EP1658089A2 - Compositions pour le traitement de pathologies qui necessitent la suppression des secretions d'acide gastrique - Google Patents

Compositions pour le traitement de pathologies qui necessitent la suppression des secretions d'acide gastrique

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Publication number
EP1658089A2
EP1658089A2 EP04769171A EP04769171A EP1658089A2 EP 1658089 A2 EP1658089 A2 EP 1658089A2 EP 04769171 A EP04769171 A EP 04769171A EP 04769171 A EP04769171 A EP 04769171A EP 1658089 A2 EP1658089 A2 EP 1658089A2
Authority
EP
European Patent Office
Prior art keywords
beads
gastric
ppi
oral composition
coated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04769171A
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German (de)
English (en)
Other versions
EP1658089A4 (fr
Inventor
Ayelet David
Sabina Glozman
Lada Paul
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vecta Ltd
Original Assignee
Vecta Ltd
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Publication of EP1658089A2 publication Critical patent/EP1658089A2/fr
Publication of EP1658089A4 publication Critical patent/EP1658089A4/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2207—Gastrins; Cholecystokinins [CCK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel oral compositions for inhibition of gastric acid secretion that possess fast onset, prolonged inhibition effect on gastric acid secretion and are meal-independent.
  • a wide number of pathological conditions are characterized by the need to suppress gastric acid secretion. Such conditions include, but are not limited to Zollinger/Ellison syndrome (ZES), gastroesophageal reflux disease (GERD), peptic ulcer disease, duodenal ulcers, esophagitis, and the like. Conditions such as peptic ulcers can have serious complications and represent some of the most prevalent diseases in industrialized nations.
  • the main therapies employed in the treatment of GERD and peptic ulcer diseases include agents for reducing the stomach acidity, for example by using the histamine H 2 -receptor antagonists or proton pump inhibitors (PPI's).
  • PPI's act by inhibiting the parietal cell FT7K + ATPase proton pump responsible for acid secretion from these cells.
  • PPI's such as, omeprazole, and its pharmaceutically acceptable salts are disclosed for example in EP 05129, EP 124495 and US Patent No. 4,255,431.
  • PPI agents are acid-labile pro-drugs that are usually administered in enteric-coated granules. Following their absorption in the small intestine PPIs, which are weak bases, preferentially accumulate within the acid milieu of parietal cells.
  • the acid environment within the acid milieu of parietal cells causes the conversion of the pro-drugs into the active sulfenamids, which are the active agents that bind and inhibit the parietal cell FT7K + ATPase pumps.
  • PPIs have notable limitations. The time of dosing and ingestion of meals may influence the pharmacokinetics of these agents as well as their ability to suppress gastric acid secretion (Hatlebakk et al., Aliment Pharmacol Ther. 2000; 14(10): 1267-72). Specifically, the PPI must be taken prior to ingestion of food in order to achieve optimal suppression of gastric acid secretion.
  • PPIs have a relatively • slow onset of pharmacological action and may require several days to achieve maximum acid suppression and symptom relief, limiting their usefulness in on-demand GERD therapy (Sachs G, Eur J Gastroenterol Hepatol. 2001; 13 Suppl 1:S35-41). Moreover, PPIs fail to provide 24-h suppression of gastric acid and nocturnal acid breakthrough that leads to heartburn pain in GERD patients and occurs even with twice-daily dosing of PPIs (Tytgat GN, Eur J Gastroenterol Hepatol. 2001; 13 Suppl l:S29-33).
  • Pentagastrin ( ⁇ -alanyl-L-tryptophyl-L-methionyl-L- aspartyl-L-phenyl-alanyl amide; SEQ ID NO: 2) is a pentapeptide containing the carboxyl terminal tetrapeptide of gastrin. This carboxyl terminal tetrapeptide is the active portion found in essentially all natural gastrins.
  • PG acts to induce gastric acid secretion mainly via induction of histamine release from enterochromafin-like (ECL) cells residing in the stomach.
  • ECL enterochromafin-like
  • PG acts directly on the parietal cells to induce its activation.
  • PG is typically used in the art as a diagnostic agent for the evaluation of gastric acid secretory function.
  • the '985 publication does, however, disclose genetically that PG and PPI can be administered by intravenous, parenteral, or oral means.
  • the '985 publication also generically discloses that PPI and PG could be prepared in a tablet.
  • the '985 publication does not disclose any particular dosage or formulation that should be used and does not provide any working examples.
  • the '985 publication does not provide any teachings or suggestion how one might avoid the prior art teachings that PG is not effective if delivered orally and provides no examples of suggested oral dosage amounts of PG that would be effective.
  • the '985 publication also does not disclose that PG is active locally in the stomach, which the present inventors surprisingly discovered.
  • the '985 publication also does not teach the use of PG preservation agents to preserve the biological activity of PG activity in the stomach in order to achieve local effect in the gastric lumen.
  • the '985 publication's generic disclosure fails to motive one skilled in the art to prepare an oral composition comprising PG for local delivery.
  • De Graef et al., Gastroenterology, 91, 333-337 (1986) discloses that omeprazole is more effective in inhibiting gastric acid secretion when administered to dogs pretreated intravenously with PG.
  • parietal cell activators disclosed in the Phillips patents include, for example, chocolate, sodium bicarbonate, calcium, peppermint oil, spearmint oil, coffee, tea and colas, caffeine, theophylline, theobromine and amino acids residues. As indicated in the Phillips patents, all these proposed parietal cell activators induce the release of endogenous gastrin that exerts both inhibitory and stimulatory effects on acid secretion.
  • PPI gastric H + /K + - ATPase proton pump inhibitor
  • the oral compositions comprises an irreversible gastric H + /K + - ATPase proton pump inhibitor (PPI) as a gastric acid secretion inhibitor, pentagastrin (PG) and/or a PG analogue as an activator of parietal cells and one or more agents that preserve the availability of PG in the gastric fluids, so that the biological activity of PG is maintained thus enabling PG to act locally in the stomach.
  • PPI gastric H + /K + - ATPase proton pump inhibitor
  • PG pentagastrin
  • PG PG analogue
  • the compositions of the present invention possess anti-acid activity in the stomach that is meal-independent and exhibit fast onset and prolonged inhibition of acid secretion.
  • the present compositions may be used for treating a subject suffering from chronic or acute disorders in which suppression of acid secretion in the stomach is required.
  • the proton pump inhibitors (PPIs) are compounds that inhibit the activity of the l ⁇ 7K + -adenosine triphosphatase (ATPase) proton pump in the gastric parietal cells.
  • PPI is non-ionized and therefore is capable of passing through the cellular membrane of the parietal cells. Once reaching the parietal cells, the non-ionized PPI moves into the acid-secreting portion of activated parietal cells, the secretory canaliculus.
  • the present invention is based on the inventors surprising discovery that PG is active locally when administered orally, preferably by acting locally in the gastric lumen to activate the parietal cells. Active parietal cells possess acidic pH, which is required for the conversion of the PPI to the active protonated sulfenamide form. Therefore, the synchronized activation of the parietal cells by PG acting directly in the gastric lumen maximizes the inhibition of the pumps by the PPI.
  • the oral compositions of the present invention exhibit the following advantages over the known PPI-based compositions aimed to reduce gastric acid secretion.
  • the present compositions permit activation of the parietal cells by PG without any side effects associated with systemic administration of PG due to the local effect of PG in the gastric lumen.
  • Pre- activation of parietal cells by PG facilitates the conversion of the PPI to the active sulfenamide form leading to fast onset of the effect of PPI.
  • the present compositions exhibit fast onset of anti-acid activity in the stomach in a meal-independent manner.
  • the combined active agents in the oral compositions provide an efficient solution for acute conditions in which fast reduction of acid secretion is required.
  • the present oral compositions provide prolonged suppression of gastric acid secretion for at least 24 h using a single medication.
  • the oral compositions according to the present invention comprise PG or a PG analogue as an local activator of parietal cells in the gastric lumen.
  • PG that comprises the amino acid sequence ⁇ Ala-Trp-Met-Asp-PheNH 2 (SEQ ID NO:2)
  • this invention contemplates the use of gastrin or PG analogues or derivatives thereof as parietal cell activators.
  • Such variants include, but are not limited to the 34-, 17-, and 14-amino acid species of gastrin, and other truncation variants comprising the active C-terminal tetrapeptide of gastrin Trp-Met-Asp-PheNH 2 (SEQ ID NO: 1), which is reported in the literature to have full pharmacological activity (see Tracey and Gregory (1964) Nature (London), 204: 935). Also included are variants of gastrin and/or truncated gastrins where native amino acids are replaced with conservative substitutions.
  • compositions according to the present invention further comprise one or more agents that preserve the availability of PG in the acidic gastric fluids.
  • agents preferably are in an amount sufficient to preserve the availability of PG in the gastric fluids by retaining the solubility of PG in the gastric fluids and preventing its degradation, so that the local biological activity of PG in the stomach is preserved. This enables PG to act locally in the stomach to activate the parietal cells.
  • agents are preferably antacids or alkaline agents that when dissolved in the gastric juice are capable of temporally elevating the pH of the gastric fluids to a value in which pepsin is inhibited, thereby inhibiting the degradation of PG in the gastric fluids by pepsin.
  • the temporal elevation of the pH in the gastric fluids ensures that at least significant proportion of PG remains soluble in the gastric fluids.
  • any weak or strong base can be utilized as the alkaline agent in the present oral compositions.
  • the alkaline agent or the antacid is present in the composition in an amount sufficient to substantially preserve the stability and the solubility of PG in the acidic gastric fluids. Therefore, the alkaline agent of the present invention, when dissolved in the gastric juice, is capable of elevating the pH of the stomach to a value sufficient to achieve adequate availability of PG to effect therapeutic action.
  • the alkaline agent in the composition is present in an amount sufficient to elevate the pH of the gastric fluids to a value above 4, and more preferably above 5, for a time period sufficient for PG to reach and activate the parietal cells in the stomach.
  • the alkaline agent is capable of elevating the pH of the gastric fluids to a value above 5 for a time period ranging from 5 to 60 minutes, preferably for a time period ranging from 5 to 30 minutes.
  • the alkaline agent according to the present invention preserves the solubility of PG in the gastric fluids for a time period sufficient for PG to activate the parietal cells.
  • the temporal alkali condition in the gastric fluid prevents the degradation of PG by pepsin that is active only in acidic pH.
  • the present compositions further comprise other agents that preserve the availability of PG in the acidic gastric fluids.
  • agents are for example pepsin inhibitors (i.e., pepstain and its derivative bacitracin -cyclic dodecapeptide) that reduce the degradation of the peptide in the stomach or mucolytic agents that reduce the viscosity of the gastric mucosa, thereby accelerating the ability of PG to reach the cells responsible for acid secretion.
  • Such mucolytic agents are for example reducing agents such as N-acetyl cysteine, dithiothreitol, citric acid or mannitol.
  • the present compositions may further comprise an antibiotic effective against bacteria residing in the stomach.
  • the active ingredients of the present invention may be formulated in a single oral dosage form, preferably a solid dosage form. Liquid dosage forms such as suspensions may be used as well.
  • the PPI, PG and the agent that preserves the availability of PG in the gastric fluids may be formulated as multi-layered tablets, suspension tablets, effervescent tablets, powder, pellets, granules, hard gelatin capsules comprising multiple beads, or soft gelatin capsules containing a lipid-based vehicle.
  • the solid dosage form of the present invention is a capsule or a multi-layered tablet containing PPI particles coated with either enteric pH- dependent release polymers or non-enteric time-dependent release polymers, particles of PG and particles of one or more alkaline agents.
  • the single oral dosage form may comprise PG beads coated with time-dependent release polymer that extends the PG releasing time in the stomach.
  • the extension of PG release in the stomach permits the synchronization between the activity of PG and the activity of the PPI on the parietal cells.
  • the active ingredients of the present invention may also be formulated in separate dosage forms.
  • PG and the agent that preserves the availability of PG in the gastric fluids may be formulated in an oral suspension or a solid dosage form such as capsules, tablets, suspension tablets, or effervescent tablets and the PPI may be formulated in a separate solid dosage form, preferably capsules or tablets comprising beads with enteric pH- dependent release polymers or non-enteric time-dependent release polymers.
  • the separate dosage forms may be provided as a kit containing PG and the agent that preserves the availability of PG in the gastric fluids in one dosage form and the PPI in a separate dosage form. In this case, the PG is administered in conjunction with the PPI so that there is at least some chronological overlap in their physiological activity.
  • the PPI and PG can be administered simultaneously and/or sequentially.
  • the PPI particles used in the present invention may be coated with either enteric pH- dependent release polymer, non-enteric time-dependent release polymer or may be without coating layer.
  • enteric pH- dependent release polymer non-enteric time-dependent release polymer
  • the stability of the non-coated PPI while passing the stomach is preserved by the one or more alkaline agents present in the composition. It was previously demonstrated that the absorption of buffered suspension of non-enteric-coated PPI in the proximal part of the small intestine is faster than the absorption of the enteric-coated PPI granules (Pilbrant and Cederberg, Scand. J. Gastroenterol 1985:20 (supp. 108): 113-120).
  • the present invention is directed to a method of treating a subject suffering from a disorder in which suppression of gastric acid secretion is required or a disorder normally treated by suppression of gastric acid secretion.
  • compositions of the present invention may be used for preventing or treating pathologies in a mammal in which inhibition of gastric acid secretion is required.
  • the mammal is human.
  • the compositions of the present invention are effective both in treating the pathologies and in minimizing the risk of development of such pathologies before onset of symptoms.
  • compositions of the present invention may be used in a wide 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), gastroesophageal reflux disease (GERD), esophagitis, peptic ulcer diseases, duodenal ulcers, gastritis and gastric erosions, dyspepsia, and the like.
  • ZES Zollinger/Ellison syndrome
  • GERD gastroesophageal reflux disease
  • esophagitis peptic ulcer diseases, duodenal ulcers, gastritis and gastric erosions, dyspepsia, and the like.
  • the present invention also includes an oral pharmaceutical kit.
  • the kit typically comprises as active ingredients a pharmaceutically effective amount of: (i) a peptide comprising the amino acid sequence of SEQ ID NO:l; (ii) an irreversible gastric Ff7K + - ATPase proton pump inhibitor (PPI); and (iii) at least one agent that preserves the availability of the peptide in the gastric fluids.
  • the active ingredients are formulated in separate dosage unit forms.
  • the kit may be used to treat or prevent a disorder in a subject in which suppression of gastric acid secretion is required by administering to a subject the active ingredients.
  • the peptide is typically administered simultaneously, prior to or following the administration of the PPI.
  • FIGURES Figure 1 demonstrates that NaHCO 3 preserves PG stability in artificial gastric fluid;
  • Figure 2 demonstrates the percentage of non-degraded PG in various pH values;
  • Figure 3 is a schematic illustration of a double-layered tablet comprising PG, non- enteric-coated omeprazole and buffering agents;
  • Figure 4 is a schematic illustration of PG granules used in the multi particulate capsule formulation;
  • Figure 5 is a schematic illustration of a capsule comprising time release-coated beads;
  • Figure 6 demonstrates that PG stimulates gastric acid secretion in rats in a dose- dependent manner ;
  • Figure 7 demonstrates that PG enhances PPI-mediated effect on gastric acid secretion in rats;
  • Figure 8 demonstrates that Lansoprazole inhibits gastric acid secretion in conscious animals in a dose-dependent manner;
  • Figure 9 demonstrates that PG increases the efficacy of Lansoprazole in the blockade of gastric acid secretion when Lanso
  • alkaline agent refers to any pharmaceutically appropriate weak base or strong base (and mixtures thereof) that, when formulated or delivered with (e.g., before, during and/or after) PG, functions to temporally elevate the pH in the gastric lumen to a value that substantially preserves the availability of PG in the stomach.
  • an agent that preserves the availability of PG in the stomach refers to any agent that is capable of maintaining the solubility and stability of PG in the stomach. Specifically, such an agent is capable of maintaining at least a substantial amount of PG in a soluble form and non-degraded in the gastric juice, so that the biological activity of PG in the stomach is maintained.
  • biological activity of PG in the stomach refers to its activation of parietal cells located in the gastric lumen.
  • the term “in conjunction with” means that when the PPI and the PG are administered in separate dosage forms, there is at least some chronological overlap in their physiological activity.
  • the PPI and PG can be administered simultaneously and or sequentially.
  • the present invention is based on the surprising discovery that PG is capable of remaining active following oral administration to activate the parietal cells, preferably by acting locally in the stomach.
  • parietal cell activation is required for the conversion of the PPI pro-drug to the active form that acts as an irreversible inhibitor of the gastric H + /K + - ATPase proton pump.
  • compositions of the present invention provide a unique combination of active agents that increase the efficacy of the PPI in inhibiting gastric acid secretion.
  • the compositions of the present invention may be used for preventing or treating pathologies in a mammal in which inhibition of gastric acid secretion is required.
  • the compositions of the present invention are effective both in treating the pathologies and in minimizing the risk of development of such pathologies before onset.
  • pathologies include for example: reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer.
  • the compositions of the present invention may be used for treatment or prevention of other gastrointestinal disorders where gastric acid inhibitory effect is desirable, e.g.
  • NSAID nonsteroidal anti-inflammatory drugs
  • GIS nonsteroidal anti-inflammatory drugs
  • GIS nonsteroidal anti-inflammatory drugs
  • ZES Zollinger-Ellison syndrome
  • Werner's syndrome and systemic mastocytosis.
  • the parietal cell activator according to the present invention is preferably PG having the amino acid sequence denoted as SEQ ID NO:2.
  • any PG analog that comprises the C-terminal tetrapeptide of gastrin Trp-Met-Asp-PheNH 2 (denoted as SEQ ID NO:l) may be used as a parietal cell activator.
  • Such analogues include, but are not limited to the 34-, 17-, and 14-amino acid species of gastrin, and other truncation variants. Also included are variants of gastrin and or truncated gastrins where native amino acids are replaced with conservative substitutions.
  • Suitable protecting groups for PG include standard hydroxyl protecting groups known in the art, e.g., methoxymethyl (MOM), ⁇ -methoxyethoxymethyl (MEM), trialkylsilyl, triphenylmethyl (trityl), tert- butoxycarbonyl (t-BOC), ethoxyethyl (EE), f-MOC (methoxycarbonyl), TROC, etc.
  • the protecting group(s) may be removed by using standard procedures generally known to those skilled in the art to give the desired PG derivatives (T. W.
  • PG can be chemically synthesized using well-known peptide synthesis methodologies (see, e. g. Barany and Merrifield Solid- Phase Peptide Synthesis; pp. 3-284 in The Peptides: Analysis, Synthesis, Biology. Vol. 2 : Special methods in peptide synthesis, part a.; Merrifield et al. (1963) J. Am. Chem. Soc, 85: 2149-2156; and Stewart et al. (1984) Solid Phase Peptide Synthesis, 2nd ed. Pierce Chem.
  • compositions of the present invention comprise PG or an analog thereof in an effective amount to achieve a pharmacological effect on the parietal cells without undue adverse side effects.
  • the standard approximate amount of PG present in the compositions is preferably in an amount of 1-100 mg, more preferably 2-60 mg, and most preferably 4-40 mg of PG (or an equivalent amount of a PG analogue).
  • compositions of the present invention further comprise a PPI that acts as an irreversible inhibitor of the gastric FfVK + - ATPase proton pump.
  • the PPI used in the present invention can be any substituted benzimidazole compound having FT 1" , K + -ATPase inhibiting activity.
  • the term "PPI” shall mean any substituted benzimidazole possessing pharmacological activity as an inhibitor of H + ,K + -ATPase, including, but not limited to, omeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, perprazole (s-omeprazole magnesium), donprazole, ransoprazole, pariprazole, and leminoprazole in neutral form or a salt form, a single enantiomer or isomer or other derivative or an alkaline salt of an enantiomer of the same.
  • gastric Ff7K + - ATPase proton pump inhibitors examples include gastric Ff7K + - ATPase proton pump inhibitors.
  • European Patent Nos. 322133 and 404322 disclose quinazoline derivatives
  • European Patent No. 259174 describes quinoline derivatives
  • 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 PPI particles in the compositions according to the present invention may be either coated or non-coated.
  • the preparation of enteric-coated particles comprising a PPI such as Omeprazole is disclosed for example in US Patents Nos. 4,786,505 and 4,853,230.
  • the compositions of the present invention comprise a PPI in an effective amount to achieve a pharmacological effect or therapeutic improvement without undue adverse side effects.
  • a therapeutic improvement includes but is not limited to: raising of gastric pH, reduced gastrointestinal bleeding, or improvement or elimination of symptoms.
  • the typical daily dose of the PPI varies and will depend on various factors such as the individual requirements of the patients and the disease to be treated. In general, the daily dose of PPI will be in the range of 1-400 mg.
  • a preferred standard approximate amount of a PPI present in the composition is typically about 20-40 mg of omeprazole, about 30 mg lansoprazole, about 40 mg pantoprazole, about 20 mg rabeprazole, and the pharmacologically equivalent doses of the following PPIs: donprazole, pariprazole, dontoprazole, ransoprazole, perprazole (s-omeprazole magnesium), and leminoprazole.
  • the compositions of the present invention further comprise one or more agents that preserve the availability of PG in the acidic gastric fluids. More specifically, the preservation agent maintains the stability or the solubility of PG in the gastric fluids.
  • Such agents are preferably alkaline agents or antacids that when dissolved in the gastric juice are capable of elevating the pH of the gastric fluids to a pH in which the gastric-residing peptidases are inhibited and at least significant proportion of PG remains soluble in the gastric fluids.
  • Alkaline agents to be used in the present invention include for example: sodium or potassium bicarbonate, magnesium oxide, hydroxide or carbonate, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminium, calcium, sodium or potassium carbonate, phosphate or citrate, di-sodium carbonate, disodium hydrogen phosphate, a mixture of aluminum glycinate and a buffer, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. It is noted that while sodium bicarbonate dissolves easily in water, calcium carbonate is water-insoluble and is slowly soluble only in acidic environment. Therefore, calcium carbonate may be useful when sustained dissolution of the alkaline agent in the stomach is desired.
  • Antacids to be used in the present invention include one or more of the following: alumina, calcium carbonate, and sodium bicarbonate; alumina and magnesia; alumina, magnesia, calcium carbonate, and simethicone; alumina, magnesia, and magnesium carbonate; alumina, magnesia, magnesium carbonate, and simethicone; alumina, magnesia, and simethicone; alumina, magnesium alginate, and magnesium carbonate; alumina and magnesium carbonate; alumina, magnesium carbonate, and simethicone; alumina, magnesium carbonate, and sodium bicarbonate; alumina and magnesium trisilicate; alumina, magnesium trisilicate, and sodium bicarbonate; alumina and simethicone; alumina and sodium bicarbonate; aluminum carbonate, basic ; aluminum carbonate, basic, and simethicone ; aluminum hydroxide; calcium carbonate; calcium carbonate and magnesia; calcium carbonate, magnesi
  • the compositions of the present invention comprise one or more alkaline agents or antacids in an effective amount to achieve a pharmacological effect.
  • the alkaline agents or antacids in the composition are present in an amount sufficient to elevate the pH of the gastric fluids to a pH above the pH optima for proteases found in the stomach for a time period sufficient for PG to activate the parietal cells in the stomach.
  • the alkaline agents or antacids are present in an amount sufficient to elevate the pH of the gastric fluids to a pH above 5 for a time period ranging from 5 to 60 minutes, preferably for a time period ranging from 5 to 30 minutes.
  • the quantity of alkaline agents required in the compositions of the present invention will necessarily vary with several factors including the type of alkaline agent used and the equivalents of base provided by a given alkaline agent.
  • the amount required to provide good availability of PG in the stomach is an amount which, when added to a solution of 200 milliliters of artificial gastric fluid (prepared according to the United States Pharmacopea (USP) guideline), raises the pH of that HC1 solution to at least pH 5.0.
  • at least 100 milligrams, and more preferably at least 300, and most preferably at least 500 milligrams of the alkaline agents are used in the pharmaceutical compositions of the invention.
  • compositions of the present invention further comprise other agents that preserve the availability of PG in the acidic gastric fluids.
  • the compositions may comprise pepsin inhibitors such as the activated pentapeptide pepstatin and its derivatives, either of natural or synthetic origin. These inhibitors might decrease the degradation of PG by pepsin.
  • the compositions may comprise mucolytic agents that reduce the viscosity of the gastric mucosa, thereby accelerating the ability of PG to reach the parietal cells.
  • mucolytic agents are for example reducing agents such as N-acetyl cysteine, dithiothreitol, citric acid or mannitol.
  • compositions alternatively may also comprise a polymeric coating for PG, such as, an enteric-coating of polymers to protect the PG from the acidic environment of the stomach.
  • the active ingredients of the present invention are preferably formulated in a single oral dosage form containing all active ingredients.
  • the compositions of the present invention may be formulated in either solid or liquid form. It is noted that solid formulations are preferred in view of the improved stability of solid formulations as compared to liquid formulations.
  • the PPI particles, PG and the one or more agents that preserve the availability of PG in the gastric fluids are formulated in a single solid dosage form such as multi-layered tablets, suspension tablets, effervescent tablets, powder, pellets, granules or capsules comprising multiple beads.
  • the active agents may be formulated in a single liquid dosage form such as suspension containing all active ingredients or dry suspension to be reconstituted prior to use.
  • the PPI particles and the PG particles may be coated with either enteric pH-dependent release polymer or non-enteric, time-dependent release polymer in order to synchronize between the local biological activity of PG in the stomach and the systemic effect of the PPI on parietal cells.
  • enteric pH-dependent release polymer or non-enteric, time-dependent release polymer in order to synchronize between the local biological activity of PG in the stomach and the systemic effect of the PPI on parietal cells.
  • coated PPI particles are used resulting in delayed absorption in blood, it is desirable that the PG particles be coated as well to delay its release.
  • the PPI particles are coated with a thick non- enteric layer so as the release of the PPI is preferably delayed by between, 20-80 min, more preferably 25-75 min, most preferably 30-60 min, and the PG particles are coated with a thin non-enteric polymer layer so as the release of PG is preferably delayed by 5-60 min, more preferably between 8-45 min, and most preferably 10-30 min.
  • These conditions permit pre- activation of the parietal cells by PG prior to the achievement of a pharmacological PPI plasma concentration.
  • Non-limiting examples of suitable pH-dependent enteric polymers to be used in the present invention are: cellulose acetate phthalate, hydroxypropylnethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures of any of the foregoing.
  • a suitable commercially available enteric material for example, is sold under the trademark Eudragit L 100-55. This coating can be spray coated onto the substrate.
  • Non-enteric time-dependent release polymers include, for example, one or more polymers that swell in the stomach via the absorption of water from the gastric fluid, thereby increasing the size of the particles to create thick coating layer.
  • the time-dependent release coating generally possesses erosion and/or diffusion properties that are independent of the pH of the external aqueous medium.
  • the active ingredient is slowly released from the particles by diffusion or following slow erosion of the particles in the stomach.
  • the erosion properties of the polymer in the stomach resulting from the interaction of fluid with the surface of the dosage form are determined mainly by the polymer molecular weight and the drug/polymer ratio. In order to ensure a delay of between about 10 min to about 60 min in the release of PG and PPI, it is recommended that the molecular weight of the polymer be in the range from about 10 to about 10 gram/mol.
  • PG or PPI/polymer ratio be in the range of about 2:3 to about 9:1, preferably about 3:2 to 9:1, and most preferably about 4:1 to 9:1.
  • Suitable non-enteric time-dependent release coatings are for example: film-forming compounds such as cellulosic derivatives, such as methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, and/or acrylic polymers including the non- enteric forms of the Eudragit brand polymers.
  • film-forming compounds such as cellulosic derivatives, such as methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, and/or acrylic polymers including the non- enteric forms of the Eudragit brand polymers.
  • Other film-forming materials may be used alone or in combination with each other or with the ones listed above.
  • These other film forming materials generally include poly(vinylpyrrolidone), Zein, poly(ethylene glycol), poly(ethylene oxide), poly( vinyl alcohol), poly(vinyl acetate), and ethyl cellulose, as well as other pharmaceutically acceptable hydrophilic and hydrophobic film-forming materials.
  • film-forming materials may be applied to the substrate cores using water as the vehicle or, alternatively, a solvent system. Hydro-alcoholic systems may also be employed to serve as a vehicle for film formation.
  • Other materials which are suitable for making the time-dependent release coating of the invention include, by way of example and without limitation, water soluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, pectin, and xanthan; water-soluble salts of polysaccharide gums such as sodium alginate, sodium tragacanthin, and sodium gum ghattate; water-soluble hydroxyalkylcellulose wherein the alkyl member is straight or branched of 1 to 7 carbons such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; synthetic water-soluble cellulose-based lamina formers such as methyl cellulose and its hydroxyalkyl methylcellulose cellulose derivatives such as a member selected from the
  • lamina forming materials that can be used for this purpose include poly(vinylpyrrolidone), polyvinylalcohol, polyethylene oxide, a blend of gelatin and polyvinyl-pyrrolidone, gelatin, glucose, saccharides, povidone, copovidone, poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer.
  • Another approach for delaying the release of PG in the stomach is the use of floating particles having density lower than the gastric fluid, thereby delaying the release of PG from the particles.
  • floating particles are obtained by the release of carbon dioxide within ethylcellulose-coated sodium bicarbonate beads upon contacting with the gastric juice.
  • Caldwell Caldwell, L. J., Gardener, C. R., Cargill, R. C. (1988), U.S. Pat. No. 4,767,627) describes a cross shaped device made of erodible polymer and loaded with drug which is folded and inserted into a hard gelatin capsule. Following oral administration the gelatin shell disintegrates and the folded device opens out. With a minimum size of 1.6 cm and a maximum size of 5 cm it will not pass from the stomach through the pylorus until the polymer erodes to the point where the system is sufficiently small that it can be passed from the stomach.
  • An alternative approach to prolong the retention time of PG in the stomach is to use a hydrophilic erodible polymer system such as Poly(ethylene oxide) (Polyox) and Hydroxypropyl-methylcellulose (HPMC) that is of a convenient size for administration to humans.
  • a hydrophilic erodible polymer system such as Poly(ethylene oxide) (Polyox) and Hydroxypropyl-methylcellulose (HPMC) that is of a convenient size for administration to humans.
  • Poly(ethylene oxide) Polyox
  • HPMC Hydroxypropyl-methylcellulose
  • the composition of the present invention is formulated as a single dosage form comprising multiple beads contained in hard or soft gelatin capsules.
  • the capsules contain mixed population of beads selected from: beads comprising enteric-coated PPI or beads comprising PPI coated with time-dependent release polymer, beads comprising calcium carbonate and beads comprising ethylcellulose sodium bicarbonate beads coated with PG, calcium carbonate and hydroxypropyl methylcellulose.
  • the cellulose-based polymer in the composition permits the floating of the PG beads, thus delaying the release of PG from the beads.
  • the rate of PG release is determined by the thickness and the erosion rate of the hydroxypropyl methylcellulose.
  • the gelatin capsules contain mixed population of beads selected from: beads comprising enteric-coated PPI or beads comprising PPI coated with time-dependent release coating, beads comprising calcium carbonate and beads comprising alginate coated with PG, calcium carbonate and hydroxypropyl methylcellulose.
  • the gelatin capsules contain mixed population of beads selected from: beads comprising enteric-coated PPI, beads comprising PPI coated with time-dependent release polymer, beads comprising calcium carbonate and particles in the form of mini-tabs comprising PG, calcium carbonate and hydroxypropyl methylcellulose.
  • the compositions of the present invention are formulated as press-coat or double-layered tablets comprising enteric-coated PPI in one layer and PG, calcium carbonate and hydroxypropyl methylcellulose in a second layer.
  • compositions of the present invention may be formulated as two layer non-aqueous semi-solid fill into hard gelatin capsules in which the PPI is solubilized in a lipid base (non-aqueous, quick release) which is liquid above room temperature but forms a semi-solid on cooling and can therefore be filled into hard gelatin capsules.
  • a lipid soluble alkaline agent such as an amine or a fine suspension of sodium bicarbonate may be included as well.
  • the single dosage form compositions of the present invention preferably comprise non-coated PPI instead of the enteric-coated PPI particles or the time-dependent release particles. The absorption of non-coated PPI in the upper portion of the small intestine is faster than the absorption of the coated PPI.
  • the use of non-coated PPI in the compositions permits more precise synchronization between the biological activity of PG in the stomach and the time period in which the PPI is active without the need for delaying the release of PG.
  • the compositions according to the present invention are formulated as double-layered tablets, press-coat tablets, effervescent tablets or suspension tablets comprising PG, non-coated PPI and one or more alkaline agents.
  • the active ingredients of the present invention may be formulated in a multiple oral dosage forms in which PG and the one or more agents that preserve the availability of PG in the gastric fluids are administered in a separate dosage form but in conjugation with the PPI.
  • PG and the one or more agents that preserve the availability of PG in the gastric fluids may be formulated in oral suspension or a solid dosage form such as capsules, tablets, suspension tablets, or effervescent tablets and the PPI may be formulated in a separate solid dosage form, preferably enteric-coated beads or time-dependent release beads contained in capsules or tablets.
  • the PG and the one or more agents that preserve the availability of PG in the gastric fluids can be administered before, simultaneously with, or after the PPI. In sequential administration, there may be some substantial delay (e. g., minutes or even few hours) between the administration of PG and the PPI as long as the PG has exerted some physiological effect when the PPI is administered or becomes active.
  • the PPI administered is in the enteric-coated or the time-dependent release form.
  • the PPI administration precedes the PG administration in order to ensure that the PPI absorbed in the proximal part of the small intestine will be available for inhibiting the H + /K + - ATPase pumps while PG is still active in the stomach.
  • the active ingredients of the present invention may be incorporated within inert pharmaceutically acceptable beads.
  • the drug(s) may be mixed with further ingredients prior to being coated onto the beads.
  • Ingredients include, but are not limited to, binders, surfactants, fillers, disintegrating agents, alkaline additives or other pharmaceutically acceptable ingredients, alone or in mixtures.
  • Binders include, for example, celluloses such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and carboxymethyl-cellulose sodium, polyvinyl pyrrolidone, sugars, starches and other pharmaceutically acceptable substances with cohesive properties.
  • Suitable surfactants include pharmaceutically acceptable non-ionic or ionic surfactants.
  • An example of a suitable surfactant is sodium lauryl sulfate.
  • the particles may be formed into a packed mass for ingestion by conventional techniques. For instance, the particles may be encapsulated as a "hard-filled capsule" using known encapsulating procedures and materials. The encapsulating material should be highly soluble in gastric fluid so that the particles are rapidly dispersed in the stomach after the capsule is ingested.
  • the active ingredients of the present invention are packaged in compressed tablets.
  • compressed tablet generally refers to a plain, uncoated tablet for oral ingestion, prepared by a single compression or by pre-compaction tapping followed by a final compression.
  • Such solid forms can be manufactured as is well known in the art. Tablet forms can include, for example, one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmaceutically compatible carriers.
  • the manufacturing processes may employ one, or a combination of, four established methods: (1) dry mixing; (2) direct compression; (3) milling; and (4) non-aqueous granulation.
  • Lachman et al. The Theory and Practice of Industrial Pharmacy (1986).
  • Such tablets may also comprise film coatings, which preferably dissolve upon oral ingestion or upon contact with diluent.
  • alkaline agents which could be utilized in such tablets include sodium bicarbonate, alkali earth metal salts such as calcium carbonate, calcium hydroxide, calcium lactate, calcium glycerophosphate, calcium acetate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum hydroxide or aluminum magnesium hydroxide.
  • compositions of the present invention are formulated in compressed forms, such as suspension tablets and effervescent tablets, such that upon reaction with water or other diluents, the aqueous form of the composition is produced for oral administration. These forms are particularly useful for medicating children and the elderly and others in a way that is much more acceptable than swallowing or chewing a tablet.
  • the present pharmaceutical tablets or other solid dosage forms disintegrate alkaline agent with minimal shaking or agitation.
  • suspension tablets refers to compressed tablets which rapidly disintegrate after they are placed in water, and are readily dispersible to form a suspension containing a precise dosage of the PPI, the PG and the alkaline agent.
  • the suspension tablets may comprise 20-40 mg omeprazole, 4 mg PG and about 1-4 grams of sodium or calcium bicarbonate as an alkaline agent.
  • a disintegrant such as Croscarmellose sodium may be added to the formulation.
  • the disintegrant may be blended in compressed tablet formulations either alone or in combination with microcrystalline cellulose, which is well known for its ability to improve compressibility of difficult to compress tablet materials.
  • Microcrystalline cellulose 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 of difficult to compress tablet materials. It is commercially available under the Avicel trademark.
  • the suspension tablet composition may, in addition to the ingredients described above, contain other ingredients often used in pharmaceutical tablets, including flavoring agents, sweetening agents, flow aids, lubricants or other common tablet adjuvants, as will be apparent to those skilled in the art.
  • Other disintegrants such as crospividone and sodium starch glycolate may be employed, although croscarmellose sodium is preferred.
  • the oral dosage forms described above may also contain suitable quantities of other materials, e.g.
  • Example 1 NaHC ⁇ 3 preserves PG stability in artificial gastric fluid
  • the stability of PG in acidic pH in the presence of NaHCO 3 was tested in vitro using artificial gastric fluid.
  • Artificial gastric fluid was prepared in accordance with U.S.
  • Example 2 Press-coated or double-layered tablets comprising PG, non-enteric- coated omeprazole, sodium bicarbonate and calcium carbonate Press-coated or double-layered tablets are formulated as a single dosage form in which each tablet containing the following ingredients: Omeprazole (powder) 40 mg
  • HPMC Croscarmellose sodium hydroxypropyl methylcellulose
  • Press-coated or double-layered tablets are prepared in a two-step process.
  • 4 mg PG, 250 mg calcium carbonate and microcrystalline cellulose are mixed and pre-compressed into the first layer of the tablet.
  • the layer containing the PG is further coated with a thin layer of HPMC that permits a delay of 10-15 min in the release of PG from the tablet.
  • 40 mg of non-enteric-coated omeprazole powder together with 500 mg NaHCO3, 250 mg CaCO 3 and the appropriate binders are compressed onto the PG layer to form the second layer of the tablet.
  • the second layer of the tablet disintegrates immediately after digestion to permit prompt release of omeprazole.
  • a schematic illustration of a double-layered tablet comprising PG, non-enteric-coated omeprazole, sodium bicarbonate and calcium carbonate is presented in Figure 3.
  • Example 3 Fast disintegrating tablets comprising PG, non-enteric-coated omeprazole, sodium bicarbonate and calcium carbonate Fast disintegrating tablets are formulated as a single dosage containing the following ingredients:
  • Non-enteric-coated omeprazole 40 mg
  • PG 4 mg
  • NaHCO3, CaCO 3 Croscarmellose sodium
  • Microcrystalline cellulose and Magnesium stearate are mixed and the resulting mixture is compressed into tablets using standard tablet pressing to yield a fast disintegrating tablet (intravescent).
  • Effervescent sacs comprising PG, enteric-coated omeprazole, and sodium bicarbonate Effervescent tablets are formulated as a single dosage containing the following ingredients:
  • Enteric-coated omeprazole 40 mg
  • PG 4mg
  • Enteric-coated omeprazole 40 mg
  • PG 4mg
  • Sodium bicarbonate, citric acid, potassium carbonate and all other excipients are added to the mixture to form a homogeneous mixture of effervescent powder.
  • the resulting powder is mixed with 40mg enteric-coated omeprazole and packed in packets of unit dose.
  • Example 5 Capsules comprising ethylce ⁇ lulose-PG beads, enteric-coated omeprazole beads, and calcium carbonate. This example illustrates the steps involved in manufacturing multi particulate hard gelatin capsules. Hard gelatin capsules are formulated as a single dosage form comprising mixed population of particles. Each capsule contains the following ingredients: 40 mg omeprazole as enteric-coated beads
  • PG solution is prepared by dissolving PG in ammonium carbonate buffer pH 8.
  • the PG solution is sprayed on the ethylcellulose-coated sodium bicarbonate beads in a fluidized bed apparatus. After drying, the PG-sodium bicarbonate beads are further coated with CaCO 3 and with hydroxypropyl methylcellulose (HPMC) to form the final PG particles.
  • the final PG particles are packed together with enteric-coated omeprazole beads and calcium carbonate powder into size 0 hard gelatin capsules in an amount corresponding to 40 mg omeprazole, 4 mg PG and 600 mg calcium carbonate per capsule.
  • the HPMC layer of the PG-containing beads expands and the gastric acid reacts with sodium bicarbonate to form CO 2 inside the bead core.
  • the release of carbon dioxide from the ethylcellulose-coated sodium bicarbonate core permits the buoyancy of the particles, thereby delaying the release of PG and calcium carbonate from the particles.
  • the rate of PG release is determined by the thickness and the erosion rate of the HPMC layer of the PG beads.
  • CaCO 3 increases the gastric pH for a prolonged period of time, to protect PG upon release.
  • the enteric-coated omeprazole beads pass the stomach and omeprazole is absorbed in the upper part of the small intestine without any delay.
  • Example 6 Capsules comprising alginate-PG beads, enteric-coated omeprazole beads, and calcium carbonate
  • Hard gelatin capsules are formulated as a single dosage form comprising mixed population of particles. Each capsule contains the following ingredients:
  • Alginate particles are made by dropping an alginate solution into calcium chloride solution following by freeze-drying to yield alginate particles.
  • the PG solution prepared as in Example 5 is sprayed on the alginate particles in a fluidized bed apparatus. After drying, the PG-alginate beads are further coated with CaCO 3 and with hydroxypropyl methylcellulose (HPMC) to form the final PG particles.
  • the final PG particles together with the enteric- coated omeprazole beads and calcium carbonate powder are packed into size 0 hard gelatin capsules in an amount corresponding to 40 mg omeprazole, 4 mg PG and 600 mg calcium carbonate per capsule.
  • the PG beads are expanded due to the contact of the HPMC layer with the gastric juice.
  • the freeze-dried alginate particles permit the buoyancy of the particles due to their low density thereby delaying the release of PG from the particles.
  • the rate of PG release is determined by the thickness and the erosion rate of the HPMC layer of the PG beads.
  • the enteric-coated omeprazole beads pass the stomach and omeprazole is absorbed in the upper part of the small intestine without any delay.
  • Example 7 Capsules comprising sucrose-PG beads, enteric-coated omeprazole beads, and calcium carbonate Hard gelatin capsules are formulated as a single dosage form comprising mixed population of particles. Each capsule contain the following ingredients:
  • the PG solution is sprayed on inert sugar pellets (Nu-Pareils, 25/30) in a fluidized bed apparatus. After drying, the PG-sugar beads are further coated with CaCO 3 and with hydroxypropyl methylcellulose (HPMC) to form the final PG particles.
  • a schematic illustration of the PG granules is presented in Figure 4.
  • the final PG particles together with the enteric-coated omeprazole beads and calcium carbonate powder are packed into size 0 hard gelatin capsules in an amount corresponding to 40 mg omeprazole, 4 mg PG and 600 mg calcium carbonate per capsule.
  • the PG beads Upon dissociation of the gelatin capsules in the stomach, the PG beads are expanded due to the contact of the HPMC layer of the PG-containing beads with the gastric juice, thereby delaying the release of PG from the particles.
  • the rate of PG release is determined by the thickness and the erosion rate of the HPMC layer of the PG beads.
  • the enteric-coated omeprazole beads pass the stomach and omeprazole is absorbed in the upper part of the small intestine without any delay.
  • Example 8 Hard gelatin capsules comprising HPMC-PG minitabs, enteric-coated omeprazole beads, and calcium carbonate Hard gelatin capsules are formulated as a single dosage form comprising mixed population of particles. Each capsule contains the following ingredients:
  • PG is granulated in combination with HPMC and CaCO 3 and compressed into mini- tabs.
  • the mini-tabs possess the ability of fast swelling upon contact with the gastric juice of the stomach, thereby enabling gastric retention.
  • the release of PG into the stomach is controlled by the erosion rate of the polymeric matrix of the swelled mini-tabs.
  • the PG mini- tabs together with the enteric-coated omeprazole beads are packed into size 0 hard gelatin capsules in an amount corresponding to 40 mg omeprazole, 4 mg PG and 600 mg calcium carbonate per capsule.
  • Example 9 Multi particulate capsules containing Omeprazole and PG beads coated with non-enteric time-dependent release coating: This example illustrates the steps involved in manufacturing multi particulate hard gelatin capsules.
  • Capsules are formulated as a single dosage form comprising mixed population of particles: PG beads coated with time-dependent release coating, omeprazole beads coated with time-dependent release coating, and calcium carbonate.
  • a schematic illustration of the capsule is present in Figure 5.
  • Each capsule contains the following ingredients: • 40 mg omeprazole beads coated with thick HPMC layer • 4 mg PG loaded on sugar spheres and coated with thin HPMC layer • 600 mg calcium carbonate (CaCO 3 )
  • the composition of the coating is designed such that the core is rapidly disintegrated into an aqueous environment when the media come into contact with the core.
  • Sugar sphere will be coated with an antacid (NaHCO 3 or CaCO 3 ) layer.
  • PG solution is prepared by dissolving PG in ammonium carbonate buffer pH 8. The PG solution is sprayed on to the above antacid-coated beads in a fluidized bed apparatus. After drying, the beads are further coated with a thin layer of HPMC to create PG particles with approx. 10 min delayed release.
  • Omeprazole is layered over the antacid-coated Sugar spheres and is covered with a thick time-release HPMC coating.
  • a disintegrant also may be added to the core of the particle to facilitate the prompt release of omeprazole after the HPMC is dissolved.
  • the coated Omeprazole beads are aimed to pass the stomach and are absorbed at the upper parts of the small intestine after the HPMC is dissolved and the Omeprazole is released at once.
  • the final PG particles are packed together with the omeprazole beads and calcium carbonate powder into size 0 hard gelatin capsules in an amount corresponding to 40 mg omeprazole, 4 mg PG and 600 mg calcium carbonate per capsule.
  • the rate of PG and OMP release is determined by the thickness and the erosion rate of the HPMC layer of the beads.
  • CaCO 3 increases the gastric pH for a prolonged period of time, to preserve PG upon release.
  • Example 10 Press-coated tablets comprising PG, enteric-coated omeprazole beads, and calcium carbonate Press-coated tablets are formulated as a single dosage form containing the following ingredients:
  • Press-coated tablets are prepared in a two-step process.
  • 4 mg PG, 900 mg calcium carbonate and HPMC are mixed and pre-compressed into the central core of the tablet.
  • 40 mg of enteric-coated omeprazole beads are press-coated onto the PG core to form the external layer of the tablet.
  • the final tablet is composed of controlled-release PG core layer and immediate release outer layer of omeprazole enteric-coated beads.
  • the active ingredients are compressed into double-layered tablet wherein the first layer comprises 4 mg PG, 900 mg calcium carbonate and HPMC and the second layer comprises 40 mg of enteric-coated omeprazole beads.
  • the compressed tablet may include one or more of the following excipients: lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmaceutically compatible carriers.
  • excipients lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmaceutically compatible carriers.
  • Example 11 Fast disintegrating tablets comprising PG, enteric-coated omeprazole beads and calcium carbonate Fast disintegrating suspension tablets are formulated as a single dosage containing the following ingredients:
  • PG granules are coated with CaCO 3 and with hydroxypropyl methylcellulose (HPMC) to form the final PG particles.
  • the final PG particles are mixed with enteric-coated omeprazole beads and the excipients listed above and the resulting mixture is compressed into tablets using standard tablet pressing.
  • the resulting tablets possess rapid disintegration time and may be swallowed with water for fast disintegration in the stomach.
  • the PG particles Upon disintegration of the suspension tablet, the PG particles are expanded due to the contact of the HPMC layer of the PG-containing beads with aqueous environment, thereby delaying the release of PG from the particles.
  • the rate of PG release is determined by the thickness and the erosion rate of the HPMC layer of the PG beads.
  • the enteric-coated omeprazole beads pass the stomach and omeprazole is absorbed in the upper part of the small intestine without any delay.
  • Example 12 Stimulation of Gastric Acid Secretion Following Oral Administration ofPG in Rats inhibition of gastric acid secretion by a combination of PG and PPI is based on the ability of orally administered PG to trigger acid secretion locally within the stomach.
  • anesthetized rats were administered (per os) with increasing amounts of PG and gastric acid secretion was monitored in a pylorus-ligated stomachs.
  • Increasing amounts (10, 30, and 90 ⁇ g/kg) of PG were administered by oral gavage to pylorus-ligated rats.
  • Example 13 The effect ofPG administered with omeprazole on intragastric pH
  • omeprazole 10 mg/kg alone or in combination with PG (350 ⁇ g/kg). Rats treated with the combination received PG 15 minutes before omeprazole. The gastric juice was collected by suction at 30, 45, and 60 minutes after the treatment and an effect of drags on gastric acid secretion was detected by monitoring pH.
  • Example 14 Lansoprazole inhibits gastric acid secretion in conscious animals in a dose-dependent manner.
  • a different model of pylorus-ligated rats that permits the analysis of the effect of drugs on gastric acid secretion in conscious animals was used. This model eliminates the effect of anesthesia on gastric acid secretion.
  • the study drugs alone or in combination were administered per os.
  • One or two hours later the animals were anesthetized using anesthetic gas machine for a short period (5 minutes) that is sufficient to perform the pylorus ligation procedure and to close the abdomen. The animals were then placed back into its cage for recovery.
  • Lansoprazole was administered by oral gavage as a simplified suspension (SLS). SLS was prepared as follows: the content of one 30 mg capsule (Zoton) was suspended in 8.4% sodium bicarbonate. Rats were treated with three doses of Lansoprazole (20, 5 and 1.25 mg/kg) 2 hours before pylorus ligation. 8.4% NaHCO3 was administered into the control group as a placebo.
  • Figure 8 demonstrates that Lansoprazole inhibited the gastric acid secretion in a dose-dependent manner.
  • Example 15 The effect of Lansoprazole administered in combination with PG on gastric acid secretion in conscious pylorus-ligated rats.
  • rats were treated with SLS at a dose 5 mg/kg either 15 minutes before (A) or after (B) PG (300 ⁇ g/kg).
  • the control rats were injected with combination of 8.4% NaHCO3 and PG-vehicle as a placebo. All drags were administered by oral gavage 2 hours before pylorus ligation. The gastric juice was collected during 3 hours. Data is presented as mean ⁇ SEM. Number of animals is 8-9 in each experimental group.
  • the control rats were injected with combination of 8.4% NaHCO3 and PG-vehicle as a placebo. All drugs were administered by oral gavage. The pylorus ligation was performed on third day 2 hours following treatment. The gastric juice was collected during 3 hours. Data is presented as mean ⁇ SEM. Number of animals is 8 in each experimental group. As demonstrated in Figures 10 A and 10B, administration of SLS in combination with PG during 3 consecutive days resulted in significantly higher intragastric pH as compared to SLS alone. Similarly, the gastric acid secretion in rats treated with SLS/PG combination for three consecutive days was lower than that following administration of SLS alone.
  • Example 16 The effect of a CCK-B Antagonist on PG-Mediated gastric acid secretion in rats As PG is a gastrin hormone homologue, its local effect is thought to be mediated via gastrin pathway, i.e. an activation of gastrin receptor (CCKB). To test this hypothesis the effect of the specific CCKB antagonist (Itriglumide) on PG-mediated acid secretion in rats was examined. In this study, rats were anesthetized with Ketamine and Domitor mixture and provided with 20 mg/kg of Itriglumide that was administered intraduodenally (i.d.). Following 15 min, gastric pylorus was ligated and 300 ⁇ g/kg PG was administered into the stomach (i.g.).
  • CCKB gastrin receptor
  • Example 17 The effect of intraduodenal injection of PG on acid secretion in anesthetized pylorus-ligated rats The effect of intraduodenal injection of PG on acid secretion in anesthetized pylorus- ligated rats was examined. In this study, 300 ⁇ g/kg PG was administered intraduodenaly in anesthetized pylorus-ligated rats and the level of gastric acid secretion was determined 30 minutes later. Gastric juice was obtained, centrifuged and the volume and pH of the supernatants were measured.

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Abstract

L'invention porte sur des compositions orales innovantes comprenant un inhibiteur de la pompe à protons (IPP) agissant de manière irréversible comme antisécrétoire sur l'activité l'ATPase H+ K+ des cellules gastriques, de la pentagastrine (PG) ou un analogue de la pentagastrine comme activateur des cellules pariétales de la lumière intestinale. Dans un mode de réalisation préféré, les compositions comprennent en outre au moins un agent qui maintient la disponibilité de la pentagastrine dans les fluides gastriques, ce qui permet à la pentagastrine d'agir localement dans l'estomac. De manière inattendue, les compositions de l'invention démontrent une activité locale antiacide au niveau de l'estomac, indépendamment des repas consommés, et agissent rapidement tout en maintenant une inhibition prolongée des sécrétions d'acide.
EP04769171A 2003-08-27 2004-08-25 Compositions pour le traitement de pathologies qui necessitent la suppression des secretions d'acide gastrique Withdrawn EP1658089A4 (fr)

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JP2007506730A (ja) * 2003-09-24 2007-03-22 ベクタ・リミテッド ペンタガストリンを含む胃酸分泌刺激用経口組成物
US7803817B2 (en) * 2005-05-11 2010-09-28 Vecta, Ltd. Composition and methods for inhibiting gastric acid secretion
US7981908B2 (en) 2005-05-11 2011-07-19 Vecta, Ltd. Compositions and methods for inhibiting gastric acid secretion
US20090104264A1 (en) * 2005-12-28 2009-04-23 Takeda Pharmaceutical Company Limited Controlled release solid preparation
SG184754A1 (en) * 2005-12-28 2012-10-30 Takeda Pharmaceutical Controlled release solid preparation
DK2046334T3 (da) 2006-07-25 2014-08-25 Vecta Ltd Sammensætninger og fremgangsmåder til at hæmme mavesyresekretion ved at anvende derivater af små dicarboxylsyrer i kombination med PPI
CA2694602A1 (fr) * 2007-07-27 2009-02-05 Depomed, Inc. Formes medicamenteuses de retention gastrique pulsatile
EP4311542A1 (fr) * 2022-07-27 2024-01-31 Roquette Freres Formes posologiques à languette flottante

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WO2004034957A2 (fr) * 2002-10-14 2004-04-29 Vecta Ltd. Methodes de traitement de troubles associes a helicobacter pylori

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PT1130978E (pt) * 1998-11-17 2005-03-31 Hickory Specialities Inc Metodo para cobrir um produto alimentar com colagenio

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US4910021A (en) * 1985-11-29 1990-03-20 R. P. Scherer Corporation Targeted enternal delivery system
WO2001010405A1 (fr) * 1999-08-04 2001-02-15 Ranbaxy Laboratories Limited Systeme de delivrance orale de medicament a equilibre hydrodynamique
WO2004034957A2 (fr) * 2002-10-14 2004-04-29 Vecta Ltd. Methodes de traitement de troubles associes a helicobacter pylori

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KATHLEEN PARFITT (ED): "Martindale The Complete Drug Reference" 1999, PHARMACEUTICAL PRESS , LONDON, GB , XP002409837 ISSN: 0263-5364 ISBN: 0 85369 429 X * 32nd Edition pages 1204-1206 * *
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EP1658089A4 (fr) 2007-03-14
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AU2004268446A1 (en) 2005-03-10
CA2536906A1 (fr) 2005-03-10
IL173944A0 (en) 2006-07-05
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KR20060083198A (ko) 2006-07-20
WO2005020879A2 (fr) 2005-03-10

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