JP2013006843A - Gastric acid secretion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide compositions for reducing gastic acid secretion in a mammal that are capable of enhancing anti-acid activity of gastic H/K-ATPase proton pump inhibitor (PPI) in the stomach.SOLUTION: The compositions comprise an irreversible PPI (for example, pantoprazole) as a gastic acid secretion inhibitor and one or more small carboxylic acid molecules such as saturated or unsaturated monocarboxylic acid, dicarboxylic or tricarboxylic acid molecules having between three to six carbon atoms, as parietal cell activators in the gastic lumen.

Description

RELATED APPLICATION DATA This application is based on US Provisional Application 60 / 679,664 (filed May 11, 2005) and claims priority, the disclosure of which is hereby incorporated by reference in its entirety. Incorporated into.

FIELD OF THE INVENTION The present invention is a novel oral composition that inhibits gastric acid secretion and is a proton pump inhibitor in an amount sufficient to activate one or more small monocarboxylic, dicarboxylic or tricarboxylic parietal cells. It is related with the composition containing together. The invention further relates to methods of using such compositions to reduce gastric acid secretion in mammals.

BACKGROUND OF THE INVENTION A great many pathological conditions are characterized by the need to suppress gastric acid secretion. Such conditions include, but are not limited to, Zollinger-Ellison syndrome (ZES), gastro-esophageal reflux disease (GERD), peptic ulcer disease, duodenal ulcer, esophagitis, and the like. Symptoms such as peptic ulcers have serious complications and represent some of the most common diseases in developed countries.

Currently, the main therapies used in the treatment of GERD and peptic ulcer disease include drugs to reduce stomach acidity, such as histamine H ₂ receptor antagonists or proton pump inhibitors (PPIs) It is done by use. PPI acts by inhibiting mural cell H ⁺ / K ⁺ ATPase proton pump responsiveness for acid secretion from mural cells. PPIs such as omeprazole and pharmaceutically acceptable salts thereof are disclosed, for example, in EP 05129, EP 124495 and US Pat. No. 4,255,431.

PPI agents are acid labile prodrugs, which are usually administered in the form of enteric coated granules and are weak to the base. Following absorption in the small intestine, PPI accumulates in the acid environment of mural cells that preferentially secrete acid. The acid environment in the parietal cell acid environment causes the conversion of the prodrug to the active sulfenamide, which is an active agent that binds to and inhibits the parietal cell H ⁺ / K ⁺ ATPase pump. Thus, preactivation of mural cells is required for conversion from PPI to its active protonate form. Mural cell preactivation is usually achieved by food intake that initiates gastrin-dependent mural cell activation. In fact, the patient is instructed to take a PPI one hour before eating to ensure that the mural cells are activated when they reach the mural cells via the bloodstream.

  Despite their good literature described effects, PPI has some notable limitations. Conversion from PPI to its active form requires preactivation of mural cells. Mural cell preactivation is usually achieved by food intake. Therefore, the PPI must be taken before food intake to synchronize between preactivation of mural cells and absorption of PPI into the blood. In addition, PPIs are relatively slow to produce pharmacological activity, reach maximum acid suppression and take several days for symptoms to be relieved, and those in GERD therapy on demand. (Sachs G, Eur J Gastroenterol Hepatol. 2001; 13 Suppl 1: S35-41).

  Furthermore, PPI causes 24-hour gastric acid and heartburn pain in GERD patients, failing to provide nighttime acid breakthrough suppression at twice daily doses of PPI. (Tytgat GN, Eur J Gastroenterol Hepatol. 2001; 13 Suppl 1: S29-33; Shaker R. et al., Am. J. of Gastroenterology, 98 (7), 2003). Finally, these drugs show substantial patient-to-patient variation in pharmacokinetics and cause significant interactions with other drugs (Hatlebakk et al., Clin Pharmacokinet. 1996; 31 (5): 386 -406). Thus, improving PPI-mediated activity is a well-understood challenge in gastroenterology.

  Maleic acid and succinic acid are chemically characterized by 4-carbon dicarboxylic acids and are known as potent gastric acid secretion stimulators (Teyssen et al., J. Clin Invest. 1999 103 (5): 707-713). Teyssen et al. Studied the stimulation of gastric acid secretion in fermented alcoholic beverages (eg, beer and wine) produced by fermentation. Interestingly, when produced by beer, champagne, wine and pentagastrin (which stimulates the induction of potent exogenous acid secretion), maleic acid and succinic acid, without the mediator of their action, gastrin Has been shown to stimulate gastric acid excretion in humans.

  U.S. Pat.No. 5,559,152 shows that a mixture of succinic acid and citric acid at a dose of 3.5 mg / kg in dogs as indicated by a marked decrease in gastric fluid pH measured in the empty stomach 40 minutes after drug administration. Disclose that it is possible to induce gastric acid secretion. The patent further discloses that succinic acid and citric acid stimulate acid secretion in healthy human volunteers.

  Pokrovskiy et al. Also suggested that molecules related to the mitochondrial respiratory chain (Krebs cycle), such as pyruvate, succinate, α-ketoglutarate, malate or glucose, stimulate proton secretion in ex vivo models of frog mucosa. (Physiologicheskiy Z'urnal 10: 1567-1573, 1973).

  US Pat. Nos. 6,489,346; 6,645,988; and 6,699,885 (patents to Phillips (collectively referred to as “Phillips patents”) consist of a pharmaceutical composition and PPI, at least one buffer and a specific wall cell activator. Disclosed is a method of treating acid-induced gastrointestinal disorders using an oral composition, such as the malignant cell activator disclosed in the Philips patent includes, for example, chocolate, sodium bicarbonate, calcium, peppermint oil, Contains spearmint oil, coffee, tea, cola and caffeine, theophylline, theobromine and amino acid residues, all of which have been proposed as wall cell activators, as shown in the Philips patent, to release endogenous gastrin. Induces and stimulates acid secretion.

  All mural cell stimulants taught by the prior art to promote PPI activity are either gastrin analogs or mural cell stimulants that induce the release of endogenous gastrin. Applicants have surprisingly found compositions and methods that effectively promote inhibitory activation of PPI in a gastrin-independent manner without activation of the gastrin-histamine pathway. The prior art does not teach or suggest promoting the inhibitory effect of PPI in a gastrin-independent manner.

  The long felt need to develop effective gastrin-independent therapies for pathologies where it is desired to inhibit gastric acid secretion would be met. Despite widespread use of PPIs, the need to enhance the PPI effect, such as prolonged effects to control nighttime acid breakthrough, stronger effects at lower doses and diet independence There is still a need for administration. Applicants' invention disclosed herein satisfies many of these long felt needs.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a PPI-based composition with enhanced activity that inhibits gastric acid secretion.

In one embodiment, the invention provides a composition comprising a substituted benzimidazole H ⁺ / K ⁺ -ATPase proton pump inhibitor (PPI) as a gastric acid secretion inhibitor, one or more as a mural cell activator. The present invention relates to a composition comprising a small or unsaturated small monocarboxylic acid, dicarboxylic acid or tricarboxylic acid, salt or derivative thereof. Preferred acids to be used as mural cell activators are small monocarboxylic acids, dicarboxylic acids or tricarboxylic acids associated with the mitochondrial respiratory circuit (Krebs circuit). Surprisingly, the composition of the present invention can enhance the anti-acid activity of PPI in the stomach. The compositions of the present invention can be used to treat subjects suffering from chronic or acute diseases that require suppression of acid secretion in the stomach.

The substituted benzimidazole proton pump inhibitor according to the present invention is a compound that inhibits the activity of the H ⁺ / K ⁺ -adenosine triphosphatase (ATPase) proton pump in gastric wall cells. In its prodrug form, the PPI is in a non-ionized state and can therefore pass through the cell membrane of mural cells. Once reaching the mural cell, the non-ionized PPI moves to the acid-secreting portion of the activated mural cell, the secretory tubule. The PPI trapped in the tubule is protonated and thereby converted to an activated sulfenamide form, forming a disulfide covalent bond with a cysteine residue in the alpha subunit of the proton pump, thereby allowing the proton pump to Inhibits irreversibly.

  The present invention is a surprising discovery of the inventors that small monocarboxylic, dicarboxylic or tricarboxylic acid molecules related to the mitochondrial respiratory circuit (Krebs circuit), such as maleic acid and succinic acid, are protons in inhibiting gastric acid secretion. It is based on the possibility of increasing the activity of pump inhibitors. Such small saturated or unsaturated dicarboxylic acids activate mural cells. Active wall cells have an acidic pH, which is required to convert PPI to the activated protonated sulfinamide form. Thus, synchronized activation of mural cells by the small molecule of the present invention maximizes inhibition of the pump by PPI.

  The compositions of the present invention exhibit the following advantages over known PPI-based compositions aimed at reducing gastric acid secretion. The present composition allows for preactivation of mural cells with the mural cell activating molecule of the present invention instead of food intake. Preactivation of mural cells by these molecules facilitates the conversion of PPI to the activated flufenamide form. Moreover, the composition of the present invention exhibits anti-acid activity in the stomach in a meal-independent manner because it no longer requires a meal for mural cell preactivation. Thus, the combined activator of the composition of the present invention provides an effective solution for PPI administration at bedtime in GERD patients who teach not to eat food at bedtime.

  The composition according to the present invention may comprise any small monocarboxylic acid, dicarboxylic acid or tricarboxylic acid, salts or derivatives thereof, in an amount sufficient to activate mural cells in the gastric lumen. Preferred carboxylic acids are small saturated or unsaturated monocarboxylic, dicarboxylic or tricarboxylic acids associated with the Krebs cycle. The most preferred small dicarboxylic acids are saturated or unsaturated dicarboxylic or tricarboxylic acids such as maleic acid, succinic acid or citric acid or any derivative or salt thereof. Also, small carboxylic acid molecules related to other Krebs cycles that fall within the scope of the present invention are, for example, pyruvate, α-ketoglutarate, succinyl-CoA, fumarate or oxaloacetate.

  The composition according to the invention is preferably an oral composition, however parenteral compositions are also included within the scope of the invention. The activating component of the present invention may be formulated in a single oral dosage form, preferably a solid dosage form. In this case, the release of PPI and small carboxylic acids is regulated so that a synchrony between activation of mural cells and absorption of PPI into the blood is achieved. Thus, in one embodiment, the PPI and mural cell activator according to the present invention is a multilayer tablet, suspension tablet, effervescent tablet, powder, pellet, granule, hard gelatin capsule containing a large number of beads or a lipid based vehicle. May be formulated as a soft gelatin capsule containing Liquid dosage forms such as suspensions may be used as well.

  According to one embodiment, the solid dosage form of the invention comprises a PPI particle coated with either an enteric pH-dependent release polymer or a non-enteric time-dependent release polymer and a mural cell activator according to the invention. It may be a capsule containing particles or a multilayer tablet. In order to ensure that the parietal cells activated by the small carboxylic acid synchronize with the absorption of PPI in the proximal part of the small intestine, the single oral dosage form is time-dependent to extend the release time in the stomach Small carboxylic acid beads coated with release polymer may be included. In particular, slowing the release of small carboxylic acids in the stomach leads to activation of carboxylic acids as activators of mural cells and conversion of PPI in activated mural cells to their protonated form in PPI Allows tuning between absorption of

  The active ingredients of the present invention may also be formulated in separate dosage forms. For example, the small carboxylic acids according to the present invention may be formulated into oral suspensions or solid dosage forms such as capsules, tablets, suspensions, or effervescent tablets, with the solid dosage separated from the PPI. Forms, preferably capsules or tablets comprising beads with enteric pH-dependent release polymers or non-enteric time-dependent release polymers may be formulated. The separated dosage form may be provided as a kit comprising small carboxylic acid beads in one dosage form and PPI beads in a separated dosage form. In this case, the small carboxylic acids are administered in combination with the PPI so that there is at least some temporal overlap in their physiological activity. The PPI and small carboxylic acid may be administered simultaneously and / or over time.

  The active ingredients of the present invention may also be formulated in dosage forms suitable for parenteral administration, such as dosage forms for intravenous administration and subcutaneous injection. It is also possible for one of the active ingredients to be administered orally (such as in a tablet or capsule) and for the second active ingredient to be administered parenterally by intravenous or subcutaneous injection.

  In another embodiment, the present invention is directed to a method for treating a subject suffering from a disease in need of inhibition of gastric acid secretion or a disease that is normally treated by inhibition of gastric acid secretion. The method comprises administering to the subject a pharmaceutical composition comprising PPI as a gastric acid secretion inhibitor and one or more small carboxylic acids as activators of mural cells.

  The compositions of the invention may be used to prevent or treat pathologies in mammals in need of inhibition of gastric acid secretion. Preferably, the mammal is a human. The compositions of the present invention are effective in treating the pathology and in minimizing the risk of developing such pathology before the appearance of symptoms.

  The pharmaceutical compositions of the present invention may be used in a large number of pathological conditions that are treated by suppression of gastric acid secretion. Such conditions include, but are not limited to, Zollinger-Ellison syndrome (ZES), gastric-esophageal reflux disease (GERD), esophagitis, peptic ulcer disease, duodenal ulcer, gastritis and stomach Includes erosion, dyspepsia, NSAID-induced gastric disease.

The present invention also includes a pharmaceutical kit, preferably an oral pharmaceutical kit. The kit typically contains, as an active ingredient, a pharmaceutically effective amount of (i) one or more small carboxylic acids according to the present invention; (ii) a substituted benzimidazole H ⁺ / K ⁺ -ATPase proton pump inhibitor. including. In one embodiment, the active ingredient is formulated in a separate dosage unit form. The kit may be used to treat or prevent a disease in a subject in need of inhibition of gastric acid secretion by administering an active ingredient to the subject. The one or more small carboxylic acids are typically administered concurrently with the PPI, prior to the PPI, or subsequent to the administration of the PPI.

The present invention also provides, as an active ingredient, a pharmaceutically effective amount of (i) one or more wall cell activators of a delayed release formulation; (ii) a substituted benzimidazole H + / K + -ATPase of the delayed release formulation. An oral pharmaceutical composition comprising a proton pump inhibitor, wherein the release of mural cell activator from the composition is delayed, thereby activating mural cell activator in mural cells and circulating PPI in the blood Allows synchronization between absorption into Preferably, the mural cell activator is released prior to releasing the PPI from the composition, so that when already activated by the mural cell activator, the PPI becomes mural cells via the bloodstream. To be able to reach. However, according to other embodiments, if the PPI remains in the blood for a longer period of time to ensure overlap with the activity of the mural cell activator, the PPI is It may be released prior to the release of the agent. This synchronization is necessary to maximize inhibition of the H ⁺ / K ⁺ -ATPase proton pump by PPI. Both PPI and the parietal cell activator particles may be coated with either an enteric coating polymer (pH-dependent release polymer) or a non-enteric coating polymer (time-dependent release polymer).

  These and further aspects will be apparent from the detailed description and examples that follow.

FIG. 1 shows that succinic acid induces gastric acid secretion in rats. FIG. 2 shows that administration of pantoprazole (panto) and succinic acid (ScA) resulted in higher pH values in gastric juice samples compared to pantoprazole alone. FIG. 3 shows that administration of pantoprazole and succinic acid (panto-ScA) resulted in lower gastric acid excretion values in the stomach compared to pantoprazole (panto) alone. FIG. 4 shows that both succinic acid and maleic acid promote the effects of pantoprazole in gastric acid secretion. FIG. 5 shows that succinic acid was able to induce gastric acid secretion when administered to pyloric ligated rats.

Detailed Description of the Invention Activation of mural cells is necessary for the conversion of PPI prodrugs to active forms that act as irreversible inhibitors of the gastric H ⁺ / K ⁺ -ATPase proton pump. The compositions of the present invention provide a unique combination of active agents that increase the effectiveness of PPI in inhibiting gastric acid secretion without the need for food intake.

  The compositions of the present invention may be used to prevent or treat disease states in mammals in need of inhibition of gastric acid secretion. The compositions of the present invention are effective in both treating a condition and minimizing the risk of developing such condition before onset. Such pathologies include, for example: reflux esophagitis, gastritis, duodenal inflammation, gastric ulcer and duodenal ulcer. Further, the compositions of the present invention can be used, for example, in patients on non-steroidal anti-inflammatory drugs (NSAIDs) treatment (including low-dose aspirin), patients with non-ulcer dyspepsia, symptomatic gastro-esophageal reflux disease (GERD) and patients with gastrinoma may be used for the treatment or prevention of gastrointestinal diseases where a gastric acid inhibitory effect is desirable. They are also used for the prevention and treatment of stress ulcers in patients in intensive care situations, in patients with acute upstream gastrointestinal bleeding, in preoperative and postoperative conditions to prevent gastric acid aspiration May be. In addition, they may be useful in the treatment of Helicobacter infection and related diseases. Other conditions that are highly suitable for treatment include, but are not limited to, Zollinger-Ellison syndrome (ZES), Werner syndrome, and systemic mastocytosis.

The parietal cell activator according to the invention is preferably one or more small monocarboxylic acids, dicarboxylic acids or tricarboxylic acids or their derivatives or salts. Preferably the acid molecule is a small carboxylic acid associated with the Krebs cycle. Particularly preferred acid molecules are saturated aliphatic and unsaturated dicarboxylic acids, which may be used as mural cell activators according to the present invention. Small aliphatic dicarboxylic acids are generally represented by: HO ₂ C— (CH ₂ ) _n —CO ₂ H (where n = 0 to 5). Specific small saturated aliphatic dicarboxylic acids are oxalic acid (n = 0), malonic acid (n = 1), succinic acid (n = 2), glutaric acid (n = 3), adipic acid (n = 4 ) And pimelic acid (n = 5). Preferred aliphatic dicarboxylic acids to be used as mural cell activators according to the present invention are aliphatic dicarboxylic acids of 2 to 6 carbon atoms, more preferably 4 carbon atoms, for example succinic acid. Preferred unsaturated dicarboxylic acids to be used as mural cell activators according to the present invention are 4-carbon maleic acid and fumaric acid. Instead of the free dicarboxylic acids, the corresponding dicarboxylic acid derivatives may be used, for example dicarboxylic esters, amides, halides or hydrides of dicarboxylic acids. Also included within the scope of the present invention are small carboxylic acid molecules associated with the mitochondrial respiratory chain (Krebs cycle), such as pyruvate, citrate, fumarate, α-ketoglutarate, succinyl-CoA or oxaloacetate. .

  The compositions of the present invention comprise an amount of one or more small carboxylic acids or analogs effective to achieve a pharmacological effect in mural cells without severe adverse side effects. The standard approximate amount of the small carboxylic acid present in the composition is preferably 1-2500 mg, more preferably 10-1000 mg and most preferably 50-400 mg.

  In one preferred embodiment, the composition of the present invention comprises one or more fatty acid tricarboxylic acids, preferably citric acid, in combination with one or more dicarboxylic acids. The standard approximate amount of one or more tricarboxylic acids present in the composition is preferably 1-1000 mg, more preferably 10-1000 mg and most preferably 50-200 mg.

The composition of the present invention further comprises a PPI that acts as a reversible inhibitor of the gastric H ⁺ / K ⁺ -ATPase proton pump. The PPI used in the present invention may be any substituted benzimidazole compound having H ⁺ / K ⁺ -ATPase inhibitory activity. For the purposes of the present invention, the term “PPI” shall mean any substituted benzimidazole having pharmacological activity as an inhibitor of H ⁺ / K ⁺ -ATPase, and is not limited thereto. Although not in neutral or salt forms of omeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazol, perprazol (s-omeprazole magnesium), habeprazole, lansoprazole, pariprazole, tenatoprazole and remino Including prazole, single enantiomers or isomers thereof or other derivatives or alkali salts of these enantiomers.

Examples of gastric H ⁺ / K ⁺ -ATPase proton pump inhibitors that may be used in the present invention are disclosed in US Pat. No. 6,093,738, which describes novel thiadiazole compounds that are effective as peptone pump inhibitors. European Patents 322133 and 404322 describe quinazoline derivatives, European Patent 259174 describes quinoline derivatives, and WO 91/13337 and US Patent 5,750,531 disclose pyrimidine derivatives as proton pump inhibitors. Suitable proton pump inhibitors are also disclosed, for example, in EP-A1-174726, EP-A1-166287, GB 2 163 747 and W090 / 06925, W091 / 19711, W091 / 19712, W094 / 27988 and W095 / 01977 The

  In a non-limiting embodiment, the ratio of small carboxylic acid molecules or salts thereof to the PPI is from about 20: 1 to about 1: 5.

  The composition of the present invention is preferably for proper oral administration. The PPI particles in the oral composition according to the present invention may be coated or uncoated. The manufacture of enteric coated particles comprising PPI, such as omeprazole, is disclosed, for example, in US Pat. Nos. 4,786,505 and 4,853,230.

  The compositions of the present invention comprise PPI in an amount effective to achieve a pharmacological effect or achieve a therapeutic improvement without undue adverse side effects. Therapeutic improvements include, but are not limited to: increasing gastric pH, reducing gastrointestinal bleeding, improving or eliminating symptoms. According to a preferred embodiment, the typical daily dosage of PPI may vary and will depend on various factors such as the individual needs of the patient and the disease to be treated. In general, the daily dose of PPI will be in the range of 1 to 400 mg. Preferred standard approximate PPI amounts included in the composition are typically about 20 to 40 mg omeprazole, about 30 mg lansoprazole, about 40 mg pantoprazole, about 20 mg rabeprazole and the following PPI Pharmacologically equivalent doses of: bebeprazole, pariprazole, dontoprazole, lansoprazole, perprazole (s-omeprazole magnesium), tenatoprazole and leminoprazole.

  The active ingredients of the present invention are preferably formulated in a single oral dosage form containing all active ingredients. The composition of the present invention may be formulated in either a solid or liquid form. Solid formulations are preferred from the standpoint of improving the stability of solid formulations as compared to liquid formulations and from the perspective of better patient compliance.

  In one embodiment, the PPI particles and one or more small carboxylic acids are formulated in a single solid dosage form, such as a multi-layer tablet, suspension tablet, effervescent tablet, powder, pellets, granules or capsules containing multiple beads. It becomes. In another embodiment, the active agent is formulated into a single liquid dosage form, such as a suspension containing all the active ingredients, or a dry suspension to be reconstituted prior to use. Also good.

  The acid labile PPI particles of this composition are preferably formulated as enteric coated delayed release granules to avoid contact with gastric juice. However, the parietal cell activator of the present invention can be used in an immediate release formulation to facilitate rapid parenchymal cell activation, or between the biological activity of the parietal cell activator and PPI in parietal cells. It may be formulated in any of the delayed release formulations for better synchronization. In this case, both PPI and mural cell activator particles are coated with either an enteric coating polymer (pH-dependent release polymer) or a non-enteric coating (time-dependent release polymer). For example, if coated PPI particles are used and are absorbed late into the blood, it is desirable that the mural cell activator particles be coated so that their release and absorption delay is good. In one specific embodiment, the PPI particles are thickly coated with a non-enteric coating layer so that the release of PPI is preferably from 40 to 100 minutes, more preferably from 40 to 80 minutes, most preferably from 60. Delayed 80 minutes, the mural cell activator is coated with a thin non-enteric coating polymer layer, whereby the release of the mural cell activator is synchronized with the release of the PPI, preferably 20-80 minutes, Most preferably it is delayed 30 to 60 minutes. These conditions allow for pre-activation of mural cells by mural cell activators prior to reaching pharmacological PPI levels.

  Non-limiting examples of pH dependent enteric coating polymers to be used in the present invention are as follows: cellulose acetate phosphate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid copolymer, shellac, hydroxypropyl methylcellulose Succinate, cellulose acetate trimellitate, and mixtures of any of the foregoing. Suitable commercially available enteric substances are sold, for example, under the registered trademark Eudragit L 100-55. This coating agent is spray coated onto the substrate.

  Non-enteric coating time-dependent release polymers include, for example, one or more polymers that swell in the stomach via absorption of water from gastric juice, thereby creating a thick coating layer and increasing particle size. Time-dependent release coatings generally have erosion and / or diffusion properties that depend on the pH of the external aqueous medium. Thus, the active ingredient is released slowly from the particles by diffusion or following the slow erosion of the particles in the stomach.

The erosion characteristics of the polymer in the stomach resulting from the interaction of the fluid with the surface of the dosage form are mainly determined by the polymer molecular weight and the drug / polymer ratio. It is recommended that the molecular weight of the polymer be about 10 ⁵ to about 10 ⁷ grams / mol to ensure a delay of about 10 to about 60 minutes in the release of the mural cell activator and PPI. Further, the ratio between mural cell activator and polymer or PPI and polymer is about 2: 3 to about 9: 1, preferably about 3: 2 to 9: 1, most preferably about 4: 1 to 9 :. A range of 1 is recommended.

  Suitable non-enteric time-dependent release coatings are, for example, film-forming compounds, such as cellulose derivatives, such as methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, and / or acrylic polymers, Eudragit® ) Includes non-enteric forms of brand polymers. Other film-forming materials may also be used alone or in combination with each other or with one of those listed above. These other film-forming materials are generally poly (vinyl pyrrolidone), zein, poly (ethylene glycol), poly (ethylene oxide), poly (vinyl alcohol), poly (vinyl acetate), and ethyl cellulose, and other Includes pharmaceutically acceptable hydrophilic and hydrophobic film-forming substances. These film-forming materials may be applied to the substrate core using water or a solvent system as the vehicle. Hydroalcohol systems may be used for use as a vehicle for film formation.

  Other materials suitable for making the time-dependent release coating of the present invention include, but are not limited to, water soluble polysaccharide gums such as carrageenan, fucoidan, gatch gum, Gum tragacanth, arabinogalactan, pectin and xanthan; water soluble salts of polysaccharide gums such as sodium alginate, sodium tragacanthin and sodium gum ghattate; water soluble hydroxyalkylcellulose; Where the alkyl moiety is a linear or branched 1 to 7 carbon, such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; a synthetic water-soluble cellulose-based lamina A composition such as methylcellulose and its hydroxyalkylmethylcellulose cellulose derivatives such as those selected from the group consisting of hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and hydroxybutylmethylcellulose; other cellulose polymers such as sodium carboxymethylcellulose; and Other materials known to those skilled in the art. Other laminating substances that can be used for this purpose are poly (vinyl pyrrolidone), polyvinyl alcohol, polyethylene oxide, mixtures of gelatin and polyvinyl pyrrolidone, gelatin, glucose, saccharides, povidone, copovidone, poly (vinyl pyrrolidone) poly ( Vinyl acetate) copolymers.

  In a specific example, the composition of the invention is formulated as a single dosage form comprising a number of beads in a hard gelatin capsule. The capsule comprises a mixed population of beads selected from: beads containing enteric coated PPI or beads containing PPI coated with a time-dependent release polymer and coated with either hydroxypropyl methylcellulose or alginate A bead comprising a bead comprising one or more small carboxylic acids. The rate of carboxylic acid release is determined by the thickness and erosion rate of hydroxypropyl methylcellulose.

  In yet another example, the composition of the present invention comprises a pressure coating or double coating comprising an enteric coated PPI in one layer and a small carboxylic acid coated with hydroxypropylmethylcellulose in the second layer. It is formulated as an agent.

  In a further example, the composition of the present invention is liquid above room temperature and forms a semi-solid upon cooling, thereby filling a hard gelatin capsule, where the PPI is lipid-based (non-aqueous, rapid release) And may be formulated as a non-aqueous semi-solid bilayer filled in hard gelatin capsules.

  The active ingredient of the present invention may be formulated in a dosage form in which the mural cell activator is separated and in a multiple oral dosage form that is administered together with PPI. For example, the parietal cell activator may be formulated in an oral suspension, or a solid dosage form, such as a capsule, tablet, suspension tablet or effervescent tablet, and the PPI is in another solid dosage. It may be formulated into an enteric coated bead or time dependent release bead contained in a form, preferably a capsule or tablet.

  When using a multiple oral dosage form, the mural cell activator can be administered prior to, simultaneously with, or after the PPI. In sequential administration, when the PPI is administered or activated, the parietal cell activator is some substantial (eg, minutes or hours) long enough to exert some physiological effect. ) There may be a delay between administration of mural cell activator and PPI. In preferred embodiments, the administered PPI is in an enteric coating or time-dependent release form. According to this embodiment, to ensure that the PPI absorbed at the proximal site of the small intestine is obtained to inhibit H + / K + -ATPase while the mural cell activator is already active in mural cells. Preferably, PPI administration precedes administration of the mural cell activator.

It is also possible to add a buffer to the formulation to facilitate the release of PPI from the enteric coated pellet, thereby increasing the absorption of PPI into the blood. In particular, a buffering agent such as sodium bicarbonate may be added in an amount sufficient to bring the pH of the stomach to 5 or higher. For example, 300 to 2000 mg of sodium bicarbonate may be added to the formulation. Non-enteric PPI pellets can also be used in the formulation if rapid absorption of PPI into the blood is required. In this case, the stability of the PPI in the stomach will be protected due to a buffer that makes the stomach pH 5 or higher. Rapid absorption of PPI in the blood can be absorbed into the systemic reflux when the mural cell activator has direct activity in mural cells through the gastric lumen, or through the stomach. This is particularly important. In this case, it is recommended that the retention of mural cell activators in the stomach be extended to allow local activity or for absorption through the stomach.
Prolonging the retention time of the mural cell activator in the stomach is possible, for example, by using a dosage form that rapidly expands in the stomach to a size that resists emptying the stomach. Such systems will maintain their integrity over an extended period of time and will not empty from the stomach at all until degradation into small parts occurs. Caldwell (Caldwell, LJ, Gardener, CR, Cargill, RC (1988), US Pat. No. 4,767,627) is a cloth made of an erodible polymer and loaded with a drug folded and inserted into a hard gelatin capsule Describe the shape device. Following oral administration, the gelatin shell collapses and the folded device opens. If the minimum size is 1.6 cm and the maximum size is 5 cm, it will not pass through the stomach through the pylorus until the polymer is eroded by the time that the system is small enough to pass through the stomach.

  An alternative approach for extended retention time of mural cell activators in the stomach is to use lipophilic erodible polymer systems such as poly (ethylene oxide) (polyoxy) and hydroxypropylmethylcellulose (HPMC) It is a convenient size for administration to humans. Ingesting liquids, the system will expand to a size that facilitates extending gastric retention in a short time, and continuously deliver the contained drug to the upper gastrointestinal absorption site Enable. Because these systems are made from erodible and hydrophilic polymers or polymer blends, they are easily eroded beyond a reasonable time to pass through the stomach. The extended time is such that it does not occur in the esophagus, and if the system reaches the intestine in a partially expanded state, the erodible and elastic properties of the hydrated polymer Will eliminate the chance of intestinal damage.

  The active ingredients of the present invention may be incorporated into inert pharmaceutically acceptable beads. In this case, the drug (s) may be mixed with further ingredients prior to coating the beads. Ingredients include, but are not limited to, binders, surfactants, fillers, disintegrants, alkaline additives or other pharmaceutically acceptable ingredients, alone or as a mixture. Binders include, for example, cellulose such as hydroxypropylmethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose, polyvinylpyrrolidone, sugars, starches and other substances with pharmaceutically acceptable binding properties. Suitable surfactants include pharmaceutically acceptable nonionic or ionic surfactants. An example of a suitable surfactant is sodium lauryl sulfate.

  The particles may be formed into a packed mass for consumption by conventional techniques. For example, the particles may be encapsulated as “hard-filled capsules” using known encapsulation methods and materials. The encapsulating material should be highly soluble in gastric juice so that the particles are rapidly dispersed in the stomach after the capsule is ingested.

  In another embodiment, the active ingredient of the present invention is packaged in a compressed tablet. “Pressurized tablets” generally refer to flat, uncoated tablets for oral consumption and are prepared by a single press or pre-compression tapping followed by a final press. Such solid forms are produced as is well known in the art. Tablet forms include, for example, one or more lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, gum arabic, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid and other additives. Contains excipients, colorants, diluents, buffers, humidifiers, preservatives, flavoring agents and pharmaceutically compatible carriers. The manufacturing method may be used in one of the following four established methods or a combination thereof: (1) dry mixing; (2) direct pressing; (3) kneading: and (4) non-aqueous. Granulation. Lachman et al., The theory and Practice of Industrial Pharmacy (1986)). Such tablets may also include a film coating, which preferably dissolves upon oral ingestion or upon contact with a diluent.

  In another alternative embodiment, the composition of the present invention is formulated in a compressed form, such as a suspension tablet and an effervescent tablet, reacted with water or other diluent, and then the aqueous composition. Formulated so that the form is made for oral administration. These forms are particularly useful for medication to children and the elderly and others who are more tolerable than swallowing or chewing tablets. The pharmaceutical tablet or other solid dosage form disintegrates with minimal shaking or diffusion into the alkaline agent.

  As used herein, the term “suspension tablet” rapidly disintegrates after being placed in water to form a suspension containing the correct dose of PPI and the mural cell activator. Refers to a compressing agent that is easily dispersed. In order to achieve rapid disintegration of the tablet, a disintegrant, such as croscarmellose sodium, may be added to the formulation. The disintegrant may be combined in a compressed tablet formulation alone or in combination with microcrystalline cellulose, which is well known for its ability to improve compressibility where it is difficult to compress the tablet material. Microcrystalline cellulose, either alone or co-processed with other ingredients, is also a common additive for compressed tablets and is well known for its ability to improve compressibility, making it difficult to compress tablet materials . It is commercially available as Avicel (R).

  In addition to the ingredients described above, the suspension tablet composition contains other ingredients, seasonings, sweeteners, flow aids, lubricants or other conventional tablet aids often used in pharmaceutical tablets. Ingredients may be included, as will be apparent to those skilled in the art. Other disintegrants such as crospividone and sodium starch glycolate may be used, but croscarmellose sodium is preferred.

  In addition to the above ingredients, the above oral dosage forms may contain other substances in appropriate amounts, such as diluents, lubricants, binders, granulation aids, colorings customary in the pharmaceutical art. Agents, fragrances and glidants may be included. The amount of these additional substances will be sufficient to give the desired effect for the desired formulation. Pharmaceutically acceptable carriers and excipients that can be used for the formulated oral dosage form are the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). Which is incorporated by reference herein.

  For parenteral administration, the active ingredient is administered by either intravenous, subcutaneous or intramuscular injection in a composition comprising a pharmaceutically acceptable vehicle or carrier. For administration by injection, the active ingredient is preferably used in solution in a sterile aqueous vehicle, the sterile aqueous vehicle containing other solutes such as buffers or preservatives, as well as solutions that are isotonic with blood. A sufficient amount of a pharmaceutically acceptable salt or glucose may be included to prepare. In formulating the pharmaceutical composition in the form of a solution or suspension, any diluent customarily used in the art can be used. Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose or glycerol may be combined with the therapeutic agent in an amount sufficient to produce an isotonic solution. The therapeutic agent may further contain conventional solubilizers, buffers and preservatives, and optionally coloring agents, fragrances, flavoring agents, sweetening agents, and other pharmacologically active agents known in the art.

  The dose of the small carboxylic acid molecule of the present invention depends on the type of disease, the severity of the condition to be treated, etc., and may be about 1 to 100 mg per human adult by parenteral administration with multiple doses per day.

  The following examples are presented in order to more fully illustrate certain embodiments of the invention. They should in no way be construed as limiting the broad scope of the invention. Those skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

EXAMPLE [Example 1] Stimulation of gastric acid secretion following oral administration of sodium succinate in rats Rats were administered 15 mg / kg sodium succinate using gavage. After 30 minutes, the rats were anesthetized with ketamine / domitor and the pylorus was ligated. After an additional 60 minutes, gastric juice was collected from the gastric lumen. Acid excretion was measured by titration with NaOH. Total acid excretion expressed in mEq HCl was calculated by multiplying the volume of the sample by the acid concentration. Results were expressed as mean ± SEM of 12 animals from each experimental group. As shown in FIG. 1, oral administration of sodium succinate significantly promoted gastric acid secretion in pyloric ligated rats.

[Example 2] Succinic acid promotes the inhibitory effect of pantoprazole on gastric acid secretion In order to examine the effect of succinic acid on the inhibition of gastric acid secretion by pantoprazole, an experimental model of conscious pyloric ligation rats was used. This experimental model makes it possible to analyze the effect of drugs on gastric acid secretion in conscious animals and to avoid the effect of anesthesia on gastric acid secretion. The case of pantoprazole alone (10 mg / ml) and succinic acid (15 mg / ml) was analyzed by oral gavage. Water was administered as a placebo. After 15 minutes, the animals were anesthetized using an anesthetic gas machine for a short time (5 minutes) sufficient to perform and close the pyloric ligation procedure. The animals were then returned to their cages for an additional 90 minutes and sacrificed. Ligation was performed around the esophagus, the stomach was removed, and stomach contents were collected. Following centrifugation, gastric emptying and pH of gastric juice samples were measured. Data were expressed as mean ± SD of gastric emptying and pH value. The number of animals is 4 to 8 in each experimental group.

  As shown in FIG. 2, administration of succinic acid and pantoprazole (panto) resulted in higher pH values in gastric juice samples than pantoprazole alone. FIG. 3 further shows that the administration of pantoprazole and succinic acid led to lower gastric emptying in the stomach compared to pantoprazole alone. These results indicate that succinic acid enhances the effect of pantoprazole in inhibiting gastric acid secretion. As shown in FIG. 4, maleic acid (14.7 mg / kg) also promotes the inhibitory effect of pantoprazole (3 mg / kg) on gastric acid secretion.

  The possibility that succinic acid induces gastric acid secretion via local effects in the gastric lumen was tested in animals administered sodium succinate to animals after pyloric ligation. Under these conditions, sodium succinate exerts local action in the stomach. As shown in FIG. 5, sodium succinate induces acid secretion via local action in the gastric lumen when administered after ligation. However, succinic acid may have been absorbed into the systemic circulation through the gastric lumen.

[Example 3] Oral preparation containing proton pump inhibitor (PPI) and succinic acid [hard gelatin capsule]
Hard gelatin capsules may contain a granule population mixed with succinic acid (ScA) and PPI. ScA granules are immediate release or delayed release formulations and PPIs are enteric coated granules or time dependent release coatings (delayed release). The granules may be packaged in hard gelatin capsules in an amount corresponding to 40 mg PPI and 200 mg ScA per capsule.

A) Immediate release ScA formulation:
40 mg enteric coating (Eudragit) or time-dependent release coating (HPMC) PPI granules;
200 mg ScA granules;
Diluent.

B) Delayed release ScA formulation:
40 mg enteric coating or time-dependent release coated PPI granule 200 mg ScA granule (HPMC coating);
Diluent.

  For delayed release ScA formulations, ScA solution is sprayed onto inert beads on a fluid bed apparatus. After drying, the ScA beads are further coated with hydroxypropyl methylcellulose (HPMC) to form the final granules. ScA release rate is determined by HPMC thickness and erosion rate. ScA is intended to be released from the coated beads 10 minutes after administration.

[Tablets or capsules]
The pharmaceutical composition may be in the form of a tablet or more preferably a capsule. The capsules are to be pressurized to ScA (immediate release or delayed release as described above), enteric coated or time dependent release coated PPI (stable under pressure) and capsule formulation as a mixed granule mass. Conventional tablet adjuvants.

[Minitab in hard gelatin capsule (stomach maintenance dosage form)]
ScA is granulated with a combination of Polyox WSR N60 and HPMC K100M. These granules are further combined with lactose and HPMC and later pressed into minitabs that can rapidly expand to a size large enough to be retained in the stomach. The polymer matrix controls ScA release into the stomach.

  The ScA minitab is mixed with enteric coated PPI pellets and filled into hard gelatin capsules. Following degradation of the capsule gelatinous body, the PPI pellet passes through the duodenum through the stomach and the enteric coating dissolves. The ScA minitabs remain in the stomach and slowly release their contents in a controlled release gastric retention mode.

[Press coated tablets]
The inner core of the tablet is composed of ScA combined with a mixture of hydrogels that assists in controlled release and facilitates the expansion of the dosage form. The expanded core has gastric retention properties. Gum-like mixtures: xanthan gum, gellan gum: may be applied with cellulose derivatives such as sodium carboxymethylcellulose or HPMC.

  The core is further coated with an outer layer consisting of enteric-coated PPI pellets (stable under pressure) and the appropriate fillers that accompany it, and is rapidly disintegrated after digestion to quickly remove the PPI. discharge. The end product consists of an inner controlled release ScA core and an immediate release outer layer with an enteric coating or a time-dependent release coating PPI.

[Pulse release dosage form]
Hard gelatin capsules are filled with:
a) ScA granules combined with HPMC K100M and vitamin E-TPGS, combined with sodium chloride (osmotic agent to attract water to the capsule) b) Hydrogel-like polyox WSR N60, with a mixture of carboxymethylcellulose Intumescent layer c) Enteric coating or time-dependent release coating PPI pellets d) Optionally, 300 to 2000 mg of sodium bicarbonate granules may be added.

  The capsule body is coated with a non-soluble coating layer such as ethyl cellulose or cellulose acetate. After digestion, the central layer hydrates and expands, facilitating the release of PPI pellets into the stomach. The ScA remains in the capsule and acts as a controlled release dosage form retained in the stomach, while the release is controlled by the hydrogel layer.

[Powder for oral suspension]
Powders for oral suspensions include ScA and enteric coated or time dependent release coated PPI granules. ScA granules may be rapid release or delayed release formulations (as described above). PPIs are formulated as enteric coatings or time-dependent release coated granules (delayed release). The compositions are individually packed to make up with water. When mixed with water, the powder becomes a uniform suspension.

[Injectable preparation]
PPI and succinic acid solutions are prepared by dissolving succinic acid in a phosphate buffered saline. For the preparation of a physiological phosphate buffered saline solution for PPI and succinic acid solutions, a concentrated (20 ×) solution of phosphate buffered saline (PBS) is diluted to obtain a 1 × solution. A 20X PBS solution is prepared by dissolving the following reagents in enough water to make a 1000 mL solution: sodium chloride, 160 grams; potassium chloride, 4.0 grams; sodium hydrogen phosphate, 23 grams; diphosphate Potassium hydrogen, 4.0 grams; and optional phenol red powder, 0.4 grams. The PBS solution is then sterilized in an autoclave for 15 minutes at 15 pounds pressure, diluted with sterile water and brought to a concentration of 1 prior to dissolution of PPI and succinic acid. To prepare a dosage form for intravenous administration, PPI and succinic acid were dissolved in 1 × PBS at concentrations of 0.2 mg and 1 mg / mL, respectively, and the resulting solution (200 mL) was added to the compound intravenously. Dispense into sealable translucent plastic bags for use in administration. These steps are performed under sterile conditions.

  Those skilled in the art will recognize that the present invention is not limited to the scope particularly shown and described herein above. Rather, the scope of the present invention is specified by the claims.

Claims (23)

A pharmaceutically effective amount as an active ingredient, (i) one or more small carboxylic acid molecules or salts thereof that activate mural cells; and (ii) an irreversible gastric H ⁺ / K ⁺ -ATPase proton pump inhibitor A pharmaceutical composition comprising (PPI), wherein the small carboxylic acid molecule is in an amount sufficient to activate mural cells located in the gastric lumen.   The pharmaceutical composition according to claim 1, wherein the small carboxylic acid molecule is a saturated or unsaturated monocarboxylic acid, dicarboxylic acid or tricarboxylic acid molecule having 3 to 6 carbon atoms.   The pharmaceutical composition according to claim 2, wherein the small carboxylic acid molecule is one or more of: maleic acid, succinic acid, pyruvate, citrate, fumarate, α-glutarate, succinyl CoA and Oxaloacetate, or any derivative or salt thereof.   The pharmaceutical composition according to claim 1, wherein the release of the active ingredient is controlled so that the activity of the PPI is synchronized with the activity of the mural cell activator.   A pharmaceutical composition according to claim 4 in a form suitable for oral administration.   6. The pharmaceutical composition according to claim 5, wherein the amount of one or more small acid molecules is 50 to 300 mg.   6. The pharmaceutical composition according to claim 5, wherein the active ingredient is formulated into a single unit oral dosage form selected from the following: bilayer tablet, press-coated tablet, multiparticulate capsule , Effervescent tablets, suspension tablets, solutions and suspensions.   8. The pharmaceutical composition according to claim 7, wherein the active ingredient is granulated into beads coated with an enteric coating, or timed to synchronize between the activity of the carboxylic acid molecule and the PPI. A pharmaceutical composition which is a dependent release polymer.   9. A pharmaceutical composition according to claim 8, wherein the time-dependent release polymer comprises at least one polymer that swells in an aqueous environment.   10. A pharmaceutical composition according to claim 9, wherein the at least one polymer is selected from the group comprising: synthetic polymers and cellulose-based polymers, or substituted derivatives thereof.   2. The pharmaceutical composition of claim 1, wherein the ratio of one or more small carboxylic acid molecules to PPI is from about 20: 1 to about 1:50.   The pharmaceutical composition of claim 1, wherein the PPI is selected from the group consisting of: rabeprazole, omeprazole, isomeurazole, lansoprazole, pantoprazole, leminoprazole, tenatoprazole, single of these Enantiomers, their alkali salts and mixtures thereof.   2. A pharmaceutical composition according to claim 1, wherein the composition further comprises an amount of buffer sufficient to provide basic pH in the stomach, or an amount of an anti-bacterial agent effective against the presence of bacteria in the stomach. A pharmaceutical composition comprising a substance. A pharmaceutically effective amount of (i) one or more small carboxylic acid molecules or any salt thereof as an active ingredient; and (ii) an irreversible gastric H ⁺ / K ⁺ -ATPase proton pump inhibitor (PPI). A pharmaceutical kit comprising, wherein the small carboxylic acid molecule is in an amount effective to activate mural cells located in the gastric lumen.   15. The kit according to claim 14, wherein the active ingredient is formulated in a separate unit dosage form.   16. The kit according to claim 15, wherein the active ingredient is in a unit dosage form separated.   A method for reducing gastric acid secretion in a mammal comprising administering an effective amount of one or more small carboxylic acid molecules or any salt thereof together with an effective amount of a proton pump inhibitor (PPI). Wherein the small carboxylic acid molecule is an amount that activates parietal cells located in the gastric lumen with PPI, thereby reducing gastric acid secretion in a mammal.   18. The method of claim 17, wherein the disease is selected from the group consisting of: reflux esophagitis, gastritis, duodenal inflammation, gastric ulcer, duodenal ulcer, non-steroidal anti-inflammatory drug (NSAID) related Pathology, non-ulcer dyspepsia, gastro-esophageal reflux disease, gastrinoma, acute upstream gastrointestinal bleeding, stress ulcer, Helicobacter pylori infection, Zollinger-Ellison syndrome (ZES), Werner syndrome, and systemic mastocytosis.   18. The method of claim 17, wherein the mammal is a human subject.   18. The method of claim 17, wherein the one or more small carboxylic acid molecules are administered prior to or subsequent to the administration of the PPI.   18. The method of claim 17, wherein the one or more small carboxylic acid molecules are selected from: maleic acid, succinic acid, pyruvic acid, citric acid, fumaric acid, α-ketoglutamic acid, succinic acid, A method which is succinyl CoA and oxaloacetic acid or a derivative or salt thereof.   18. The method of claim 17, wherein the one or more small carboxylic acid molecules are administered via oral administration with an effective amount of PPI.   18. The method of claim 17, wherein the ratio of the one or more small carboxylic acid molecules to PPI is about 20: 1 to 1: 5.

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