WO2023275642A1

WO2023275642A1 - Pharmaceutical composition comprising a proton pump inhibitor for gastric absorption

Info

Publication number: WO2023275642A1
Application number: PCT/IB2022/055310
Authority: WO
Inventors: Maribel PEDRO SANTOS; Jesús MONTOYA RETE; Jesús ANZÚRES RODRÍGUEZ
Original assignee: Laboratorios Liomont, S.A. De C.V.
Priority date: 2021-06-30
Filing date: 2022-06-08
Publication date: 2023-01-05
Also published as: MX2021008015A

Abstract

The present invention describes a pharmaceutical composition for oral administration, which comprises a proton pump inhibitor, a buffer agent and a superdisintegrant, wherein the pharmaceutical composition is designed such that the proton pump inhibitor is absorbed in the stomach and the buffer agent modifies the stomach pH, alleviating the discomfort caused by the overproduction of hydrochloric acid in the stomach and preventing the degradation of the proton pump inhibitor. Furthermore, the superdisintegrant provides a better dispersion of the components for the best use thereof.

Description

PHARMACEUTICAL COMPOSITION INCLUDING A PROTON PUMP INHIBITOR FOR GASTRIC ABSORPTION.

FIELD OF THE INVENTION

The present invention is directed to the field of the pharmaceutical and medical area, since it provides a pharmaceutical composition for oral administration that comprises a proton pump inhibitor, where the absorption of the proton pump inhibitor takes place at the level gastric, likewise, the pharmaceutical composition contains a buffer which provides relief from the symptoms caused by the overproduction of hydrochloric acid in the stomach and modifies the stomach pH to prevent the degradation of the proton pump inhibitor, on the other hand , the superdisintegrant helps a better dispersion of the components for their best use. The composition is useful for the treatment of diseases caused by the overproduction of stomach acid.

BACKGROUND

Heartburn is a painful sensation that occurs in the esophagus. The pain usually originates in the chest and may radiate to the neck or throat. Also called heartburn. Almost everyone experiences heartburn occasionally, but if it occurs frequently and progressively, you are considered to have gastroesophageal reflux disease (GERD). Reflux occurs when food or liquid is pushed back up from the stomach into the esophagus. Partially digested material is acidic and irritating to the esophagus, often causing heartburn and other symptoms.

In the process of swallowing, the muscular walls of the esophagus move to push food towards the stomach. When it has entered the stomach, a muscle called the lower esophageal sphincter closes the esophagus. If this muscle fails to close properly, the stomach contents can be pushed back up into the esophagus. Heartburn or heartburn can also be a side effect of certain medications. Yo The stomach is an organ that is part of the digestive system. Its purpose is threefold: to act as a reservoir for ingested food, as a sieve, and as a pumping system for food to reach the duodenum. The proper functioning of the digestive process requires that food be reduced to particles smaller than one millimeter. This task takes place in the stomach, the antrum and the pylorus are key elements for its realization.

The stomach secretes approximately 2.5 L of gastric juice per day. This process, known as acid secretion, can be divided into three phases: a) The cephalic phase, in which acid secretion occurs in response to gustatory, visual, and olfactory stimuli; it is a phase mediated by the vagus nerve, whose stimulation increases the secretion of acid, pepsinogen and gastrin. b) Gastric phase, which takes place when the food reaches the stomach. This is distended thanks to its muscular structure and the reflexes that stimulate acid secretion, which contains hydrochloric acid, pepsinogen and gastrin, begin. The release of gastrin exceeds that which occurs in the previous phase. If the pH drops to values close to 2, said release is inhibited c) Intestinal phase, whose intervention in the secretion of acid in response to a meal is very little. It represents almost 10% of the volume segregated per day.

In all diseases related to gastric acidity, stomach acid secretion plays a fundamental role in its etiopathogenesis. The parietal cell located in the oxyntic gland secretes hydrochloric acid into the gastric lumen, with a concentration of hydrogen ions much higher than that existing in the blood that nourishes this cell. To produce acid, the parietal cell receives three types of stimuli: a) Neurogenic, mediated by acetylcholine, which exerts a direct action on the parietal cells and stimulates pepsin secretion b) Endocrine, produced by gastrin released from central cells which stimulates the production of acid by the parietal cells c) Chemicals, due to the stimulation carried out by histamine. Consequently, histamine, gastrin, and acetylcholine play a major role in acid production. The role of the proton pump is also important. The prostaglandins PGE2 and PGI2 act by exerting an opposite effect to that of gastrin. and histamine on proton pump activity. They increase the production of mucus, which protects the gastric mucosa.

The main pathologies related to acid secretion are: a) Gastroesophageal reflux disease (GERD), is the set of symptoms and/or esophageal lesions due to the passage of gastric contents into the esophagus. The clinical spectrum of this condition is highly varied, being able to distinguish between erosive GERD, characterized by the presence of lesions in the distal esophagus, and non-erosive GERD, whose main characteristic is the presence of symptoms without esophageal lesions. Esophagitis refers to the appearance of a lesion in the esophageal mucosa, the result of contact with gastric contents. The most common clinical manifestations of GERD are heartburn and regurgitation, a bitter or sour taste, and a feeling of heaviness. Other symptoms that can occur in this disease are epigastric pain and sleep disturbances. Its main complications are peptic stricture (appears in long-standing GERD), esophageal ulcer (courses as chronic bleeding) and Barrett's esophagus (intestinal metaplasia of the squamous mucosa of the distal esophagus) b) Gastroduodenal ulcer, it is described as a circumscribed ulceration of the mucosa penetrating the muscularis mucosa and involving the area exposed to acid and pepsin. In a generic way, three types of ulcers are distinguished: Ulcers associated with Helicobacter pylori, Ulcers associated with the consumption of NSAIDs, for whose prevention gastroprotective agents are indicated, Ulcers due to stress. Etiologically, peptic ulcer has a multifactorial origin, although gastric acid hypersecretion stands out among the most significant factors. From a clinical perspective, the most common symptom is abdominal pain, its typical location being the epigastrium; the pain is often described as burning, gnawing pain, or even painful hunger pangs. Traditionally it has been associated with the absence of food in the stomach, being typical that the pain subsides or calms down with food or with the ingestion of antacids c) Gastropathy due to NSAIDs, the chronic use of these drugs is associated with gastrolesivity symptoms that constitute the most frequent side effect of NSAIDs, these drugs inhibit the activity of cyclooxygenase, which translates into a lower synthesis of prostaglandins, which in turn exert a significant gastrointestinal cytoprotective effect d) Zollinger-Ellison syndrome, characterized by hypersecretion of acid. It is a severe ulcerative disease of the upper digestive tract, with generation of tumors that affect the D cells of the pancreas and with gastrin production. These tumors are called gastrinomas. This pathology is generated by tumors that are located in the head of the pancreas or in the small intestine. These tumors produce gastrin, which leads to high levels of this hormone, with excessive production of stomach acid. Approximately 60% of gastrinomas are malignant, with metastases found in regional lymph nodes, liver, spleen, bone marrow, mediastinum, peritoneum, and skin. Clinically, the symptoms of this pathology include abdominal pain, diarrhea, stomach and duodenal ulcers, and occasionally hematemesis.

Pharmacological treatment for pathologies related to acid secretion is based on the use of a series of drugs that seek to avoid and/or reduce exposure of the esophagus to gastric or duodenal contents. The group of drugs can be divided into: a) Prokinetic drugs, which act by stimulating esophagogastric motility, increasing the tone and reducing transient relaxations of the lower esophageal sphincter (LES), and in some cases also, modifying the flow, the composition of the saliva and bicarbonate secretion by the esophageal glands. Its functions therefore are: increase digestive motility and accelerate gastric emptying b) Protective agents. Mucosal protectors exert their action by creating a barrier effect between the refluxed content and the esophageal mucosa. This group of drugs is represented by sucralfate. It is a surfactant agent composed of sucrose, aluminum and sulfate, which polymerizes in an acid medium, adhering to the mucosal surface, exerting a local cytoprotective effect through its binding to bile acids and pepsin, also facilitating wound healing. lesions by mechanisms still unknown c) Antacid drugs, are drugs that act by neutralizing the acid secretion of the stomach, more specifically the hydrochloric acid secreted by the parietal cells, which increases the gastric pH and reduces the exposure of the esophageal mucosa to stomach acid. Antacids are many and varied, but They are generally based on a combination of magnesium trisilicate, aluminum hydroxide or calcium carbonate, as is the case with almagate and magaldrate, both derived from aluminum and magnesium. The increase in stomach pH due to the action of these antacids also reduces the formation and activity of pepsin d) Antisecretory drugs, there are two types, histamine H2 receptor antagonists (anti-H2) and proton pump inhibitors (PPIs). Both inhibit acid secretion, achieving a decrease in gastric pH. They differ from each other in their different mechanisms of action. Histamine Fte receptor antagonists are drugs that decrease acid secretion through competitive and reversible inhibition of Fh histamine receptors, located on gastric parietal cells. When these receptors are stimulated, they activate the enzyme adenylate cyclase, producing an increase in cAMP levels, which, through a cascade mechanism, activates the proton pump and, therefore, gastric secretion. As they are drugs that antagonize these receptors, they therefore suppress acid secretion. Proton pump inhibitors are benzimidazoles that act as specific, noncompetitive, and irreversible inhibitors of the H+/K+ ATPase pump, located on the surface of the gastric parietal cell. The blockade of said proton pump prevents the production of gastric acid, both basal and before a stimulus, regardless of what it is (acetylcholine, gastrin and/or histamine). Proton pump inhibitors bind covalently to the proton pump; due to this, the only way for the parietal cell to recover its secretory activity is the synthesis of new pumps, which takes a long period of time and explains the long duration of the effects of proton pump inhibitors, which they can be up to four days after administration of a single dose, despite their low plasma half-life. These drugs are most effective when taken 30 minutes before the first meal of the day, because the amount of H+/K+ ATPase present in the parietal cell is greater after a prolonged fast.

Omeprazole is a substituted benzylimidazole derivative with high potency and selectivity in its inhibitory action on gastric acid secretion, both basal as stimulated. Omeprazole is a white to off-white, crystalline powder that melts at 155 °C with decomposition, has weak basic character, and is freely soluble in lipids, ethanol, and methanol, slightly soluble in acetone and isopropanol, and very sparingly soluble in water. The stability of the substance depends on the pH: it degrades rapidly in an acid medium, but it remains practically stable in alkaline conditions.

Omeprazole is an antiulcer whose unique mechanism of action to reduce acid secretion is the inhibition of the enzyme hydrogen/potassium adenosine triphosphatase or (H+/K+) gastric ATPase; its selectivity of action is based on the fact that it only acts on the enzyme of gastric origin. The action of the proton pump occurs in the common final phase of gastric secretory processes, from which it is inferred that omeprazole can reduce intragastric acidity, regardless of the nature of the primary stimulus. Omeprazole is a lipophilic weak base with a pK of 4.0 at a pH of approximately 7. Omeprazole has no electrical charge and is highly lipid soluble, so it can easily cross cell membranes. When it reaches the parietal cell, it crosses the cell membrane by passive diffusion; in the secretory canaliculi of these cells in the active phase, the drug is exposed to pH less than 2.0 (close to 1), from which omeprazole ionizes by a protonation process, originating an active molecule stable at acidic pH called sulfenamine that is not lipophilic and whose positive charge prevents it from crossing the parietal cell membrane, being accumulated and concentrated in the canaliculus. Omeprazole as such is inactive, but in an acid medium, when it becomes the active sulfenamide form, it reacts forming a covalent bond through the sulfhydryl (thiol) groups of the cisternae radicals on the extracellular surface of its alpha subunit and the H+ /K +-ATPase, irreversibly inhibiting its activity. This accumulation is essential for the effect of omeprazole, as it allows a prolonged effect to be achieved despite its short plasma half-life. The subsequent onset of secretory activity, inhibited by omeprazole, requires a new appearance, through synthesis of the inhibited enzyme whose approximate half-life is 18 hours. Exposure of omeprazole to gastric pH degrades it for the most part and gives it low bioavailability, which is why it is formulated in granules sensitive to pH, capable of releasing the substance only when pH values are higher than 6. Formulated like this, the bioavailability of omeprazole increases up to 50%. Under these conditions it is absorbed in the intestine and reaches the parietal cells of the stomach through the bloodstream. The absorption characteristics are highly dependent on the different formulations, so its oral bioavailability will also vary between the different preparations.

On the other hand, sodium bicarbonate is a salt with alkaline properties, with a neutralizing effect on the acid content of the stomach, increasing its pH, it is very soluble and reacts quickly with hydrochloric acid, in the presence of hydrochloric acid it reacts forming water and carbon dioxide, the excess sodium bicarbonate is absorbed and eliminated via the kidneys, reabsorbing 99% and eliminating only 1%. When sodium bicarbonate is administered according to established guidelines, it is associated with little or no toxicity. No associated teratogenic, mutagenic or carcinogenic alterations have been described. Sodium bicarbonate is indicated for the relief and symptomatic treatment of heartburn and heartburn in adults and adolescents over 12 years of age.

From the previously described, the diseases caused by the overproduction of hydrochloric acid in the stomach turn out to have a great impact on the health of the patients, there are different drugs for the treatment of said diseases, however, a drug is required that turns out to be palliative to address the problem in the first instance and, on the other hand, a medication is required that solves the problem from the root cause. Baking soda is an excellent alternative to relieve discomfort caused by overproduction of stomach acid since it is non-toxic and easily accessible, however, due to its nature, it only neutralizes stomach acid, on the other hand, proton pump inhibitors, such as omeprazole, turns out to be of great help for the treatment of diseases caused by the overproduction of stomach acid, treating the condition from the root cause, however, as described, omeprazole degrades in the presence of stomach acids, so it is formulated in the form of capsules containing pellets with a gastro-resistant shell at doses of 20 mg and 40 mg. It is also available as an injectable and as a solid powder for extemporaneous reconstitution. Its stability is a function of pH and when mixed with acidic vehicles for oral ingestion, a maximum shelf life of seven days is ensured. However, the effects of omeprazole are not immediate and its absorption takes place until the pellets reach the intestine.

The state of the art offers alternatives for the advantageous use of the combination omeprazole with sodium bicarbonate, said combination offers advantages in the first instance to neutralize hydrochloric acid from the stomach, so there is immediate relief from the discomfort caused by the overproduction of hydrochloric acid, as a result of said neutralization, omeprazole can be absorbed in the stomach without presenting degradation due to acid pH and thus achieving a better response. Document WO 2001051050 cites a suspension containing omeprazole, sodium bicarbonate, methylcellulose and water, where omeprazole is found in a concentration of 1.2 mg/mL. Likewise, he cites solutions containing 10 mg, 40 mg and 90 mg of omeprazole dissolved in PEG 400, bicarbonate in water, this same example describes that the administration of the solution was carried out with multiple doses of bicarbonate, before and after administration. . The examples cited in said document refer to the intake of large amounts of sodium bicarbonate and water for each administration of omeprazole to avoid its degradation, however this high intake of sodium bicarbonate produces some problems such as exacerbating the problem of reflux due to that sodium bicarbonate causes belching, another problem is related to hypertension or heart failure due to high sodium intake, and high bicarbonate intake can cause metabolic alkalosis. Due to the aforementioned complications, document WO 2001051050 mentions the need for a pharmaceutical composition that decreases the intake levels of sodium bicarbonate and water, likewise provides a simple way for its administration and that maintains the advantages of the omeprazole combination. with baking soda. The invention proposed by the document WO 2001051050 consists of a pharmaceutical composition to be administered orally, which in the first instance is a solution containing omeprazole and sodium bicarbonate, where the sodium bicarbonate is in an amount of 1 mmol for each omeprazole 2mg. In addition, it mentions the formulation of tablets, tablets for suspension, effervescent tablets or powders, so that at the moment of the reaction with water or another diluent, the liquid form is formed for oral administration, where formulations in the form of tablets, tablets for suspension, effervescent tablets or powder contains 20 mg omeprazole and about 1 to 20 mEq of sodium bicarbonate.

Document WO 2003009846 cites examples of the administration of solutions containing omeprazole and sodium bicarbonate to be administered orally, as well as the oral administration of omeprazole with intake of a sodium bicarbonate solution before and after the administration of omeprazole. Likewise, it describes a pharmaceutical composition without the need for a coating, where the compositions are characterized in that the active principle, which can be omeprazole, is absorbed in the stomach without being degraded. The compositions of the invention described in this document are designed so that buffers, such as sodium bicarbonate, produce a pH in the stomach equal to the pKa of the proton pump inhibitor plus an amount sufficient to protect it from degradation, thus the generated pH is translated into the formula pH=pKa of the proton pump inhibitor + 0.7, likewise it describes that to protect proton inhibitors from degradation it is also necessary to consider the solubility of the proton pump inhibitor and the speed of reaction of the buffering agent with hydrochloric acid in the stomach, since the lower the solubility of the proton pump inhibitor, the lower its degradation with respect to time, however it is necessary for the buffering agent to react quickly to avoid any degradation . In the case of the combination of omeprazole plus sodium bicarbonate, document WO 2003009846 establishes that the adequate amount of sodium bicarbonate to avoid omeprazole degradation is 12 to 24 mEq, it also mentions that the amount of sodium bicarbonate The employee must be able to raise the pH to a value of at least the pKa of omeprazole plus 0.7 in a time of 10 minutes and maintain it for a period of 30 minutes, this derived from gastric emptying.

Document WO 2005115474 describes pharmaceutical compositions for oral administration that contain a proton pump inhibitor in combination with at least one buffering agent, likewise it describes that most proton pump inhibitors are poorly soluble in water and demonstrate a correlation of disintegration time to bioavailability, therefore, it is important to optimize the disintegration time to improve in vivo dissolution of the drug, more so when the compositions contain a binder. To solve the disintegration problem, document WO 2005115474 describes the use of croscarmellose sodium in an amount of 2% to 5%.

The document WO 2005007115 refers to all the aforementioned problems on the combination of a proton pump inhibitor and at least one antacid, likewise, it describes the need to increase the storage life, due to the fact that the pump inhibitor of protons is not enterically coated, to favor its absorption in the stomach, its stability is compromised in its storage. To solve this problem, document WO 2005007115 describes the microencapsulation of the proton pump inhibitor with a material that improves shelf life, where the material can be: cellulose hydroxypropyl esters, low-substituted hydroxypropyl esters, hydroxypropyl esters cellulose methyl, methyl cellulose polymers, ethyl celluloses, polyvinyl alcohol, hydroxyethyl celluloses, carboxymethyl celluloses, polyethylene glycol copolymers, monoglycerides, triglycerides, polyethylene glycols, starches, acrylic polymers, cellulose acetate phthalate, sepifilms and cyclodextrins.

Based on what has been previously described, it is of great importance to develop a pharmaceutical composition that includes at least one proton pump inhibitor, which is maintained without degradation in the stomach for its absorption, with the help of at least one buffer. or agent alkalizing, where the composition is in an optimal volume for oral administration and is stable for storage.

OBJECT OF THE INVENTION

The general objective of the present invention is to provide a pharmaceutical composition that comprises at least one proton pump inhibitor and at least one alkalizing agent or buffer, where the pharmaceutical composition provides protection for the proton pump inhibitor so that it is absorbed. at the stomach level.

A particular objective of the present invention is to provide a pharmaceutical composition that comprises at least one proton pump inhibitor and at least one alkalizing agent or buffer, where the pharmaceutical composition reduces the problems associated with the dissolution of the proton pump inhibitor. .

A particular objective of the present invention is to provide a pharmaceutical composition that comprises at least one proton pump inhibitor and at least one alkalizing agent or buffer where the pharmaceutical composition is adapted in an optimal volume for oral administration.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a pharmaceutical composition comprising at least one proton pump inhibitor, at least one buffering agent, at least one dispersion aid and optionally another pharmaceutically acceptable excipient.

The pharmaceutical composition of the present invention is adapted to be administered orally, where the preferred pharmaceutical form is a solid pharmaceutical form, where the solid pharmaceutical form can be a tablet, capsule, powder, granules, mini-tablets, pellets, where the pharmaceutical form The pharmaceutical form is preferably a capsule, where the capsule dosage form may contain powder, granules, mini-tablets, pellets or a combination thereof, where it preferably contains powder. The pharmaceutical form is adapted to be administered orally, where the dissolution and absorption of the proton pump inhibitor takes place in the stomach.

The pharmaceutical composition of the present invention provides a rapid dispersion of the buffering agent in the gastric environment in such a way that it prevents the acid in the stomach from degrading the proton pump inhibitor. On the other hand, the pharmaceutical composition of the present invention also provides rapid dispersion in such a way that the proton pump inhibitor particles are exposed to a greater contact surface with a medium for their dissolution and subsequent absorption, where said medium the pH has previously been modified to a value at which the proton pump inhibitor is stable.

The present invention describes a pharmaceutical composition comprising at least one proton pump inhibitor, where the proton pump inhibitor can be omeprazole, lansoprazole, pantoprazole, rabenprazole, or a pharmaceutically acceptable isomer, salt, hydrate, polymorph of the themselves. The pharmaceutical composition of the present invention, wherein the proton pump inhibitor is preferably, but is not limited to, omeprazole or a pharmaceutically acceptable isomer, salt, hydrate, polymorph thereof. The pharmaceutical composition for oral administration comprising omeprazole in a therapeutically effective amount, preferably omeprazole is in an amount of 5mg to 200mg.

The present invention describes a pharmaceutical composition comprising at least one buffering agent, where the buffering agent can be sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, sodium citrate, tartrate sodium, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide , magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, aluminum hydroxide/sodium bicarbonate coprecipitate, mixed amino acid and buffer, mixed aluminum glycinate and buffer, mixed amino acid salt and buffer, and a mixture of an alkaline salt of an amino acid and a buffer. The pharmaceutical composition of the present invention, where the buffering agent is preferably sodium bicarbonate. The pharmaceutical composition for oral administration comprising omeprazole and at least one buffering agent, wherein the buffering agent is sodium bicarbonate, wherein the sodium bicarbonate is present in at least an amount sufficient to raise the pH of the stomach and prevent degradation of the proton pump inhibitor. The pharmaceutical composition for oral administration comprising omeprazole and at least one buffering agent, wherein the buffering agent is sodium bicarbonate, wherein the sodium bicarbonate is present in at least an amount of 5 mEq to 20 mEq.

The present invention describes a pharmaceutical composition that comprises at least one dispersion adjuvant which is useful for reducing agglomerations in the dissolution medium of the proton pump inhibitor, the buffering agent and optionally another pharmaceutical excipient, where the adjuvant of the dispersion is a synthetic super disintegrant. It has been reported that in an acid medium the disintegration force is reduced for some disintegrants such as croscarmellose sodium and sodium starch glycolate, therefore the pH value correlates with the disintegration force. There is a significant reduction in the rate of water uptake and swelling of part of croscarmellose sodium and sodium starch glycolate in an acid medium (0.1 N HCI), due to its anionic nature, since protonation occurs of the carboxyl group, which generates the slightly soluble molecular species compared to the dissociated form, the reduction in water uptake and swelling is due to the fact that these superdisintegrants contain ionizable substituents in their structure that are potentiated in the acid medium. Superdisintegrants such as croscarmellose sodium and sodium starch glycolate are anionic, a characteristic that can cause problems in binding in vitro with drugs or cationic media. The pharmaceutical composition for oral administration comprising omeprazole, at least one buffering agent and at least one dispersing aid which is a disintegrant, where the super-disintegrant is crospovidone, where the crospovidone is in an amount of 0.1% to no more 1.5% based on the total weight of the formulation.

The present invention describes a pharmaceutical composition optionally comprising one or more pharmaceutically acceptable excipients, where the pharmaceutically acceptable excipients may be chosen from but not limited to binding agents, diluting agents and lubricating agents. The pharmaceutical composition of the present invention optionally comprising a binding agent, where the binding agent may be but is not limited to: carboxymethyl cellulose, microcrystalline cellulose, alginic acid, hypromellose, carbomers or mixture thereof. The pharmaceutical composition of the present invention optionally comprising at least one diluting agent, where the diluting agent can be but is not limited to: cellulose, carboxymethylcellulose, microcrystalline cellulose, lactose, maltodextrins, povidone, dextrins, dextrose, sugar, sucrose, carbonate calcium, calcium lactate or a mixture thereof. The pharmaceutical composition of the present invention optionally comprising a lubricating agent, where the lubricating agent can be but is not limited to: calcium stearate, glycerin monostearate, magnesium stearate, stearic acid, sodium stearyl fumarate, colloidal silicon dioxide or mixture thereof.

Some examples of the compositions obtained for the development of the present invention are presented below in a more non-limiting descriptive manner: Example 1. Pharmaceutical composition with 20 mg of omeprazole.

Example 2. Pharmaceutical composition with 40 mg of omeprazole.

Example 3. Pharmaceutical composition with 20 mg of omeprazole.

Example 4. Pharmaceutical composition with 20 mg of omeprazole.

Example 5. Pharmaceutical composition with 40 mg of omeprazole.

Example 6. Pharmaceutical composition with 40.8 mg of omeprazole.

Dissolution tests were performed on some of the compositions in order to demonstrate the prompt dispersion and dissolution of the composition, likewise, to verify that there are no agglomerates that delay the dissolution of omeprazole. The dissolution test was carried out in a dissolution apparatus II with a volume of 900 mL of phosphate buffer solution at pH 7.4 at a temperature of 37.5 °C ± 0.5 °C at a speed of 75 rpm with a sampling period at 45 minutes. Below, in a descriptive but non-limiting manner, dissolution tests of some of the compositions are presented:

Table 1. Dissolution test of the pharmaceutical composition according to example 3.

Table 2. Dissolution test of the pharmaceutical composition according to example 5.

Table 3. Dissolution test of the pharmaceutical composition according to example 6.

To verify the stability and compatibility of the composition and its components, a stability study was carried out at a temperature of 30°C ± 0.2 °C and a relative humidity of 65% ± 5%. Giving satisfactory results and demonstrating the stability of the composition of the present invention. Next, it is presented in a descriptive way but not limitation, a stability study carried out on 3 batches of one of the examples, the study was carried out under the conditions described above:

Table 4. Stability study according to example 5, batch 0013, under temperature conditions of 30°C ± 0.2 °C and a relative humidity of 65% ± 5%.

Table 5. Stability study according to example 5, batch 0014, under temperature conditions of 30°C ± 0.2 °C and a relative humidity of 65% ± 5%.

Table 6. Stability study according to example 5, batch 0015, under temperature conditions of 30°C ± 0.2 °C and a relative humidity of 65% ± 5%.

To evaluate the safety and efficacy of the present invention, bioequivalence studies were carried out. The studies presented below are mentioned below in a descriptive but non-limiting manner. The first bioequivalence study was carried out at a dose of 20 mg of omeprazole and 1100 mg of sodium bicarbonate and excipients corresponding to example 3. The reference drug with which the composition of the present invention was compared is known on the market. with the name of Trinsica® 20 that comprises a dose of 20 mg of omeprazole and 1100 mg of sodium bicarbonate. The study was conducted in a single-dose, randomized, double-blind, 2 x 2 crossover design with a washout period of at least 7 half-lives, under fasting conditions in 34 healthy subjects of both genders. The pharmacokinetic parameters obtained for the reference drug were Cma _X : 760.33 ± 355.36 ng/mL, AUCo-t: 968.62 ± 669.86 Ivng/mL and AUCo-«: 993.25 ± 680.39 Ivng/mL. The pharmacokinetic parameters obtained for the pharmaceutical composition of the present invention were Cma _X : 703.75 ± 283.11 ng/mL, AUCo-t: 916.53 ± 641.71 Ivng/mL and AUCo-«: 943.02 ± 656.88 Ivng/mL. According to the statistical analysis, it is concluded that the composition The evaluated pharmaceutical of the present invention meets the bioequivalence criteria, therefore it is safe and effective.

The second bioequivalence study was carried out at a dose of 40 mg of omeprazole and 1100 mg of sodium bicarbonate and excipients corresponding to example 5. The reference medicine with which the composition of the present invention was compared is known on the market. under the name of Zegerid® comprising a dose of 40 mg of omeprazole and 1100 mg of sodium bicarbonate. The study was conducted in a single-dose, randomized, double-blind, 2 x 2 crossover design with a washout period of at least 7 half-lives, under fasting conditions in 34 healthy subjects of both genders. The pharmacokinetic parameters obtained for the reference drug were Cma _X : 1615.43 ng/mL ± 955.07 ng/mL, AUCo-t: 2304.51 ± 1983.12 h*ng/mL and AUCo- _» : 2359.93 ± 2064.69 h ^» ng/mL. The pharmacokinetic parameters obtained for the pharmaceutical composition of the present invention were Cma _X : 1476.91 ± 761.13 ng/mL, AUCo-t: 2471.97 ± 2205.25 h*ng/mL and AUCo-»: 2613.32 ± 2432.94 h ^» ng/mL. According to the statistical analysis, it is concluded that the evaluated pharmaceutical composition of the present invention meets the bioequivalence criteria, therefore it is safe and effective. The present invention that comprises a pharmaceutical composition that comprises omeprazole and sodium bicarbonate in therapeutically effective doses, as well as crospovidone and optionally another pharmaceutically acceptable excipient, where the composition is adapted in a capsule-shaped pharmaceutical form is useful for the treatment of diseases caused by overproduction of stomach acid.

Claims

CLAIMS Having described the invention, the content of the following claims is claimed as property:

1. Pharmaceutical composition for oral administration comprising omeprazole or its pharmaceutically acceptable salts, sodium bicarbonate and crospovidone.

2. Pharmaceutical composition according to claim 1, wherein the omeprazole is in a therapeutically effective amount.

3. Pharmaceutical composition according to claim 1, wherein the sodium bicarbonate is in an amount capable of maintaining the pH of gastric fluids at a pH in which omeprazole does not undergo degradation.

4. Pharmaceutical composition for oral administration comprising omeprazole or its pharmaceutically acceptable salts, sodium bicarbonate and crospovidone, wherein the pharmaceutical composition is adapted to be administered in capsule form.

5. Pharmaceutical composition according to claim 4, wherein the omeprazole is in a therapeutically effective amount.

6. Pharmaceutical composition according to claim 4, wherein the sodium bicarbonate is in an amount capable of maintaining the pH of gastric fluids at a pH in which omeprazole does not undergo degradation.

7. Pharmaceutical composition according to claim 4, where the omeprazole dissolution is not less than 75% in a time of 45 minutes.

8. Pharmaceutical composition according to claims 1 and 4, wherein the composition is useful for the treatment of diseases caused by the overproduction of stomach acid.