysfunction such as functional dyspepsia associated with the gastroesophageal reflux disease, applicable to the pharmaceutical industry. One out often people suffer from a gastroesophageal reflux disease (GERD), a condition in which there is a reflux of stomach and duodenal contents into the esophagus. That may result in inflammation of the mucosal lining of the esophagus (esophagitis) that, when chronic, may progress into erosive esophagitis and transformation of the esophageal lining into a columnar type gastric lining (Barrett's metaplasia), a significantly pre-malignant condition to esophageal adenocarcinoma. Gastroesophageal reflux disease (GERD) is commonly associated with functional dyspepsia due to transiently reduced lower esophageal sphincter pressure and reduced esophageal peristalsis, notwithstanding reflux can occur in the absence of motility changes in erosive esophagitis. Consequently, the harmful, low-pH gastroduodenal contents flow backwards to the esophageal lining, thus generating the heartburn symptom.

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Fig 1 - Action sites of drugs used in the treatment of gastroesophageal refluκ disease (GERD) (PPI proton pump inhibitors) Source: Farmacologia Integrada (Integrated Pharmacology) - Page, Curtis, Sutter, Walker & Hoffman - Editora Manole Ltda Ed..

Gastrointestinal symptoms related with dyspepsia or heartburn, or even a combination of both, occur with very often. Approximately 25 % of the population in western countries present recurring dyspepsia episodes within a period of 12 months, whilst approximately 15 % of Americans and Europeans present heartburn at least once a week and 7 % on a daily basis.

Since dyspeptic complaints are associated with morbidity and loss of productivity, these represent strong economic and public health implications. A study assessing the prescription of anti-ulcer drugs revealed that 29 % were prescribed for the treatment of heartburn and 40 % for the treatment of functional dyspepsia. These symptoms also interfere with the quality of life of the patients who largely interrupt their daily activities due to their symptoms, a poorer mental health, as well as a lesser social interaction. These data lay emphasis on the need of more effective treatments, which can reduce not only the economic costs, but mainly the social ones.

Gastroesophageal reflux is the involuntary movement of stomach contents towards the esophagus. In normal individuals, a reflux episode occurs on an hourly basis. How this physiologic process becomes pathological is not well-known. In theory, gastroesophageal reflux disease develops when the exposure to a refluxed harmful material exceeds the protection mechanisms of the esophagus. That is to say, when there is an unbalance between the aggressive and defensive factors. This unbalance produces a wide range of symptoms and abnormalities in the esophagus, including heartburn, esophagitis and ulcers (Stacher G, Lenglinger J, Bergmann H, Schneider C, Hoffman M, Wolfl G, Stacher-Janotta G. Gastric emptying: a contributory factor in gastro-oesophageal reflux activity? Gut 2000; 47:661-66 ). Most patients with reflux disease present a increased number of reflux episodes compared to normal individuals, which implies a change in the lower esophageal sphincter, considered as an increased number of transitory sphincter relaxations, which leads to more reflux episodes (Holoway RH, Hongo M, Berger K, et al. Gastric distension: a mechanism for postprandial gastroesophageal reflux. Gastroenterology 1985; 89: 779-84). Electrical muscle and gastric motility disorders, such as delayed gastric emptying and proximal stomach distention can not only be related with functional dyspepsia but also with lower sphincter relaxation, gastroesophageal reflux episodes and consequently, with the reflux disease. Lower sphincter dysfunction is not likely to be the only cause of reflux disease, because there is not correlation between the number of reflux episodes and the severity of the illness, and also because the brief exposure of the esophageal lining to refluxed material is not harmful, which suggests that a delayed emptying of esophageal refluxed material is also involved in this pathology (Stacher G, Lenglinger J, Bergmann H, Schneider C, Hoffman M, Wolfl G, Stacher-Janotta G. Gastric emptying: a contributory factor in gastroesophageal reflux activity: Gut 2000; 47:661-66 ).

The treatment of people with GERD (gastroesophageal reflux disease) is well-known to those skilled in the art, using the following drugs: - antacids and alginic acid: antacids Mg ²⁺ and Al ³⁺ are frequently administered in combination with alginic acid, an inert substance that produces a foam over the gastric acid and colloid (gel) over the stomach contents, thus reducing reflux. The colloidal foam has a high pH, but the greatest benefit of these preparations can result from the antacid contents. Alginates are also available in combination with cimetidine; - H₂ antagonists: a study demonstrated that, when the patient does not respond well to the simplest measures, a 12-week course with H₂ antagonists produced healing in up to 75 % of the patients with erosive esophagitis, but this patients did not show any improvement with a longer than 24 week course of treatment. Other studies however, claim that H₂ antagonists are merely symptomatic and do not produce healing. As examples we can mention: ranitidine, farnotidine, nizatidine, cimetidine and famotidine, among others;

- Proton pump inhibitors or blockers: long term maintenance in erosive esophagitis with a PPI (proton pump inhibitor) is evidently associated with less relapses compared to long term maintenance with H₂ antagonists. Omeprazole produced healing in 95 % of the patients, following a 12 month maintenance with omeprazole 20 mg once daily or ranitidine 150 nig twice daily, resulting in 77 % and 46 % relapse rates respectively. Nonetheless, in another study, 47 % of the patients with GERD that did not respond to H₂ antagonists and were treated for 36 months with omeprazole 20 mg daily presented relapses after initial healing. Another study comparing the effects of lansoprazole, omeprazole and ranitidine, demonstrated that lansoprazole was significantly better in suppressing gastric 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).

Proton pump inhibitors are a relatively new class of agents used for the treatment of pathological conditions associated with excessive gastric acid secretion, or excessive exposure to gastric acid, and they also take part as components in the therapeutic regimes used for the treatment of Helicobacter pylori infection. In addition, these agents are more powerful blockers of gastric acid secretion than the older drugs, in which group the histamine H₂ antagonists are included. Proton pump inhibitors differ from antimuscarinics and antihistaminics as to their mechanism of action for they act in the last step of the gastric acid formation process, altering the activity of the H⁺,K⁺ ATPase enzyme, therefore presenting greater efficacy (Freston JW. Long- term acid control and proton pump inhibitors: interactions and safety issues in perspective. Am J Gastroenterol 1997; 92 (Suppl.): 51S-57S ). Prokinetic drugs (promoters of motility): in GERD (gastroesophageal reflux disease), prokinetic drugs are better used as combination therapies with PPI's and H₂ antagonists.

Metoclopramide is a type 2 (D₂) dopamine receptor antagonist and a 5- hydroxytryptamine (5-HT) receptor stimulant. Its prokinetic effect in the stomach plus the ability to increase lower sphincter tone, probably constitute the beneficial effects mechanism in gastroesophageal reflux diseases. Metoclopramide also presents anticholinergic effects at the central nervous system (CNS) by inhibiting dopamine receptors. Domperidone, a D antagonist that does not cross the blood-brain barrier, can be an appropriate alternative.

Cisapride is a benzamide substitute with 5-HT receptors antagonist actions, whilst it stimulates the gastrointestinal motility and increases the lower esophageal sphincter pressure, by way of an mechanism of action that may involve 5-HT receptors. Some patients treated with cisapride present diarrhea, possibly due to this drug's action at the colon. Bromopride is another prokinetic agent, with a better tolerability, that acts at the lower esophageal sphincter, increasing its pressure, also acting on the smooth muscles of the stomach, increasing gastric emptying speed (Kilbinger H & Weihrauch TR. Drugs increasing gastrointestinal motility. Pharmacology 1982. 25: 61-7 ).

It is practically impossible to adequately define dyspepsia. It is not a symptom, but rather a constellation of symptoms, which is different in each patient. Efforts to define the term are yet more difficult due to the interrelationship of the biological and characteristics variables of personality, life experiences, social aspects and perception, which determine the way in which patients report their symptoms and how physicians interpret them.

Classification of patients functional dyspepsia, into subgroups of different symptom patterns, is important in order to identify the baseline illness, thus being a guide to choosing the ideal therapy. The most popular classification divided patients into groups with ulcer-like dyspepsia, poor motility, or reflux (Magalhaes AFN. Dispepsia funcional: conceito e classificacao. In: dispepsias e gastrites, 9-18). Recently, however, reflux-like dyspepsia was excluded for it is associated with gastroesophageal reflux disease without esophagitis (Talley NJ, Weaver AL, Tesmer DL, et al. Lack of discriminant value of dyspepsia subgroups in patients referred for upper endoscopy. Gastroenterology 1993, 105: 1378-86). Nevertheless, these classifications have been shown problematic because there is a considerable overlap of symptoms among patient subgroups, not mattering how these are defined.

The most common drug therapy approach to the treatment of the gastroesophageal reflux disease is gastric acid suppression, and unlike peptic ulcer treatment, dosage should be adjusted to each patient. This is an important difference between the two diseases, because even as most of the cases of peptic ulcer are infectious in origin and can be managed with a short term treatment, the gastroesophageal reflux disease is a chronic disorder, and its severity defines the intensity of gastric acid secretion inhibition. Gastric acid secretion blockers

Proton pump inhibitors are better as compared to H antagonists, as per clinical trials based on endoscopic observations, thus they should be the first choice of gastric acid secretion inhibitors, either for the healing or maintenance therapy. Prokinetics The theoretical basis for using prokinetics in the treatment of the reflux disease is that these agents would elevate lower esophageal sphincter pressure, enhance gastric emptying, as well as esophageal peristalsis, regulating some of the abnormalities observed in this disorder. Prokinetic drugs in combination with proton pump inhibitors have also been suggested for the treatment of severe or complicated reflux disease.

The main objectives of the invention have been: • to facilitate the treatment (for physicians and patients) by providing the use of the

drugs regarding two commonly associated pathologies in clinical practice: functional dyspepsia and gastroesophageal reflux. Although the frequent association of functional dyspepsia and gastroesophageal reflux is well-known, and that both share several aspects of etiopathology, especially those related with motility disorders, patients presenting these associated disorders have been relegated to a second tier, without the option of a more specific therapy. Although coherent, this conduct does not necessarily produce adequate results due to the existence of multiple gastric acid secretion blockers and prokinetics, each one of them in several dosage strengths, presentations and formulations, which could lead to an improper dosage use of one or both products, in addition to a possible decrease in patient adherence to the treatment due to a dosage regime that uses multiple drugs and different administration schedules; • to develop a product that would contemplate a proton pump inhibitor and a prokinetic agent, combined in a unique presentation, indicated for patients with functional dyspepsia, either associated with gastroesophageal reflux or not, that would facilitate patient adherence, possibly producing measurable and satisfactory clinical results; • bearing in mind that these individuals present gastroesophageal reflux, more probably gastric reflux of duodenal contents, or even esophageal reflux of duodenal contents, concurrently with digestive tract motility disorders, to develop a drug comprising a combination of a gastric acid secretion blocker and a prokinetic.

Functional dyspepsia and gastroesophageal reflux association has a high incidence. These disorders strongly present, in part, equal mechanisms of etiopathology. Currently, the group of patients presenting these pathologies combined does not have a specific and facilitated drug therapy available.

With the purpose of achieving this objective, a drug has been developed, comprising drugs that have a synergistic effect, presenting at least two types of drugs: a proton pump inhibitor and a prokinetic.

The present invention refers to pharmaceutical drugs easily used for the treatment of disorders associated with functional dyspepsia and gastroesophageal reflux, basically presenting the aforementioned proton pump inhibitor and prokinetic drugs. The invention refers to a drug combination characterized by comprising, individually, and at the same time, jointly:

One or more drug units of one or more proton pump inhibitor agents;

One or more drug units of one or more prokinetic agents; and optionally, other additives or drugs which are well-known to those skilled in the art, within the medium or excipient, also pharmaceutically acceptable.

The proton pump inhibitor (PPI) or blocker agents can be selected from the group comprising: lansoprazole, pantoprazole, omeprazole, esomeprazole magnesium, rabeprazole sodium, and others. Lansoprazole is preferably used.

Drug units are used in two dosage forms, preferably lansoprazole, its derivatives, pharmaceutically acceptable salts or pro-drugs, at the dosages of 15 mg and 30 mg, that will be ingested by the patient at least once daily, preferably in the morning and in a fasted state, during a treatment period of 14 or 28 days, or according to doctor orientation.

Lansoprazole's molecular structure, either 2-[[[3-methyl-4-(2,2,2-trifluoro- ethoxy)-2-pyridinyl]methyl]sulfynyl]-lH-benzoimidazole, or 2-(2- benzimidazolylsulfynylmethyl)-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine, consists of a pyridine ring with a trifluoroethoxy group linked to the benzoimidazole ring through a methyl sulfoxide. Its molecular weight is 369D, being a weak base of 8.5 pKa, soluble in dimethyl formamide and methanol, partially soluble in ethanol, practically insoluble in water and unstable in acid pH. Accordingly, lansoprazole is formulated as enteric release granules, since an early exposure to the gastric acid would lead to a low bioavailability due to its degradation in acid pH (Chun AHC, Shi

HH, Achari R. Lanzoprazole administration of the content of a capsule dosage formulation through a nasogastric tube. Clin Ther 1996; 18: 833-42 ). With this formulation, the drug bioavailability is greater than 80 % for 15 and 30 mg formulations. There is no change in the absorption rate following a 7-day administration, as compared to that observed on the first day of administration. Lansoprazole can be administered in capsules, or following dispersion of its enteric granules in some juice or apple puree, with no significant changes in its pharmacokinetics. Maximum plasma concentrations are reached within approximately l,lh to 2,2 h following oral ingestion, and are not dose-dependent. Concurrent ingestion with food may delay, and even reduce its absorption, as well as its bioavailability, although, apparently, the inhibitory effect of the compound has not been reduced by food ingestion following a 7-day administration. Lansoprazole has a small evident volume of distribution, of about 0,5 L/kg, following 30 mg oral administration. It links to plasma proteins at about 98 %. More than 90 % of the drug is found linked to plasma protein, mainly albumin, and no linkage to red blood cells; there are no data available as to tissue distribution of the drug following intravenous administration. Lansoprazole is rapidly metabolized in the liver, and its main metabolites are

5-hydroxy-lansoprazole, formed by CYP2C19 and 3A4, and a sulfone formed by CYP3A4; a sulfonamide is also found, at a lesser amount. The metabolites are also pro-drugs that are converted into active compounds in an acid medium, found in the parietal cells. Lansoprazole presents a elimination half-life varying from l,2h to 2,lh. Metabolites are excreted in the urine and bile, and thus recovered in the feces. Since CYP2C19 is involved in the metabolization of the drug, slow metabolizers of this enzyme present less clearance than fast metabolizers. Lansoprazole elimination is lower in elders, gastroesophageal reflux disease patients, liver cirrhosis or in patients undergoing hemodialysis, also possibly varying in patients with renal impairment, although dose adjustment is not required, except in severe liver impairment patients in elder individuals.

According to the invention, the prokinetic agents can be selected from the group comprising: bromopride, domperidone, cisapride, alizapride hydrochloride, metoclopramide, and others. Bromopride is preferably used. Drug units are used in one dosage form, preferably bromopride, its derivatives, pharmaceutically acceptable salts or pro-drugs, at the dosage of 10 mg, that will be ingested by the patient at least three times daily, preferably prior to main meals (breakfast, lunch and dinner), during a treatment period of 14 or 28 days, or according to doctor orientation. Bromopride, or 4-amino-5-bromo-N-[2-(diethylamino)ethyl]-2- methoxybenzamide, or even 4-amino-5-bromo-N-[2-(diethylamino)ethyl]-o- anisamidam, acts regulating gastric and intestinal (duodenum and jejunum) motility, by restoring muscle tone and normal peristalsis in all cases in which changes to this system occur. It also normalizes the incomplete or delayed emptying of the bile ducts and it has a complete antiemetic effect, acting centrally and peripherally. Bromopride is rapidly absorbed and its plasma half-life (Tl/2) is within approximately 4,9 hours. Its distribution volume is approximately 2100 L, and its oral absorption is changeable and around 40 to 60 %. Regarding the administration of 10 mg in a single oral dose, maximum plasma concentration (C_max) is of 22 ng/mL + / - 32 % and it occurs within approximately one hour (T_max) following drug administration.

It is indicated as an antiemetic, anti-nausea agent, and a digestive kinetics regulator (prokinetic). Nausea and vomiting of any etiology; gastroesophageal reflux, reflux esophagitis; gastroduodenal and bile dyskinesias; hiatus hernia; gastritis and duodenitis; preparation for digestive radioscopy and endoscopy.

According to the invention, the drug may be presented comprising 14 drug units containing proton pump inhibitors, preferably lansoprazole, and 42 drug units containing a prokinetic agent, preferably bromopride, which corresponds to a 14 day treatment.

Also, in a preferred embodiment of the invention, the drug may be presented comprising 28 drug units containing proton pump inhibitors, preferably lansoprazole, and 84 drug units containing a prokinetic agent, preferably bromopride, which corresponds to a 28 day treatment.

The invention also refers to a drug association characterized by comprising:

- one or more drag units containing one or more proton pump inhibitor or blocker agents;

- one or more drug units containing one or more prokinetic agents; and optionally, other additives or drugs which are well-known to those skilled in the art, within a medium or excipient, also pharmaceutically acceptable.

According to the invention, the drug association uses 15 mg or 30 mg dosages for the proton pump inhibitor drug units. Lansoprazole is preferably used, its pharmaceutically acceptable derivatives or salts. The prokinetic agents are used at the dosage of 10 mg per drug unit. Bromopride is preferably used, its pharmaceutically acceptable derivatives or salts.

According to the invention, the drug is marketed containing one or more drug units of one or more proton pump inhibitors or blockers, and one or more drag units of one or more prokinetic agents, as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable, jointly but also individually, at the dosages of 15 mg or 30 mg for the proton pump inhibitor drag units, and at the dosage of 10 mg for the prokinetic agent drug units. According to the invention, the drug is marketed containing one or more drug units of lansoprazole, and one or more drag units of bromopride, as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable, jointly but also individually, at the dosages of 15 mg or 30 mg for the lansoprazole drug units, and at the dosage of 10 mg for the bromopride drug units.

According to the invention, the drug presented in a facilitated presentation is characterized by comprising one or more drug units of lansoprazole 15 mg or 30 mg to be taken at least once daily, preferably at a fasted state, and one or more drug units of bromopride 10 mg to be taken at least three times daily, preferably prior to main meals (breakfast, lunch and dinner), as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable.

The following examples have a mere illustrative character, nonetheless, these should not have a limiting effect on the scope of the invention. Example 1: A 26-year old male patient complaining about heartburn for the past year, mainly following meals, has been presenting a dry cough for the past 60 days, approximately. He also complained about frequent eructation and a "chock-full" sensation. He denied dysphagia, vomiting and epigastric pain. 6 months before, during a physical exam, no abnormalities were detected. In this case, the choice was to apply a "therapeutic test" with the drag Lansoprazole at the dose of 30 mg/day in the morning for 2 weeks. After this period, the patient returned reporting improvement only in the heartburn. The "therapeutic test" in this patient was a great alternative to resolve the symptom associated with Gastroesophageal Reflux Disease (GERD). However, this treatment only alleviated the heartburn and did not contribute to the improvement of the chronic cough and the gastric fullness. At the return visit to the office, it was decided to keep the treatment with lansoprazole associated to a prokinetic drug, in the case, bromopride 10 mg, taken three times daily prior to main meals. This treatment was established for 3 months. At the end of that period, the patient showed an overall improvement of the symptoms: heartburn, coughing and gastric fullness.

Example 2;

A 40-year old female patient reporting "stomachache" and fullness following meals and "burning" sensation in the chest when lying down. Lansoprazole 15 mg was prescribed at one tablet in the morning for 7 days, in addition to diet orientation and rest with her head in a higher position.

After one week the patient returned with improvement of the epigastric pain and retrosternal burning sensation, however, the gastric fullness sensation persisted. She underwent high digestive tract endoscopy that revealed a mild pangastritis. It was then decided to prescribe bromopride 10 mg at one tablet following meals (breakfast, lunch and dinner) in combination with lansoprazole at one tablet in the morning for a period of 2 weeks. After the combined use of these medications the patient progressed to an overall improvement of the clinical symptoms.

Example 3:

A 50-year old male patient reported post-prandial gastric fullness for the past year, approximately. The patient received orientation that the symptom was probably related to the so-called diabetic gastroparesis, due to his diabetes history for more than 20 years. Moreover, the patient also complained about frequent regurgitations accompanied by a burning sensation in the chest.

While reviewing past treatments, it was evident that the patient properly followed the hygiene-dietary guidelines (to elevate the head of the bed, not to lie down before three hours have pasted following meals, to avoid plentiful meals, greasy or acid food, smoking and alcohol) and he had already used antacids (magnesium hydroxide and aluminum hydroxide) and H₂ blockers (ranitidine), with no therapeutic success. Before establishing a new treatment regime, the following diagnostic tests were requested: 24-hour esophageal pH monitoring and a gastric emptying X-ray study. The test findings evidenced an abnormal gastric acid exposure of the esophagus and decreased gastric motility. Therefore, the following medications were prescribed: Lansoprazole 15 mg in a fasted state plus bromopride 10 mg before breakfast, lunch and dinner during a period of 30 days. When he returned to the office, the patient reported significant improvement in the post-prandial gastric fullness sensation and reflux esophagitis.

Claims

1. A drug combination characterized by comprising, in a facilitated manner, individually, and at the same time, jointly:

- one or more drag units containing one or more prokinetic agents; and optionally, other additives or drugs which are well-known to those skilled in the art, within a medium or excipient, also pharmaceutically acceptable.

2. A drag combination according to claim 1 characterized by the fact that two dosage forms are used in the drag units containing proton pump inhibitor agents.

3. A drug combination according to claims 1 or 2 characterized by the fact that the proton pump inhibitor agents used are those selected from the group containing: lansoprazole, pantoprazole, omeprazole, esomeprazole magnesium, rabeprazole sodium, among others, or their mixtures and combinations.

4. A drug combination according to claim 1 characterized by the fact that lansoprazole is preferably used at the dosages of 15 mg and 30 mg, its pharmaceutically acceptable derivatives or salts.

5. A drag combination according to claim 1 characterized by the fact that one dosage form is used in the drag units containing prokinetic agents.

6. A drag combination according to claims 1 or 5 characterized by the fact that the prokinetic agents used are those selected from the group containing: bromopride, domperidone, cisapride, alizapride hydrochloride, metoclopramide, among others, or their mixtures and combinations.

7. A drag combination according to claim 1 characterized by the fact that bromopride is preferably used at the dosage of 10 mg, its pharmaceutically acceptable derivatives or salts.

8. A drug combination according to claim 1 characterized by the fact that the drug is preferably used for the treatment of functional dyspepsia and gastroesophageal reflux disease.

9. A drug combination according to claim 1 characterized by the fact that it presents 14 drag units containing proton pump inhibitors, and 42 drug units containing a prokinetic agent, which corresponds to a 14 day treatment.

10. A drag combination according to claim 1 characterized by the fact that it preferably presents 28 drag units containing proton pump inhibitors, and 84 drug units containing a prokinetic agent, which corresponds to a 28 day treatment.

11. A drag association characterized by comprising: one or more drug units containing one or more proton pump inhibitor or blocker agents; one or more drag units containing one or more prokinetic agents; and optionally, other additives or drugs which are well-known to those skilled in the art, within a medium or excipient, also pharmaceutically acceptable.

12. A drug association according to claim 11 characterized by the fact that two dosage forms are used in the drag units containing proton pump inhibitor agents.

13. A drag association according to claim 11 characterized by the fact that lansoprazole is preferably used at the dosages of 15 mg and 30 mg, its pharmaceutically acceptable derivatives or salts.

14. A drag association according to claim 11 characterized by the fact that one dosage form is used in the drag units containing prokinetic agents.

15. A drug association according to claim 11 characterized by the fact that bromopride is preferably used at the dosage of 10 mg, its pharmaceutically acceptable derivatives or salts.

16. A drag characterized by comprising one or more drag units of one or more proton pump inhibitors or blockers, and one or more drag units of one or more prokinetic agents, as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable, jointly but also individually, at two dosages for the proton pump inhibitor drag units, and at one dosage for the prokinetic agent drag units.

17. A drug characterized by comprising one or more drag units of lansoprazole, and one or more drug units of bromopride, as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable, jointly but also individually, at the dosages of 15 mg or 30 mg for the lansoprazole drag units, and at the dosage of 10 mg for the bromopride drag units, containing 14 drag units of lansoprazole, and 42 drag units of bromopride.

18. A drug characterized by comprising one or more drag units of lansoprazole, and one or more drug units of bromopride, as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable, jointly but also individually, at the dosages of 15 mg or 30 mg for the lansoprazole drag units, and at the dosage of 10 mg for the bromopride drag units, containing 28 drug units of lansoprazole, and 84 drag units of bromopride.

19. A drag characterized by presenting a facilitated presentation, comprising one or more drug units of lansoprazole 15 mg or 30 mg to be taken at least once daily, preferably at a fasted state, and one or more drag units of bromopride 10 mg to be taken at least three times daily, preferably prior to main meals (breakfast, lunch and dinner), as well as other additives and excipients which are well-known to those skilled in the art and pharmaceutically acceptable.

20. A drag according to claim 16 characterized by presenting a facilitated presentation, comprising 14 or 28 drug units of lansoprazole, and 42 or 84 drag units of bromopride.