Classifications

• • 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
  • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • 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
  • 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
  • A61K9/2004—Excipients; Inactive ingredients
• • 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
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

• the present invention is directed to orally administered pharmaceutical compositions that rapidly elevate the gastric pH of a patient.
• the pharmaceutical compositions include at least one H2 blocker and at least one proton pump inhibitor, both of which are released immediately after ingestion.
• the compositions may be used in the treatment of gastrointestinal disorders, and particularly for the treatment of gastroesophageal reflux disease.
• H2 blockers have a relatively rapid onset of action but a short duration of effectiveness (typically 8-12 hours). As a result, these agents provide rapid relief but may not provide sufficient protection for patients with more severe forms of GERD or for patients chronically taking NSAIDs.
• H2 blockers currently on the market are: cimetidine (Tagamet®); famotidine (Pepcid®); nizatidine (Axid®); and ranitidine (Zantac®)
• Proton pump inhibitors inhibit the enzyme responsible for secreting acid into the stomach and typically have a duration of action long enough that they only need to be taken once a day.
• proton pump inhibitors are acid labile. As a result, they are usually enterically coated and this contributes to a very slow onset of effectiveness (see
• proton pump inhibitors examples include: omeprazole (Prilosec®); esomeprazole (Nexium®); lansoprazole (Prevacid®); pantoprazole (Protonix®); rabeprazole (Aciphex®), tenatoprazole and s-tenatoprazole.
• "Reversible proton pump inhibitors” and “acid pump antagonists” that are less susceptible to acid degradation include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan (see WO9605177 and WO9605199).
• the present invention is based upon the development of dosage forms for oral administration that provide for both the rapid and long term elevation of gastric pH. This is accomplished by releasing both a PPI and an H2 blocker from the dosage forms immediately after ingestion.
• the dosage forms may be used to treat patients for diseases characterized by abnormal gastric acid secretion, especially gastric esophageal reflux disease.
• the invention is directed to a pharmaceutical composition in unit dosage form for oral administration to a patient which contains both a therapeutically effective amount of a proton pump inhibitor (ppi), and a therapeutically effective amount of an H2 blocker.
• a pharmaceutical composition in unit dosage form for oral administration contains both a therapeutically effective amount of a proton pump inhibitor (ppi), and a therapeutically effective amount of an H2 blocker.
• ppi proton pump inhibitor
• H2 blocker a pharmaceutical composition in unit dosage form for oral administration to a patient which contains both a therapeutically effective amount of a proton pump inhibitor (ppi), and a therapeutically effective amount of an H2 blocker.
• therapeutically effective amount means that, upon ingestion of one or more unit dosage forms by a patient, sufficient drug is present to achieve the desired therapeutic effect.
• a "therapeutically effective amount" of a ppi means that there is a sufficient amount of drug to produce an increase in the median of gastric pH measurements taken at regular intervals over a 24 hour period.
• the dosage forms are designed so that at least 10%, and preferably at least 20% or 50%, of both the ppi and the H2 blocker are released into the stomach of a patient within fifteen minutes, and preferably within ten, five or three minutes, after ingestion as determined using standard in vivo or in vitro methods. Unless otherwise indicated, all percentages herein are weight percentages. For example, in a tablet with 10 mg of a ppi, 10 mg of an H2 blocker and 80 mg of other components, the ppi and H2 blocker would each be present at 10%. Ten percent of both the ppi and the H2 blocker in this tablet would be released when 1 mg of ppi and 1 mg of H2 blocker were released.
• At least 1 mg (and preferably 5 or 10 mg) of a ppi and at least 1 mg (and preferably 5 or 10 mg) of an H2 blocker are released within fifteen minutes and preferably within ten, five or three minutes after ingestion, regardless of the percentage of total drug this represents. Again, the amount released may be determined using either standard in vivo or in vitro methods.
• the ppi and the H2 blocker In order to allow for immediate release, at least a portion (and preferably all) of the ppi and the H2 blocker must be free of agents or barriers that retard dissolution, e.g., at least a portion (and optionally all) of these drugs must not be surrounded by an enteric coating.
• Small amounts of buffer may be present in dosage forms to stabilize the drugs but the total amount of buffer should not exceed 15 mg, and preferably should not exceed 5 mg or 1 mg.
• the pH in the stomach of a patient with a gastric pH of 2.5 or less should rise to 3.5 or higher within 45 minutes, and preferably within 30 or 20 minutes. pH should remain elevated at or above 3.5 for at least 2 hours, and preferably for at least 6, 8, 10, 12 or 16 hours.
• the PPIs used in dosage forms should typically be present at 1-200 mg and are preferably selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole, tenatoprazole, S-tenatoprazole and rabeprazole.
• Particularly preferred are dosage forms having a ppi selected from the group consisting of: omeprazole, present at between 5 mg and 50 mg; esomeprazole, present at 5-100 mg; lansoprazole, present at 15- 150 mg; pantoprazole, present at between 10 mg and 200 mg; and rabeprazole, present at between 5 mg and 100 mg.
• H2 blockers are present in dosage forms at 1-300 mg and are selected from the group consisting of: cimetidine; ranitidine; famotidine; ebrotidine; pabutidine; lafutidine; and nizatidine.
• dosage forms having: cimetidine at 100 to 800 mg; ranitidine at 50-300 mg; famotidine at 5-100 mg; ebrotidine at 400-800 mg/unit dose; pabutidine at 40 mg/unit dose; lafutidine at 5-20 mg; and nizatidine at 50-600 mg.
• the dosage forms may be tablets, capsules or powders and have the ppi and the H2 blocker in admixture.
• the dosage forms may be multilayer tablets in which essentially all of the ppi is in one layer and essentially all of the H2 blocker is in a separate layer.
• the term "essentially all” refers to greater than 90% (and preferably greater than 95% or 99%) of the total amount of a drug present.
• the layer containing the ppi and/or the layer containing said H2 blocker also includes at least one disintegrant and/or a compound that causes effervescence.
• Disintegrants that may be used include: croscarmellose sodium, crospovidone, sodium starch glycolate, povidone, crosslinked polyvinylpyrrolidone, starch, low substituted hydroxymethylcellulose, methylcellulose, micro crystalline cellulose.
• the invention is directed to method of treating a patient for a disease or condition characterized by abnormal gastric acid production, especially gastric acid reflux disease. Treatment involves administering to the patient any of the dosage forms above.
• the invention also includes a method of treating a patient for pain or inflammation, by administering one of the NSAID-containing dosage forms described above.
• a single tablet or capsule would be a unit dosage form.
• “Proton pump inhibitors” are drugs (usually benzimidazole derivatives) that block gastric acid secretion by irreversibly inhibiting H /K + ATPase. Examples include omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.
• H2 blockers as used herein is synonymous with “H 2 -receptor antagonist” or
• H 2 antagonist These drugs block the action of histamine on parietal cells in the stomach, thereby decreasing acid production by these cells. Examples include: cimetidine; ranitidine; famotidine; ebrotidine; pabutidine; lafutidine; and nizatidine.
• a "disease or condition characterized by abnormal gastric acid production” includes all diseases and conditions in which acid secretion: a) is abnormally elevated; b) occurs at inappropriate times; or c) results in the irritation of the esophagus or other organs.
• the term includes: dyspepsia, peptic ulcers, Zollinger-Ellison syndrome, and gastroesophageal reflux disease (GORD/GERD).
• Therapeutically effective amount as to drug dosage shall mean a dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment.
• a therapeutically effective amount shall include dosages that have been determined as safe and effective for any indication. Nevertheless, this does not necessarily exclude substantially lesser (or greater) dosages than established minimum (or maximum) dosages in particular cases.
• Onset of action refers to the interval that begins when a drug is first ingested by a patient and that ends when a therapeutic effect is first observed.
• Coupled with respect to drug administration refers to the administration of a second drug for the treatment of a condition while a first drug is still present in a therapeutically effective amount.
• Multilayer tablet refers to a tablet dosage form in which components are found in two or more distinct regions.
• a multilayer tablet may contain an outer layer in which an H2 blocker is essentially the only active agent and an inner layer in which essentially the only active agent is a PPI antagonist.
• “Pharmaceutical composition” refers to a composition containing the drug combinations described herein together with one or more pharmaceutically acceptable carriers or excipients. Typical excipients would include buffering agents (e.g., phosphate or bicarbonate buffers); binders (e.g., polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose
• HPC hydroxypropyl methyl cellulose
• HPMC hydroxypropyl methyl cellulose
• plasticizers e.g., polysorbates; dimethyl phthalate, diethyl phthalate, triacetin, triethyl citrate, and polyethylene glycol (PEG)
• lubricants e.g., magnesium stearate
• disintegrants e.g., croscarmellose salts
• Flavoring agents, coloring agents and coatings may also be present.
• the present invention is directed to dosage forms that provide for the quick release of both a ppi and an H2 blocker and which may be used to elevate the gastric pH of a patient.
• These drugs are well known in the art and the preferred agents described herein are commercially available. If desired, drugs can also be manufactured using methodology well known in the art.
• drugs used in dosage forms i.e., PPIs, H2 blockers and
• NSAIDs may be used in any pharmaceutically acceptable form, e.g. they may be in the form of an acid, base or salt. Unless otherwise indicated the recitation of any drug herein encompasses all these different forms of the drug. However, the weights and percentages recited refer to the free form of the drug. Thus, a composition having 10 mg of naproxen would have the same amount of this drug even though different salt forms may be used.
• compositions and dosage forms of the present invention can be made in accordance with methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16 th edition, A. Oslow, editor, Easton, PA (1980)).
• Drugs may be prepared in admixture with conventional excipients, carriers, buffers, flavoring agents, etc.
• Typical carriers include, but are not limited to: water; salt solutions; alcohols; gum arabic; vegetable oils; benzyl alcohols; polyethylene glycols; gelatin; carbohydrates, such as lactose, amylose or starch; magnesium stearate; talc; silicic acid; paraffin; perfume oil; fatty acid esters; hydroxymethylcellulose; polyvinyl pyrrolidone; etc.
• Pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents such as: lubricants; preservatives; disintegrants; stabilizers such as cyclodextrans; wetting agents; emulsif ⁇ ers; salts; buffers; coloring agents; flavoring agents; or aromatic substances. Tablets can be made using standard technology well known in the art. Drugs may be granulated by methods such as slugging, low-shear or high-shear granulation, wet granulation, or fluidized bed granulation. Outer coatings may be formed by preparing a mixture containing appropriate polymers.
• unit dosage forms may contain anywhere from 1 mg to as much as Ig.
• Typical amounts for H2 blockers are: cimetidine, 100 to 800 mg/unit dose; ranitidine, 50-300 mg/unit dose; famotidine, 5-100 mg/unit dose; ebrotidine 400 - 800 mg/unit dose; pabutidine 40 mg/unit dose; lafutidine 5-20 mg/unit dose; and nizatidine, 50-600 mg/unit dose.
• Proton pump inhibitors will typically be present at about 5 mg to 600 mg per unit dose.
• the proton pump inhibitor omeprazole should be present in an amount from 5 to 50 mg, with about 10 or 20 mg being preferred.
• esomeprazole 5-100 mg, with about 40 mg being preferred
• lansoprazole 5-150 mg (preferably 5-50 mg), with about 7.5, 15 or 30 mg being most preferred
• pantoprazole 10-200 mg, with about 40 mg being preferred
• rabeprazole 5- 100 mg, with about 20 mg being preferred.
• compositions described above can be used to treat a patient for any disease or condition in which proton pump inhibitors are indicated. Common conditions will include GERD, duodenal ulcers, gastric ulcers, severe erosive esophagitis, and
• Zollinger Ellison syndrome In all cases, a patient should be administered a sufficient daily dosage to eliminate the symptoms associated with excess gastric acid production. Typical daily dosages of all of the preferred agents are well known in the art. As a general rule, drugs will be designed to be taken once a day but other dosing regimens may also be used.

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• 2009
  • 2009-05-29 EP EP09755268.1A patent/EP2364145A4/de not_active Withdrawn
  • 2009-05-29 CA CA2740974A patent/CA2740974A1/en not_active Abandoned
  • 2009-05-29 WO PCT/US2009/003281 patent/WO2009145905A1/en active Application Filing

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