WO2006116556A2 - Composition comprising proton pump inhibitor and buffer - Google Patents

Composition comprising proton pump inhibitor and buffer Download PDF

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Publication number
WO2006116556A2
WO2006116556A2 PCT/US2006/015939 US2006015939W WO2006116556A2 WO 2006116556 A2 WO2006116556 A2 WO 2006116556A2 US 2006015939 W US2006015939 W US 2006015939W WO 2006116556 A2 WO2006116556 A2 WO 2006116556A2
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Prior art keywords
proton pump
composition
pump inhibitor
present
amount
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PCT/US2006/015939
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French (fr)
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WO2006116556A3 (en
Inventor
Jeffrey Phillips
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The Curators Of The University Of Missouri
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Publication of WO2006116556A2 publication Critical patent/WO2006116556A2/en
Publication of WO2006116556A3 publication Critical patent/WO2006116556A3/en

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the present invention relates to, inter alia, pharmaceutical compositions comprising an acid labile proton pump inhibitor and a buffering agent; to methods for manufacture of such compositions, and to use of such compositions in treating and preventing diseases and disorders in animals.
  • Gastrointestinal disorders such as active duodenal ulcers, gastric ulcers, and gastroesophageal reflux disease (GERD) are disorders that impact animals as well as humans. Horses are particularly susceptible to such gastrointestinal disorders. Studies revealed that 80% - 90% of racehorses in training have gastric ulcers. Performance horses that are stabled on high grain low roughage diets also experience a high incidence of ulcers. Moreover, additional studies have shown that 60 — 70% of event horses, 50 - 60% of endurance horses and 50 - 60% of show horses have ulcers. In fact, it has been estimated that up to 50% of all foals will have gastric ulcers and that all horses will have some degree of gastric ulceration at sometime in their life.
  • the stomach of the horse is essentially separated into two regions covered by different cell types.
  • the upper area is called the non-glandular or squamous region, while the lower portion is known as the glandular portion of the stomach.
  • the glands lining this lower portion secrete pepsin, an enzyme, and hydrochloric acid, both of which are responsible for the breakdown of undigested feed. Additionally these glands secrete bicarbonate, a buffer, and mucus. These two secretions are protective of the stomach lining.
  • the majority of ulcers occur in the upper or non-glandular portion of the stomach.
  • H 2 antagonists act by competing for histamine type-2 receptor sites on the parietal cell and thus blocking histamine-stimulated gastric acid secretion.
  • the two most popular H 2 antagonists used in horses are cimetidine (Tagamet) and ranitidine (Zantac). These are widely used in humans and foals, but the adult horse dose is expensive and can't be used right up to racing in standardbreds.
  • a ranitidine paste for horses (Ulcerguard®) is available, but, disadvantageously, it must be administered several times per day because of its rapid clearance.
  • PPIs proton pump inhibitors
  • PPIs proton pump inhibitors
  • these PPIs are chemically stable, lipid-soluble compounds that have little or no inhibitory activity.
  • most commercially available PPIs are unstable at neutral or acidic pH and undergo decomposition in gastrointestinal fluid upon oral administration, thereby resulting in loss of therapeutic activity.
  • enteric coated solid dosage forms for example enteric coated tablets; the enteric coating protects the drug from contact with acidic stomach secretions.
  • enteric coated formulations are also expensive and time consuming to manufacture, and require elaborate technology
  • Gastrogard® is a flavored paste that is administered in an adjustable dose syringe.
  • the high cost of this product prohibits widespread use in adult horses.
  • syringe administration to a horse or companion animal can be difficult to accomplish. Therefore, there is a significant unmet need in the treatment of gastrointestinal disorders in animals, for example horses.
  • the present invention provides pharmaceutical compositions comprising at least one acid labile proton pump inhibitor and at least one buffering agent. Also provided by the present invention are methods of treating and/or preventing acid related gastrointestinal disorders by administering one or more compositions of the invention to a subject in need thereof, for example a human or animal subject, and to methods for preparing such compositions.
  • Fig. 1 shows plasma omeprazole conentration after administration of a composition of Example 1 to a 545 kg horse.
  • any ranges, ratios and ranges of ratios that can be formed by any of the numbers or data present herein represent further embodiments of the present invention. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary.
  • a proton pump inhibitor is present in a composition of the invention in an amount of about 50 mg to about 3000 mg; in another embodiment, a buffering agent is present in a composition of the invention in an amount of about 500 mg to about 5000 mg.
  • compositions have a PPLbuffering agent weight ratio of less than or greater than 1:10, less than or greater than about 1:100, less than or greater than 6:1, less than or greater than 0.6 (3000/5000), or in ranges of about 1:100 to about 6:1, about 1:10 to about 6:1, etc. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the data and numbers presented herein and all represent embodiments of the present invention.
  • compositions of the invention comprise at least one pharmaceutically acceptable acid labile, substituted imidazole, tetrabenzimidazole, or benzimidazole H ⁇ K + -ATPaSe proton pump inhibitor (PPI).
  • PPI proton pump inhibitor
  • the term "proton pump inhibitor” or “PPI” means any acid labile pharmaceutical agent possessing pharmacological activity as an inhibitor of H+/K+-ATPase.
  • a PPI may, if desired, be in the form of free base, free acid, salt, ester, hydrate, anhydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or the like, provided that the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or any other pharmacologically suitable derivative is therapeutically active or undergoes conversion within the body to a therapeutically active form.
  • illustrative PPIs are those compounds of Formula (I):
  • R 1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;
  • R 2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;
  • R 3 and R 5 are the same or different and each is hydrogen, alkyl, C 1-4 lower alkyl (e.g. methyl, ethyl, etc.), alkoxy, amino, or alkoxyalkoxy;
  • R 4 is hydrogen, alkyl, C 1-4 lower alkyl (e.g. methyl, ethyl, etc.), alkoxy which may optionally be fluorinated, or alkoxyalkoxy;
  • Q is nitrogen, CH, or CR 1 ;
  • W is nitrogen, CH, or CR 1 ; y is an integer of 0 through 4; and
  • Z is nitrogen, CH, or CR 1 ; or a free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof.
  • PPIs include esomeprazole (also referred to as S -omeprazole), ilaprazole (U.S. Pat. No. 5,703,097), lansoprazole, omeprazole, pantoprazole, pariprazole, rabeprazole, tenatoprazole, leminoprazole and nepaprazole or a free base, a free acid, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of such compounds.
  • esomeprazole also referred to as S -omeprazole
  • ilaprazole U.S. Pat. No. 5,703,097
  • lansoprazole omeprazole
  • pantoprazole pantoprazole
  • pariprazole pariprazole
  • rabeprazole tenatoprazole
  • proton pump inhibitors include but are not limited to: soraprazan (Altana); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO 96/05177) (SB- 641257) (2-pyrimidinamine, 4-(3 ,4-dihydro- 1 -methyl-2(lH)-isoquinolinyl)-N-(4-fluo- ro ⁇ henyl)-5,6-dimethyl-monohydrochloride)(YuHan); BY-112 (Altana); SPI-447 (Imidazo(l,2-a)thieno(3,2-c)pyridin-3-amine,5-methyl-2-(2-methyl-3-thieny- l) (Shinnippon); 3-hydroxymethyl-2methyl-9-phenyl-7H-8,9-dihydro-pyrano(2, ⁇ 3-c) ⁇ imidazo(l,2-a)pyridine (PCT Publication WO 95/2771
  • Still other proton pump inhibitors contemplated by the present invention include those described in the following U.S. Pat. Nos. 4,628,098; 4,689,333; 4,786,505; 4,853,230; 4,965,269; 5,021,433; 5,026,560; 5,045,321; 5,093,132; 5,430,042; 5,433,959; 5,576,025; 5,639,478; 5,703,110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855,914; 5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187,340; 6,296,875; 6,319,904; 6,328,994; 4,255,431; 4,508,905; 4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,753,265; 5,817,338; 6,093,734; 6,013,281; 6,
  • Proton pump inhibitors as well as their salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivatives may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry. See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth et al., Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).
  • “Pharmaceutically acceptable salts,” or “salts,” include the salt of a proton pump inhibitor prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, beta.-hydroxybutyric, galactaric and galacturonic acids.
  • acid addition salts are prepared from the free base forms using conventional methodology involving reaction of the free base with a suitable acid.
  • suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • an acid addition salt is reconverted to the free base by treatment with a suitable base.
  • the acid addition salts of the proton pump inhibitors are halide salts, which are prepared using hydrochloric or hydrobromic acids.
  • the basic salts are alkali metal salts, e.g., sodium salt.
  • Salt forms of proton pump inhibiting agents include, but are not limited to: a sodium salt form such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or a magnesium salt form such as esomeprazole magnesium or omeprazole magnesium, described in U.S. Pat. No. 5,900,424; a calcium salt form; or a potassium salt form such as the potassium salt of esomeprazole, described in U.S. Patent Application No. 02/0198239 and U.S. Pat. No. 6,511,996.
  • Other salts of esomeprazole are described in U.S. Pat. Nos. 4,738,974 and 6,369,085. Salt forms of pantoprazole and lansoprazole are discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.
  • esters in one embodiment, preparation of esters involves functionalizing hydroxyl and/or carboxyl groups that may be present within the molecular structure of the drug.
  • the esters are acyl-substituted derivatives of free alcohol groups, e.g., moieties derived from carboxylic acids of the formula RCOOR 1 wherej is a lower alkyl group.
  • Esters can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
  • amides may be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with an amine group such as ammonia or a lower alkyl amine.
  • Tautomers of substituted bicyclic aryl-imidazoles include, e.g., tautomers of omeprazole such as those described in U.S. Pat. Nos. 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; and 6,444,689; and U.S. Patent Publication No. 02/0156103.
  • An exemplary "isomer" of a substituted bicyclic aryl-imidazole is the isomer of omeprazole including but not limited to isomers described in: Oishi et at., Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. Patent Publication No. 02/0156284; and PCT Publication No. WO 02/085889.
  • Exemplary "polymorphs” include, but are not limited to, those described in PCT Publication No. WO 92/08716, and U.S. Pat. Nos. 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783,974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,342; 5,433,959; 5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705,517; 5,714,504; 5,731,006; 5,879,708; 5,900,424; 5,948,773; 5,997,903; 6,017
  • the proton pump inhibitor has a D 90 , D 80 , D 70 or D 50 particle size, by weight or by number, of less than about 500 ⁇ m, less than about 400 ⁇ m , less than about 300 ⁇ m, less than about 200 ⁇ m, less than about 150 ⁇ m, less than about 100 ⁇ m, less than about 80 ⁇ m, less than about 60 ⁇ m, less than about 40 ⁇ m, less than about 35 ⁇ m, less than about 30 ⁇ m, less than about 25 ⁇ m, less than about 20 ⁇ m, less than about 15 ⁇ m, or less than about 10 ⁇ m.
  • compositions of the invention comprise one or more PPIs in a total amount of about 50 mg to about 3000 mg, about 100 mg to about 2000 mg, about 200 mg to about 1500 mg, about 300 mg to about 1200 mg or about 400 mg to about 1100 mg, for example about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg , 500 mg about 600 mg about 700 mg about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg or about 2900 mg.
  • no portion of the proton pump inhibitor is enteric coated. In another embodiment, at least a detectable portion of the proton pump inhibitor is not enteric coated. In another embodiment, at least a therapeutically effective portion of the proton pump inhibitor is not enteric coated. In another embodiment, at least about 5%, about 15%, about 20%, about 30%, about 40%, about 50% or about 60% of the proton pump inhibitor is not enteric coated.
  • compositions of the invention can be in the form of an orally deliverable dosage unit.
  • oral administration or “orally deliverable” herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed.
  • oral administration includes buccal and sublingual as well as esophageal administration.
  • subject herein includes both human and animal subjects.
  • compositions of the invention are suitable for delivery to animals, for example companion animals such as dogs, cats, horses and the like.
  • Compositions of the invention comprises one or more antacids or "buffering agents".
  • Buffering agents useful in the present invention include agents possessing pharmacological activity as a weak or strong base.
  • the buffering agent when formulated with or administered substantially simultaneously with a PPI, functions to raise the pH of gastrointestinal fluid and thereby to substantially prevent or inhibit acid degradation of the PPI by gastrointestinal fluid for a period of time.
  • the period of time is a period of time sufficient for allow for absorption of a therapeutically effective amount of the proton pump inhibitor.
  • the buffering agent when formulated or delivered ⁇ e.g., before, during and/or after) with a proton pump inhibitor, functions to substantially prevent or inhibit the acid degradation of the proton pump inhibitor by gastrointestinal fluid for a period of time, for example, for a period of time sufficient to preserve the bioavailability of the proton pump inhibitor administered.
  • buffering agents useful in accordance with the present invention comprise a salt of a Group IA metal including, for example, a bicarbonate salt of a Group IA metal, a carbonate salt of a Group IA metal, an alkaline earth metal buffering agent, an amino acid, an alkaline salt of an amino acid, an aluminum buffering agent, a calcium buffering agent, a sodium buffering agent, or a magnesium buffering agent.
  • buffering agents include alkali (sodium and potassium) or alkaline earth (calcium and magnesium) carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates and the like, such as sodium or potassium phosphate, citrate, borate, acetate, bicarbonate and carbonate.
  • Non-limiting examples of suitable buffering agents include aluminum, magnesium hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate co-precipitate, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, L- arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate
  • Buffering agents useful in the present invention also include buffering agents or combinations of buffering agents that interact with HCl (or other acids in the environment of interest) faster than the proton pump inhibitor interacts with the same acids. When placed in a liquid phase such as water, these buffering agents produce and maintain a pH greater than the pKa of the proton pump inhibitor.
  • the buffering agent is present in a total amount of about 0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibitor, about 0.5 mEq/mg to about 3 mEq/mg of the proton pump inhibitor, about 0.6 mEq/mg to about 2.5 mEq/mg of the proton pump inhibitor, about 0.7 mEq/mg to about 2.0 mEq/mg of the proton pump inhibitor, about 0.8 mEq/mg to about 1.8 mEq/mg of the proton pump inhibitor, about 1.0 mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor.
  • the buffering agent is present in an amount of at least about 0.5 mEq/mg of the proton pump inhibitor, at least about 0.75 mEq/mg of the proton pump inhibitor, or at least about 1 mEq/mg of the proton pump inhibitor on a dry weight basis.
  • one or more buffering agents are present in a total amount of about 5 mEq to about 1000 mEq, about 10 mEq to about 900 mEq, about 15 mEq to about 800 mEq, about 20 mEq to about 700 mEq, or about 25 mEq to about 600 mEq.
  • a composition of the invention can comprise about 6 mEq, or about 8 mEq, or about 12 mEq, or about 18 mEq, or about 22 mEq, or about 30 mEq, or about 35 mEq, or about 40 mEq, or about 55 mEq, or about 60 mEq, or about 65 mEq, or about 70 mEq, or about 75 mEq, or about 80 mEq, or about 85 mEq, or about 90 mEq, or about 100 mEq, or about 110 mEq, or about 120 mEq, or about 130 mEq, or about 140 mEq, or about 150 mEq, or about 200 mEq, or about 300 mEq, or about 400 mEq, or about 500 mEq, or about 600 mEq, or about 700 mEq of buffering agent.
  • one or more buffering agents and the PPI are present in a weight ratio of at least about 5:1, at least about 7:1, at least about 10:1, at least about 20:1, greater than 20:1, at least about 21:1, at least about 22:1, at least about 23:1, at least about 25:1, at least about 30:1, at least about 35:1, at least about 40:1, greater than 40:1, or at least about 45:1.
  • the amount of buffering agent present in a composition of the invention ranges from about 250 mg to about 100 g, about 300 mg to about 75 g, about 400 mg to about 50 g, about 500 mg to about 1O g, about 500 mg to about 5 g, about 500 mg to about 2.5 g, or about 500 mg to about 50 g, about 500 mg to about 10 g or about 500 mg to about 5 g.
  • the amount of buffering agent present in a composition of the invention is about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 1700 mg, or about 1800 mg, or about 1900 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg, or about 2600 mg, or about 2700 mg, or about 2800 mg, or about 2900 mg, or about 3000 mg, or about 3100 mg, or about 3200 mg, or about 3300 mg, or about 3200 mg, or about 3300 mg.
  • the two or more buffering agents comprise at least two non-amino acid buffering agents, wherein the combination of at least two non-amino acid buffering agents comprises substantially no aluminum hydroxide-sodium bicarbonate co-precipitate.
  • the pharmaceutical composition comprises an amino acid buffering agent, the total amount of amino acid buffering agent present in the pharmaceutical composition is less than about 5 mEq, or less than about 4 mEq, or less than about 3 mEq.
  • amino acid buffering agent includes amino acids, amino acid salts, and amino acid alkali salts including: glycine, alanine, threonine, isoleucine, valine, phenylalanine, glutamic acid, asparagininic acid, lysine, aluminum glycinate and/or lysine glutamic acid salt, glycine hydrochloride, L-alanine, DL- alanine, L-threonine, DL-threonine, L-isoleucine, L-valine, L-phenylalanine, L- glutamic acid, L-glutamic acid hydrochloride, L-glutamic acid sodium salt, L- asparaginic acid, L-asparaginic acid sodium salt, L-lysine and L-lysine-L-glutamic acid salt.
  • non-amino acid buffering agent herein includes buffering agents as defined hereinabove but does
  • the buffering agent is a mixture of sodium bicarbonate, calcium carbonate, and magnesium hydroxide, wherein the sodium bicarbonate, calcium carbonate, and magnesium hydroxide are each present in an amount of about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg of the proton pump inhibitor.
  • the pharmaceutical composition comprises substantially no or no poly[phosphoryl/sulfon]-ated carbohydrate and is in the form of a solid dosage unit.
  • a composition comprises a poly[phosphoryl/sulfon]-ated carbohydrate (e.g. sucralfate or sucrose octasulfate)
  • the weight ratio of poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is less than 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05).
  • the poly[phosphoryl/sulfon]-ated carbohydrate is present in the composition, if at all, in an amount less than 50 mg, less than 25 mg, less than 10 mg or less than 5 mg.
  • compositions comprising at least one soluble buffering agent.
  • soluble buffering agent refers to an antacid that has a solubility of at least 500 mg/mL, or 300 mg/mL, or 200 mg/mL, or 100 mL/mL in the gastrointestinal fluid.
  • the buffering agent has a defined particle size distribution.
  • the D 50 , D 70 , D 85 , or D 90 particle size of the buffering agent, by weight or by number is no greater than about 20 ⁇ m, no greater than about 30 ⁇ m, no greater than about 40 ⁇ m, no greater than about 50 ⁇ m, no greater than about 60 ⁇ m, no greater than about 70 ⁇ m, no greater than about 80 ⁇ m, no greater than about 90 ⁇ m, no greater than about 100 ⁇ m in diameter, no greater than about 200 ⁇ m in diameter, no greater than about 300 ⁇ m in diameter, no greater than about 400 ⁇ m in diameter, or no greater than about 100 ⁇ m in diameter.
  • compositions of the invention optionally comprise a protein component in addition to or instead of the buffering agent.
  • protein component includes protein isolates, hydrolyzed proteins (protein hydrolysates) as well as protein concentrates. Also included within the definition of a protein component are peptone, tryptone, and peptides. The term “protein component” does not embrace amino acids.
  • compositions of the invention can comprise one or more of a protein isolate, a protein hydrolysate, a protein concentrate, peptone, tryptone, and/or peptides.
  • a suitable protein component can be derived from any origin including plants, animals, or a combination thereof. Non-limiting examples of suitable sources of protein component include soy, corn, whey, egg, casein, fish, meat, poultry etc.
  • Protein isolate typically comprises at least about 85%, for example about 85 - 95% protein on a dry basis.
  • Suitable protein isolates can be prepared using any suitable procedure, for example by using an alcohol wash, water wash or ionization concentration techniques that separate at least a portion of carbohydrates and fats from the protein itself.
  • Protein concentrate typically comprises about 50% to about 85% protein on a dry basis, for example about 60 to about 85%.
  • Protein concentrate can be prepared using any suitable process, for example by concentrating the desired protein through high heat drying (dehydration), acid extraction or filtration to reduce the original source to a more concentrated protein.
  • Protein hydrolysates are protein molecules that have been lysed, typically but not exclusively with water, into smaller peptides.
  • Protein isolates suitable for the instant invention include substantially pure protein isolate or protein isolate formulations, for example liquid or powder formulations.
  • powder protein hydrolysate formulations include Alimentum, Nutramigen, and Pregestimil.
  • compositions of the invention comprise a protein component in a total amount of about 1% to about 95%, about 5% to about 90%, or about 10% to about 85% on a dry weight basis in the composition.
  • compositions of the invention comprise a protein component in a total amount of about 1 mg to about 1O g, about 10 mg to about 5 g, about 20 mg to about 3 g, or about 25 mg to about 2.5 g on a dry weight basis.
  • the weight ratio of PPI to protein component, on a dry basis is about 0.001 to about 1, about 0.0025 to about 0.5, or about 0.1 to about 0.05.
  • the protein component has a Protein Digestibility-Corrected Amino Acid Score (PDCAAS) of at least about 0.68, at least about 0.75, at least about 0.80 at least about 0.85, at least about 0.90, at least about 0.92, at least about 0.95, at least about 0.98, or about 1.
  • PDCAAS Protein Digestibility-Corrected Amino Acid Score
  • the protein component has a Protein Digestibility-Corrected Amino Acid Score (PDCAAS) of about 0.68 to about 1, about 0.80 to about 1, about 0.90 to about 1, about 0. 92 to about 1 or about 0.95 to about 1.
  • PDCAAS Protein Digestibility-Corrected Amino Acid Score
  • the protein component upon administration of a composition of the invention to a subject, the protein component sacrificially combines with available hydrogen ion (in the GI tract) thereby preventing, slowing or delaying acid-related degradation of the PPI.
  • the PPI upon administration of a composition of the invention to a human subject, the PPI undergoes reduced gastrointestinal degradation by comparison with administration of PPI alone. This can be determined by any suitable method, for example by sampling and assaying contents of the subjects stomach at various time points after ingestion of a composition of the invention or a comparative PPI composition comprising no protein component (e.g. naked PPI).
  • a composition of the invention does not contain an amino acid. In yet another embodiment, a composition of the invention does not contain an alkali earth metal buffering agent. In still another embodiment, a composition of the invention does not contain an alkaline earth metal buffering agent. In another embodiment, a composition of the invention does not contain aluminum and/or aluminum glycinate.
  • compositions of the invention can, if desired, include one or more pharmaceutically acceptable excipients.
  • excipient herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition.
  • Excipients include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, lubricants, glidants, surface modifying agents, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • excipients can be used in any dosage forms of according to the present invention, including liquid, solid or semi-solid dosage forms.
  • Excipients optionally employed in compositions of the invention can be solids, semi-solids, liquids or combinations thereof.
  • Compositions of the invention containing excipients can be prepared by any known technique of pharmacy that comprises admixing an excipient with a drug or therapeutic agent.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable diluents as excipients.
  • suitable diluents illustratively include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., CelutabTM and EmdexTM); mannitol; sorbitol; xylitol; dextrose (e.g., CereloseTM 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of ⁇ - and amorphous cellulose (e.g.,
  • Such diluents if present, constitute in total about 5% to about 99%, about 10% to about 85%, or about 20% to about 80%, of the total weight of the composition.
  • the diluent or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
  • extragranular microcrystalline cellulose that is, microcrystalline cellulose added to a wet granulated composition after a drying step
  • hardness for tablets
  • disintegration time for disintegration time
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablet formulations.
  • Suitable disintegrants include, either individually or in combination, starches, including sodium starch glycolate (e.g., ExplotabTM of PenWest) and pregelatinized corn starches (e.g., NationalTM 1551, NationalTM 1550, and ColocornTM 1500), clays (e.g., VeegumTM HV), celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-SolTM of FMC), alginates, crospovidone, and gums such as agar, guar, xanthan, locust bean, karaya, pectin and tragacanth gums.
  • starches including sodium starch glycolate (e.g., ExplotabTM of PenWest) and pregelatinized corn starches (e.g
  • Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to a granulation step or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, about 0.2% to about 10%, or about 0.2% to about 5%, of the total weight of the composition.
  • Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and, if present, typically constitutes about 0.2% to about 10%, about 0.2% to about 7%, or about 0.2% to about 5%, of the total weight of the composition.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients, particularly for tablet formulations.
  • binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion.
  • Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., NationalTM 1511 and NationalTM 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., TyloseTM); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g., KlucelTM); and ethylcellulose (e.g., EthocelTM).
  • Such binding agents and/or adhesives if present, constitute in total about 0.5% to about 25%, about 0.75% to about 15%, or about 1% to about 10%, of the total weight of the composition.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients.
  • surfactants that can be used as wetting agents in compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and di glycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients.
  • suitable lubricants include, either individually or in combination, glyceryl behapate (e.g., CompritolTM 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (e.g., SterotexTM); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., CarbowaxTM 4000 and CarbowaxTM 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
  • Such lubricants if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%, or about 0.25% to about
  • Suitable anti-adherents include talc, cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates.
  • Talc is a anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend. Talc, if present, constitutes about 0.1% to about 10%, about 0.25% to about 5%, or about 0.5% to about 2%, of the total weight of the composition.
  • Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred.
  • compositions of the present invention can comprise one or more anti-foaming agents.
  • Simethicone is an illustrative anti-foaming agent.
  • compositions of the present invention can comprise one or more flavoring agents, sweetening agents, and/or colorants.
  • Flavoring agents useful in the present invention include, without limitation, acacia syrup, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butter, butter pecan, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citrus punch, citrus cream, cocoa, coffee, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, MagnaSweet®, maltol, mannitol, maple, menthol, mint, mint cream, mixed berry, nut, orange,
  • Sweetening agents that can be used in the present invention include, for example, acesulfame potassium (acesulfame K), alitame, aspartame, cyclamate, cylamate, dextrose, isomalt, MagnaSweet®, maltitol, mannitol, neohesperidine DC, neotame, Prosweet® Powder, saccharin, sorbitol, stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the like.
  • Sweetening agents if present, constitute about 0.001% to about 40%, about 0.001% to about 30%, or about 0.001% to about 20%, of the total weight of the composition.
  • compositions of the invention comprise glycerine, triglycerides, fatty acid esters and/or polyethyleneglycols.
  • excipients can have multiple roles as is known in the art.
  • starch can serve as a filler as well as a disintegrant.
  • the classification of excipients above is not to be construed as limiting in any manner.
  • compositions of the present invention can be formulated as solid, liquid or semi-solid dosage forms.
  • such compositions are in the form of discrete dose units or dosage units.
  • dose unit and/or “dosage unit” herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect.
  • dosage units may be administered one to a small plurality ⁇ i.e. 1 to about 4) of times per day, or as many times as needed to elicit a therapeutic response.
  • a particular dosage form can be selected to accommodate any desired frequency of administration to achieve a specified daily dose.
  • one dose unit, or a small plurality (i.e. up to about 4) of dose units provides a sufficient amount of the active drug to result in the desired response or effect.
  • compositions of the invention can also be formulated for rectal, topical, or parenteral (e.g. subcutaneous, intramuscular, intravenous and intradermal or infusion) delivery.
  • parenteral e.g. subcutaneous, intramuscular, intravenous and intradermal or infusion
  • compositions of the invention are suitable for rapid onset of therapeutic effect, particularly with respect to the PPI component.
  • at least a therapeutically effective amount of the PPI is available for absorption in the stomach of the subject.
  • enteric coating to prevent exposure of the PPI to gastrointestinal fluids (and consequent drug degradation) by way of pH dependent coatings. Such coating, in turn, prevents rapid PPI absorption and therapeutic onset of action.
  • compositions of the present invention do not require enteric coating to maintain drug stability in gastrointestinal fluids and thereby provide for rapid absorption and onset of therapeutic effect.
  • a single dosage unit comprises a therapeutically effective amount or a therapeutically and/or prophylactically effective amount of PPI.
  • therapeutically effective amount or “therapeutically and/or prophylactically effective amount” as used herein refers to an amount of compound or agent that is sufficient to elicit the required or desired therapeutic and/or prophylactic response, as the particular treatment context may require.
  • a therapeutically and/or prophylactically effective amount of a drug for a subject is dependent inter alia on the body weight of the subject.
  • a "subject" herein to which a therapeutic agent or composition thereof can be administered includes a human subject of either sex and of any age, and also includes any nonhuman animal, particularly a domestic or companion animal, illustratively a cat, dog or a horse.
  • compositions of the invention are in the form of solid dosage forms.
  • suitable solid dosage forms include tablets (e.g. suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, effervescent tablets, bilayer tablets, etc), caplets, capsules (e.g. a soft or a hard gelatin capsule), powder (e.g. a packaged powder, a dispensable powder or an effervescent powder), lozenges, sachets, cachets, troches, pellets, granules, microgranules, encapsulated microgranules, powder aerosol formulations, or any other solid dosage form reasonably adapted for oral administration.
  • Tablets are an illustrative dosage form for compositions of the invention. Tablets can be prepared according to any of the many relevant, well known pharmacy techniques. In one embodiment, tablets or other solid dosage forms can be prepared by processes that employ one or a combination of methods including, without limitation, (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion.
  • the individual steps in the wet granulation process of tablet preparation typically include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation and final grinding.
  • Dry granulation involves compressing a powder mixture into a rough tablet or "slug" on a heavy-duty rotary tablet press. The slugs are then broken up into granular particles by a grinding operation, usually by passage through an oscillation granulator.
  • the individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation). Typically, no wet binder or moisture is involved in any of the steps.
  • solid dosage forms such as tablets can be prepared by mixing a PPI with at least one buffering agent as described herein above and, if desired, with one or more optional pharmaceutical excipient to form a substantially homogeneous preformulation blend.
  • the preformulation blend can then be subdivided and optionally further processed (e.g. compressed, encapsulated, packaged, dispersed, etc.) into any desired dosage forms.
  • Compressed tablets can be prepared by compacting a powder or granulation composition of the invention.
  • the term “compressed tablet” generally refers to a plain, uncoated tablet suitable for oral ingestion, prepared by a single compression or by pre-compaction tapping followed by a final compression. Tablets of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of improved handling or storage characteristics. Preferably, however, any such coating will be selected so as to not substantially delay onset of therapeutic effect of a composition of the invention upon administration to a subject.
  • the term “suspension tablet” as used herein refers to a compressed tablet that rapidly disintegrates after placement in water.
  • a composition of the invention comprises a multi-layer tablet having a core comprising a proton pump inhibitor; the core is substantially or completely surrounded by the buffering agent.
  • the buffering agent layer completely surrounds the core.
  • the buffering agent layer partially surrounds the core.
  • the buffering agent layer is in contact with a portion of or with all of the surface area of the core.
  • one or more intermediate layers exists in between the core and the buffering agent.
  • the intermediate layers can comprise any pharmaceutically acceptable material, preferably inert and non-pH sensitive coating materials such as polymer based coatings.
  • compositions of the invention can be microencapsulated, for example as is described in U.S. Patent Publication No. 2005/0037070, hereby incorporated by reference herein in its entirety.
  • a composition of the invention comprises a proton pump inhibitor and a buffering agent mixed together in powder form and optionally filled into a capsule, for example a hard or soft gelatin or HPMC capsule.
  • a composition of the invention is in the form of a molded article, for example a pellet.
  • molded article herein refers to a discrete dosage form that can be formed by compression, extrusion, or other similar processes.
  • the molded article is moldable.
  • moldable in the present context means capable of being shaped or molded by hand. A moldable article herein will therefore have a hardness lower than a conventional pharmaceutical tablet. Such a moldable article will also be capable of being chewed by an animal, for example a horse.
  • Such an article can comprise, in addition to the PPI and buffering agent, and other excipients described herein, a filler, a sweetener and a flavoring agent.
  • Extrusion is a process of shaping material by forcing it to flow through a shaped opening in a die or other solid. Extruded material emerges as an elongated article with substantially the same profile as the die opening.
  • compositions can be in the form of liquid dosage forms or units.
  • suitable liquid dosage forms include solutions, suspension, elixirs, syrups, liquid aerosol formulations, etc.
  • compositions of the invention are in the form of a powder for suspension that can be suspended in a liquid vehicle prior to administration to a subject. While the powder for suspension itself, can be a solid dosage form of the present invention, the powder dispersed in liquid also comprises a liquid embodiment of the invention.
  • Suspension compositions of the invention comprise at least one PPI, a buffering agent, a liquid media (e.g. water, de-ionized water, etc.), vitamin B 12 and or iron, and one or more optional pharmaceutical excipients.
  • a liquid media e.g. water, de-ionized water, etc.
  • vitamin B 12 and or iron e.g., vitamin B 12 and or iron
  • a composition of the present invention can further include one or more parietal cell activators.
  • Parietal cell activators such as chocolate, calcium and sodium bicarbonate and other alkaline substances stimulate the parietal cells and enhance the pharmacologic activity of the PPI administered.
  • Parietal cell activator or “activator” shall mean any compound or mixture of compounds possessing such stimulatory effect including, but not limited to, chocolate, sodium bicarbonate, calcium (for example, calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate and calcium glycerophosphate), peppermint oil, spearmint oil, coffee, tea and colas (even if decaffeinated), caffeine, theophylline, theobromine, and amino acids (particularly aromatic amino acids such as phenylalanine and tryptophan) and combinations thereof.
  • Parietal cell activators if desired, are typically present in a composition of the invention in an amount sufficient to produce the desired stimulatory effect without causing untoward side effects to patients.
  • chocolate as raw cocoa, is administered in an amount of about 5 mg to 2.5 g per 20 mg dose of omeprazole (or equivalent pharmacologic dose of another proton pump inhibiting agent).
  • dose of activator administered to a subject, for example, a horse, in the context of the present invention should be sufficient to result in enhanced effect of a PPI over a desired time frame.
  • compositions of the present invention are useful for treating and/or preventing, inter- alia, gastrointestinal disorders and, in particular, acid related gastrointestinal disorder in a subject in need thereof.
  • the phrase "acid related gastrointestinal disorder” or “acid related gastrointestinal disease” refers generally to a disease or disorder that occurs due to an imbalance between acid and pepsin production on the one hand, so-called aggressive factors, and mucous, bicarbonate, and prostaglandin production on the other hand, so-called defensive factors.
  • subject means a human or an animal. In one embodiment, the subject is an animal such as a horse, a dog, or a cat.
  • treat refers to any treatment of a disorder or disease associated with a gastrointestinal disorder, and includes, but is not limited to, preventing the disorder or disease from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, for example, arresting the development of the disorder or disease; relieving the disorder or disease, for example, causing regression of the disorder or disease; or relieving the condition caused by the disease or disorder, for example, stopping the symptoms of the disease or disorder.
  • prevent in relation to a gastrointestinal disorder or disease, means preventing the onset of gastrointestinal disorder or disease development if none had occurred, or preventing further gastrointestinal disorder or disease development if the gastrointestinal disorder or disease was already present.
  • gastrointestinal disorders include, but are not limited to, duodenal ulcer, gastric ulcer, acid dyspepsia, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, (acid reflux), heartburn, nighttime heartburn symptoms, nocturnal acid breakthrough (NAB), and gastrointestinal pathological hypersecretory conditions such as Zollinger Ellison Syndrome.
  • Illustrative acid-related gastrointestinal disorders including duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease (GERD), erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease (acid reflux), pathological gastrointestinal hypersecretory disease, Zollinger Ellison Syndrome, acid dyspepsia, heartburn, and/or NSAED induced ulcer.
  • compositions of the invention are to be administered and dosed in accordance with good medical practice, talcing into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration and other factors known to medical practitioners
  • the percent of intact drug that is absorbed into the bloodstream is not narrowly critical, as long as a therapeutic-disorder-effective amount, for example a gastrointestinal-disorder-effective amount of a proton pump inhibiting agent, is absorbed following administration of the pharmaceutical composition to a subject. It will be understood that the amount of proton pump inhibiting agent and/or antacid that is administered to a subject is dependent on various factors including the sex, general health, diet, and/or body weight of the subject.
  • the amount of proton pump inhibitor administered to a subject is about 0.5 to about 3 mg/Kg of body weight or about 1 to about 2.5 mg/Kg of body weight, illustratively about 0.5 mg/Kg of body weight, about 1 mg/Kg of body weight, about 1.5 mg/Kg of body weight, about 2 mg/Kg of body weight or about 2.5 mg/Kg of body weight.
  • Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for subject administration. Studies in animal models generally may be used for guidance regarding effective dosages for treatment of gastrointestinal disorders or diseases in accordance with the present invention. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route chosen for administration, the condition of the particular subject.
  • the composition is administered to a subject, for example a horse, in an amount sufficient to achieve a measurable serum concentration of a non-acid degraded or non-acid reacted proton pump inhibitor greater than about 100 mcg/L within about 30 minutes or about 15 minutes or about 10 minutes after administration of the composition.
  • the composition is administered to a subject, for example a horse, in an amount sufficient to achieve a measurable serum concentration of the proton pump inhibitor greater than about 100 mcg/L within about 15 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 100 mcg/L from about 15 minutes to about 1 hour after administration of the composition.
  • the composition is administered to the subject in an amount sufficient to achieve a measurable serum concentration of the proton pump inhibitor greater than about 100 mcg/L within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 100 mcg/L from about 15 minutes to about 1 hour after administration of the composition.
  • the composition is administered to a subject, for example a horse, in an amount sufficient to achieve a measurable serum concentration of the proton pump inhibitor greater than about 100 mcg/L within about 30 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 100 mcg/L from about 30 minutes to about 1 hour after administration of the composition.
  • the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibitor greater than about 100 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 100 ng/ml from about 30 minutes to about 1 hour after administration of the composition.
  • Contemplated compositions of the present invention provide a therapeutic effect as proton pump inhibiting agent medications over an interval of about 5 minutes to about 24 hours after administration, enabling, for example, once-a-day, twice-a-day, or three times a day administration if desired.
  • the subjects upon oral administration of a composition of the invention to a plurality of subjects, exhibit an average T max of PPI within about 30 seconds to about 90 minutes, within about 1 minute to about 80 minutes, within about 5 minutes to about 60 minutes, within about 10 minutes to about 50 minutes, or within about 15 minutes to about 45 minutes.
  • pellets were prepared, each comprising non-enteric coated omeprazole, sodium bicarbonate, pregelatinized starch, sucrose and flavoring agent (apple). These ingredients were dry blended and compressed in Parr pellet press. The pellets were then administered to a horse as follows.
  • omeprazole administered was 1090 mg (2 mg/kg). Blood was drawn at several time points over a period of four hours following administration. Plasma was collected from the horse in tubes without anticoagulant. The blood was allowed to clot and was then centrifuged; serum was frozen for later extraction. Extraction was performed using 75 microliter of 0.1 M sodium bicarbonate and 3 microgram/ml of lansoprazole (internal standard) were added to 0.5 ml serum. Five ml of ether: dichloromethane (7:3) were added to each tube. The tubes were mixed by vortexing for 20 seconds, and centrifuged for 10 min at 2500 RPM. A 2.5 ml aliquot of the top organic layer was transferred to a new tube and the solvent was evaporated using a stream of oxygen. The dry samples were reconstituted in 0.25 ml of the HPLC mobile phase.
  • the HPLC column was an Alltech Prevail Cl 8 5 micron, 15 cm length.
  • the mobile phase consisted of 50% of 15 mM sodium phosphate pH 7.4, 40% methanol and 10% acetonitrile used at a flow rate of 1.1 ml/r ⁇ in.
  • a UV detector was used to detect the peaks at 300 nm. Data are shown in Fig. 1, below.

Abstract

The present invention relates to, inter alia, pharmaceutical compositions comprising an acid labile proton pump inhibitor, a buffering agent, and at least one additional pharmaceutically acceptable excipient. Also provided are methods for manufacture of such compositions, and to use of such compositions in treating and preventing diseases and/or disorders.

Description

VETERINARY PHARMACEUTICAL COMPOSITIONS COMPRISING A PROTON PUMP INHIBITOR AND A BUFFERING AGENT AND METHODS
OF USING SAME
FIELD OF THE INVENTION
The present invention relates to, inter alia, pharmaceutical compositions comprising an acid labile proton pump inhibitor and a buffering agent; to methods for manufacture of such compositions, and to use of such compositions in treating and preventing diseases and disorders in animals.
BACKGROUND OF THE INVENTION
Gastrointestinal disorders such as active duodenal ulcers, gastric ulcers, and gastroesophageal reflux disease (GERD) are disorders that impact animals as well as humans. Horses are particularly susceptible to such gastrointestinal disorders. Studies revealed that 80% - 90% of racehorses in training have gastric ulcers. Performance horses that are stabled on high grain low roughage diets also experience a high incidence of ulcers. Moreover, additional studies have shown that 60 — 70% of event horses, 50 - 60% of endurance horses and 50 - 60% of show horses have ulcers. In fact, it has been estimated that up to 50% of all foals will have gastric ulcers and that all horses will have some degree of gastric ulceration at sometime in their life.
It has been has proposed that the major cause of gastric ulcers in the horse is prolonged exposure of the squamous mucosal lining to gastric acid. The stomach of the horse is essentially separated into two regions covered by different cell types. The upper area is called the non-glandular or squamous region, while the lower portion is known as the glandular portion of the stomach. The glands lining this lower portion secrete pepsin, an enzyme, and hydrochloric acid, both of which are responsible for the breakdown of undigested feed. Additionally these glands secrete bicarbonate, a buffer, and mucus. These two secretions are protective of the stomach lining. The majority of ulcers occur in the upper or non-glandular portion of the stomach. The only protection that this portion of the stomach has from gastric acid and pepsin comes from saliva production. If adequate saliva is not produced to buffer the gastric acid and coat the surface of this part of the stomach, then gastric irritation occurs and ulcers may develop. Turning a horse out to graze without work for a month may help heal some ulcers, but this option is often not practical. Therefore, treating ulcers involves either inhibiting gastric acid secretion or neutralizing the acid produced. There are two classes of drugs that can be used to inhibit gastric acid secretion, histamine type-2 (H2) antagonists and substituted benzimidazoles.
H2 antagonists act by competing for histamine type-2 receptor sites on the parietal cell and thus blocking histamine-stimulated gastric acid secretion. The two most popular H2 antagonists used in horses are cimetidine (Tagamet) and ranitidine (Zantac). These are widely used in humans and foals, but the adult horse dose is expensive and can't be used right up to racing in standardbreds. A ranitidine paste for horses (Ulcerguard®) is available, but, disadvantageously, it must be administered several times per day because of its rapid clearance.
Direct inhibition of the proton pump can be achieved by a class of substituted benzimidazoles known as proton pump inhibitors or PPIs. At neutral pH, these PPIs are chemically stable, lipid-soluble compounds that have little or no inhibitory activity. Unfortunately, most commercially available PPIs are unstable at neutral or acidic pH and undergo decomposition in gastrointestinal fluid upon oral administration, thereby resulting in loss of therapeutic activity.
To overcome this acid instability, such compounds have formulated for oral delivery to humans as enteric coated solid dosage forms, for example enteric coated tablets; the enteric coating protects the drug from contact with acidic stomach secretions. An undesirable consequence of such enteric coating is that therapeutic onset time is significantly delayed by comparison with non-enteric coated dosage forms. Such prolonged time to therapeutic onset would also be particularly undesirable for animals in need of rapid relief from one or more of the above described disorders or symptoms. Enteric coated formulations are also expensive and time consuming to manufacture, and require elaborate technology
The only proton pump inhibitor currently approved for horses is omeprazole (Gastrogard®). Gastrogard® is a flavored paste that is administered in an adjustable dose syringe. Unfortunately, the high cost of this product prohibits widespread use in adult horses. Furthermore, syringe administration to a horse or companion animal can be difficult to accomplish. Therefore, there is a significant unmet need in the treatment of gastrointestinal disorders in animals, for example horses. SUMMARY OF THE INVENTION
The present invention provides pharmaceutical compositions comprising at least one acid labile proton pump inhibitor and at least one buffering agent. Also provided by the present invention are methods of treating and/or preventing acid related gastrointestinal disorders by administering one or more compositions of the invention to a subject in need thereof, for example a human or animal subject, and to methods for preparing such compositions.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows plasma omeprazole conentration after administration of a composition of Example 1 to a 545 kg horse.
DETAILED DESCRIPTION OF THE INVENTION
While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention, and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the invention in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word "about." In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. As used herein, the terms "about" and "approximately" when referring to a numerical value shall have their plain and ordinary meanings to one skilled in the art of pharmaceutical sciences or the art relevant to the range or element at issue. The amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors to be considered may include the criticality of the element and/or the effect a given amount of variation will have on the performance of the claimed subject matter, as well as other considerations known to those of skill in the art. Thus, as a general matter, "about" or "approximately" broaden the numerical value. For example, in some cases, "about" or "approximately" may mean ± 5%, or ±10%, or ±20%, or ±30% depending on the relevant technology. Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that can be formable thereby.
It is also to be understood that any ranges, ratios and ranges of ratios that can be formed by any of the numbers or data present herein represent further embodiments of the present invention. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary. For example, by way of illustration and not limitation, in one embodiment, a proton pump inhibitor is present in a composition of the invention in an amount of about 50 mg to about 3000 mg; in another embodiment, a buffering agent is present in a composition of the invention in an amount of about 500 mg to about 5000 mg. One of skill in the art will therefore recognize, for example, that additional embodiments include situations where a composition has a PPLbuffering agent weight ratio of less than or greater than 1:10, less than or greater than about 1:100, less than or greater than 6:1, less than or greater than 0.6 (3000/5000), or in ranges of about 1:100 to about 6:1, about 1:10 to about 6:1, etc. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the data and numbers presented herein and all represent embodiments of the present invention.
Proton Pump Inhibitors
Compositions of the invention comprise at least one pharmaceutically acceptable acid labile, substituted imidazole, tetrabenzimidazole, or benzimidazole H^K+-ATPaSe proton pump inhibitor (PPI). The term "proton pump inhibitor" or "PPI" means any acid labile pharmaceutical agent possessing pharmacological activity as an inhibitor of H+/K+-ATPase. A PPI may, if desired, be in the form of free base, free acid, salt, ester, hydrate, anhydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or the like, provided that the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or any other pharmacologically suitable derivative is therapeutically active or undergoes conversion within the body to a therapeutically active form.
In one embodiment, illustrative PPIs are those compounds of Formula (I):
Figure imgf000006_0001
wherein
R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;
R2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;
R3 and R5 are the same or different and each is hydrogen, alkyl, C1-4 lower alkyl (e.g. methyl, ethyl, etc.), alkoxy, amino, or alkoxyalkoxy;
R4 is hydrogen, alkyl, C1-4 lower alkyl (e.g. methyl, ethyl, etc.), alkoxy which may optionally be fluorinated, or alkoxyalkoxy;
Q is nitrogen, CH, or CR1;
W is nitrogen, CH, or CR1; y is an integer of 0 through 4; and
Z is nitrogen, CH, or CR1; or a free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof.
Specific examples of suitable PPIs include esomeprazole (also referred to as S -omeprazole), ilaprazole (U.S. Pat. No. 5,703,097), lansoprazole, omeprazole, pantoprazole, pariprazole, rabeprazole, tenatoprazole, leminoprazole and nepaprazole or a free base, a free acid, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of such compounds.
Other proton pump inhibitors include but are not limited to: soraprazan (Altana); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO 96/05177) (SB- 641257) (2-pyrimidinamine, 4-(3 ,4-dihydro- 1 -methyl-2(lH)-isoquinolinyl)-N-(4-fluo- roρhenyl)-5,6-dimethyl-monohydrochloride)(YuHan); BY-112 (Altana); SPI-447 (Imidazo(l,2-a)thieno(3,2-c)pyridin-3-amine,5-methyl-2-(2-methyl-3-thieny- l) (Shinnippon); 3-hydroxymethyl-2methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,~ 3-c)~ imidazo(l,2-a)pyridine (PCT Publication WO 95/27714) (AstraZeneca); Pharmaprojects No. 4950 (3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro- - pyrano(2,3-c)-imidazo(l,2-a)pyridine) (AstraZeneca, ceased) WO 95/27714; Pharmaprojects No. 4891 (EP 700899) (Aventis); Pharmaprojects No. 4697 (PCT Publication WO 95/32959) (AstraZeneca); H-335/25 (AstraZeneca); T-330 (Saitama 335) (Pharmacological Research Lab); Pharmaprojects No. 3177 (Roche); BY-574 (Altana); Pharmaprojects No. 2870 (Pfizer); AU- 1421 (EP 264883) (Merck); AU- 2064 (Merck); AY-28200 (Wyeth); Pharmaprojects No. 2126 (Aventis); WY-26769 (Wyeth); pumaprazole (PCT Publication WO 96/05199) (Altana); YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO 97/32854) (Dainippon); BY-686 (Altana); YM-020 (Yamanouchi); GYKI-34655 (Ivax); FPL-65372 (Aventis); Pharmaprojects No. 3264 (EP 509974) (AstraZeneca); nepaprazole (To a Eiyo); HN- 11203 (Nycomed Pharma); OPC-22575; pumilacidin A (BMS); saviprazole (EP 234485) (Aventis); SKand F-95601 (GSK, discontinued); Pharmaprojects No. 2522 (EP 204215) (Pfizer); S-3337 (Aventis); RS-13232A (Roche); AU-1363 (Merck); SKand F-96067 (EP 259174) (Altana); SUN 8176 (Daiichi Phama); Ro-18-5362 (Roche); ufiprazole (EP 74341) (AstraZeneca); and Bay-p-1455 (Bayer); or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of these compounds.
Still other proton pump inhibitors contemplated by the present invention include those described in the following U.S. Pat. Nos. 4,628,098; 4,689,333; 4,786,505; 4,853,230; 4,965,269; 5,021,433; 5,026,560; 5,045,321; 5,093,132; 5,430,042; 5,433,959; 5,576,025; 5,639,478; 5,703,110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855,914; 5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187,340; 6,296,875; 6,319,904; 6,328,994; 4,255,431; 4,508,905; 4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,753,265; 5,817,338; 6,093,734; 6,013,281; 6,136,344; 6,183,776; 6,328,994; 6,479,075; 6,559,167.
Proton pump inhibitors as well as their salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivatives may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry. See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth et al., Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).
"Pharmaceutically acceptable salts," or "salts," include the salt of a proton pump inhibitor prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, beta.-hydroxybutyric, galactaric and galacturonic acids.
In one embodiment, acid addition salts are prepared from the free base forms using conventional methodology involving reaction of the free base with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
In other embodiments, an acid addition salt is reconverted to the free base by treatment with a suitable base. In a further embodiment, the acid addition salts of the proton pump inhibitors are halide salts, which are prepared using hydrochloric or hydrobromic acids. In still other embodiments, the basic salts are alkali metal salts, e.g., sodium salt.
Salt forms of proton pump inhibiting agents include, but are not limited to: a sodium salt form such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or a magnesium salt form such as esomeprazole magnesium or omeprazole magnesium, described in U.S. Pat. No. 5,900,424; a calcium salt form; or a potassium salt form such as the potassium salt of esomeprazole, described in U.S. Patent Application No. 02/0198239 and U.S. Pat. No. 6,511,996. Other salts of esomeprazole are described in U.S. Pat. Nos. 4,738,974 and 6,369,085. Salt forms of pantoprazole and lansoprazole are discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.
In one embodiment, preparation of esters involves functionalizing hydroxyl and/or carboxyl groups that may be present within the molecular structure of the drug. In one embodiment, the esters are acyl-substituted derivatives of free alcohol groups, e.g., moieties derived from carboxylic acids of the formula RCOOR1 wherej is a lower alkyl group. Esters can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.
"Amides" may be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with an amine group such as ammonia or a lower alkyl amine.
"Tautomers" of substituted bicyclic aryl-imidazoles include, e.g., tautomers of omeprazole such as those described in U.S. Pat. Nos. 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; and 6,444,689; and U.S. Patent Publication No. 02/0156103.
An exemplary "isomer" of a substituted bicyclic aryl-imidazole is the isomer of omeprazole including but not limited to isomers described in: Oishi et at., Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. Patent Publication No. 02/0156284; and PCT Publication No. WO 02/085889.
Exemplary "polymorphs" include, but are not limited to, those described in PCT Publication No. WO 92/08716, and U.S. Pat. Nos. 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783,974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,342; 5,433,959; 5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705,517; 5,714,504; 5,731,006; 5,879,708; 5,900,424; 5,948,773; 5,997,903; 6,017,560; 6,123,962; 6,147,103; 6,150,380; 6,166,213; 6,191,148; 5,187,340; 6,268,385; 6,262,086; 6,262,085; 6,296,875; 6,316,020; 6,328,994; 6,326,384; 6,369,085; 6,369,087; 6,380,234; 6,428,810; 6,444,689; and 6,462,0577.
In one embodiment, the proton pump inhibitor has a D90, D80, D70 or D50 particle size, by weight or by number, of less than about 500 μm, less than about 400 μm , less than about 300 μm, less than about 200 μm, less than about 150 μm, less than about 100 μm, less than about 80 μm, less than about 60 μm, less than about 40 μm, less than about 35 μm, less than about 30 μm, less than about 25 μm, less than about 20 μm, less than about 15 μm, or less than about 10 μm.
In another embodiment, compositions of the invention comprise one or more PPIs in a total amount of about 50 mg to about 3000 mg, about 100 mg to about 2000 mg, about 200 mg to about 1500 mg, about 300 mg to about 1200 mg or about 400 mg to about 1100 mg, for example about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg , 500 mg about 600 mg about 700 mg about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg or about 2900 mg.
In one embodiment, no portion of the proton pump inhibitor is enteric coated. In another embodiment, at least a detectable portion of the proton pump inhibitor is not enteric coated. In another embodiment, at least a therapeutically effective portion of the proton pump inhibitor is not enteric coated. In another embodiment, at least about 5%, about 15%, about 20%, about 30%, about 40%, about 50% or about 60% of the proton pump inhibitor is not enteric coated.
Compositions of the invention can be in the form of an orally deliverable dosage unit. The terms "oral administration" or "orally deliverable" herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed. Thus "oral administration" includes buccal and sublingual as well as esophageal administration. The term "subject" herein includes both human and animal subjects. In one embodiment, compositions of the invention are suitable for delivery to animals, for example companion animals such as dogs, cats, horses and the like.
Buffering Agent
Compositions of the invention comprises one or more antacids or "buffering agents". Buffering agents useful in the present invention include agents possessing pharmacological activity as a weak or strong base. In one embodiment, the buffering agent, when formulated with or administered substantially simultaneously with a PPI, functions to raise the pH of gastrointestinal fluid and thereby to substantially prevent or inhibit acid degradation of the PPI by gastrointestinal fluid for a period of time. In one embodiment, the period of time is a period of time sufficient for allow for absorption of a therapeutically effective amount of the proton pump inhibitor.
In one embodiment, the buffering agent, when formulated or delivered {e.g., before, during and/or after) with a proton pump inhibitor, functions to substantially prevent or inhibit the acid degradation of the proton pump inhibitor by gastrointestinal fluid for a period of time, for example, for a period of time sufficient to preserve the bioavailability of the proton pump inhibitor administered. In another embodiment, buffering agents useful in accordance with the present invention comprise a salt of a Group IA metal including, for example, a bicarbonate salt of a Group IA metal, a carbonate salt of a Group IA metal, an alkaline earth metal buffering agent, an amino acid, an alkaline salt of an amino acid, an aluminum buffering agent, a calcium buffering agent, a sodium buffering agent, or a magnesium buffering agent. Other suitable buffering agents include alkali (sodium and potassium) or alkaline earth (calcium and magnesium) carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates and the like, such as sodium or potassium phosphate, citrate, borate, acetate, bicarbonate and carbonate.
Non-limiting examples of suitable buffering agents include aluminum, magnesium hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate co-precipitate, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, L- arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, and trometarnol. (Based in part upon the list provided in The Merck Index, Merck & Co. Rahway, NJ. (2001)). In addition, due to the ability of proteins or protein hydrolysates to react with stomach acids, they too can serve as buffering agents in the present invention. Furthermore, combinations or mixtures of the above mentioned buffering agents can be used in the pharmaceutical formulations described herein.
Buffering agents useful in the present invention also include buffering agents or combinations of buffering agents that interact with HCl (or other acids in the environment of interest) faster than the proton pump inhibitor interacts with the same acids. When placed in a liquid phase such as water, these buffering agents produce and maintain a pH greater than the pKa of the proton pump inhibitor.
In various other embodiments of the present invention, the buffering agent is present in a total amount of about 0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibitor, about 0.5 mEq/mg to about 3 mEq/mg of the proton pump inhibitor, about 0.6 mEq/mg to about 2.5 mEq/mg of the proton pump inhibitor, about 0.7 mEq/mg to about 2.0 mEq/mg of the proton pump inhibitor, about 0.8 mEq/mg to about 1.8 mEq/mg of the proton pump inhibitor, about 1.0 mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor. In another embodiment, the buffering agent is present in an amount of at least about 0.5 mEq/mg of the proton pump inhibitor, at least about 0.75 mEq/mg of the proton pump inhibitor, or at least about 1 mEq/mg of the proton pump inhibitor on a dry weight basis.
In another embodiment, one or more buffering agents are present in a total amount of about 5 mEq to about 1000 mEq, about 10 mEq to about 900 mEq, about 15 mEq to about 800 mEq, about 20 mEq to about 700 mEq, or about 25 mEq to about 600 mEq. Illustratively, a composition of the invention can comprise about 6 mEq, or about 8 mEq, or about 12 mEq, or about 18 mEq, or about 22 mEq, or about 30 mEq, or about 35 mEq, or about 40 mEq, or about 55 mEq, or about 60 mEq, or about 65 mEq, or about 70 mEq, or about 75 mEq, or about 80 mEq, or about 85 mEq, or about 90 mEq, or about 100 mEq, or about 110 mEq, or about 120 mEq, or about 130 mEq, or about 140 mEq, or about 150 mEq, or about 200 mEq, or about 300 mEq, or about 400 mEq, or about 500 mEq, or about 600 mEq, or about 700 mEq of buffering agent.
In another embodiment, one or more buffering agents and the PPI are present in a weight ratio of at least about 5:1, at least about 7:1, at least about 10:1, at least about 20:1, greater than 20:1, at least about 21:1, at least about 22:1, at least about 23:1, at least about 25:1, at least about 30:1, at least about 35:1, at least about 40:1, greater than 40:1, or at least about 45:1.
In another embodiment, the amount of buffering agent present in a composition of the invention ranges from about 250 mg to about 100 g, about 300 mg to about 75 g, about 400 mg to about 50 g, about 500 mg to about 1O g, about 500 mg to about 5 g, about 500 mg to about 2.5 g, or about 500 mg to about 50 g, about 500 mg to about 10 g or about 500 mg to about 5 g.
In other embodiments, the amount of buffering agent present in a composition of the invention is about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 1700 mg, or about 1800 mg, or about 1900 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg, or about 2600 mg, or about 2700 mg, or about 2800 mg, or about 2900 mg, or about 3000 mg, or about 3100 mg, or about 3200 mg, or about 3300 mg, or about 3200 mg, or about 3300 mg.
In other embodiments, where two or more buffering agents are present, the two or more buffering agents comprise at least two non-amino acid buffering agents, wherein the combination of at least two non-amino acid buffering agents comprises substantially no aluminum hydroxide-sodium bicarbonate co-precipitate. In other embodiments, if the pharmaceutical composition comprises an amino acid buffering agent, the total amount of amino acid buffering agent present in the pharmaceutical composition is less than about 5 mEq, or less than about 4 mEq, or less than about 3 mEq. The phrase "amino acid buffering agent" as used herein includes amino acids, amino acid salts, and amino acid alkali salts including: glycine, alanine, threonine, isoleucine, valine, phenylalanine, glutamic acid, asparagininic acid, lysine, aluminum glycinate and/or lysine glutamic acid salt, glycine hydrochloride, L-alanine, DL- alanine, L-threonine, DL-threonine, L-isoleucine, L-valine, L-phenylalanine, L- glutamic acid, L-glutamic acid hydrochloride, L-glutamic acid sodium salt, L- asparaginic acid, L-asparaginic acid sodium salt, L-lysine and L-lysine-L-glutamic acid salt. The term "non-amino acid buffering agent" herein includes buffering agents as defined hereinabove but does not include amino acid buffering agents.
In still another embodiment, the buffering agent is a mixture of sodium bicarbonate, calcium carbonate, and magnesium hydroxide, wherein the sodium bicarbonate, calcium carbonate, and magnesium hydroxide are each present in an amount of about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg of the proton pump inhibitor.
In other embodiments, the pharmaceutical composition comprises substantially no or no poly[phosphoryl/sulfon]-ated carbohydrate and is in the form of a solid dosage unit. In still another related embodiment, if such a composition comprises a poly[phosphoryl/sulfon]-ated carbohydrate (e.g. sucralfate or sucrose octasulfate), the weight ratio of poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is less than 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05). Alternatively, the poly[phosphoryl/sulfon]-ated carbohydrate is present in the composition, if at all, in an amount less than 50 mg, less than 25 mg, less than 10 mg or less than 5 mg.
Also provided herein are pharmaceutical compositions comprising at least one soluble buffering agent. The term "soluble buffering agent" as used herein refers to an antacid that has a solubility of at least 500 mg/mL, or 300 mg/mL, or 200 mg/mL, or 100 mL/mL in the gastrointestinal fluid.
In some embodiments of the present invention, the buffering agent has a defined particle size distribution. For example, in various embodiments, the D50, D70, D85, or D90 particle size of the buffering agent, by weight or by number, is no greater than about 20 μm, no greater than about 30 μm, no greater than about 40 μm, no greater than about 50 μm, no greater than about 60 μm, no greater than about 70 μm, no greater than about 80 μm, no greater than about 90 μm, no greater than about 100 μm in diameter, no greater than about 200 μm in diameter, no greater than about 300 μm in diameter, no greater than about 400 μm in diameter, or no greater than about 100 μm in diameter.
Protein Component
Compositions of the invention optionally comprise a protein component in addition to or instead of the buffering agent. The term "protein component" as used herein includes protein isolates, hydrolyzed proteins (protein hydrolysates) as well as protein concentrates. Also included within the definition of a protein component are peptone, tryptone, and peptides. The term "protein component" does not embrace amino acids.
Compositions of the invention can comprise one or more of a protein isolate, a protein hydrolysate, a protein concentrate, peptone, tryptone, and/or peptides. A suitable protein component can be derived from any origin including plants, animals, or a combination thereof. Non-limiting examples of suitable sources of protein component include soy, corn, whey, egg, casein, fish, meat, poultry etc.
Protein isolate typically comprises at least about 85%, for example about 85 - 95% protein on a dry basis. Suitable protein isolates can be prepared using any suitable procedure, for example by using an alcohol wash, water wash or ionization concentration techniques that separate at least a portion of carbohydrates and fats from the protein itself.
Protein concentrate typically comprises about 50% to about 85% protein on a dry basis, for example about 60 to about 85%. Protein concentrate can be prepared using any suitable process, for example by concentrating the desired protein through high heat drying (dehydration), acid extraction or filtration to reduce the original source to a more concentrated protein.
Protein hydrolysates are protein molecules that have been lysed, typically but not exclusively with water, into smaller peptides. Protein isolates suitable for the instant invention include substantially pure protein isolate or protein isolate formulations, for example liquid or powder formulations. Non-limiting examples of powder protein hydrolysate formulations include Alimentum, Nutramigen, and Pregestimil.
In one embodiment, compositions of the invention comprise a protein component in a total amount of about 1% to about 95%, about 5% to about 90%, or about 10% to about 85% on a dry weight basis in the composition.
In another embodiment, compositions of the invention comprise a protein component in a total amount of about 1 mg to about 1O g, about 10 mg to about 5 g, about 20 mg to about 3 g, or about 25 mg to about 2.5 g on a dry weight basis. In another embodiment, the weight ratio of PPI to protein component, on a dry basis, is about 0.001 to about 1, about 0.0025 to about 0.5, or about 0.1 to about 0.05.
In another embodiment of the invention, the protein component has a Protein Digestibility-Corrected Amino Acid Score (PDCAAS) of at least about 0.68, at least about 0.75, at least about 0.80 at least about 0.85, at least about 0.90, at least about 0.92, at least about 0.95, at least about 0.98, or about 1.
In another embodiment of the invention, the protein component has a Protein Digestibility-Corrected Amino Acid Score (PDCAAS) of about 0.68 to about 1, about 0.80 to about 1, about 0.90 to about 1, about 0. 92 to about 1 or about 0.95 to about 1.
Without being bound by theory, it is presently believed that upon administration of a composition of the invention to a subject, the protein component sacrificially combines with available hydrogen ion (in the GI tract) thereby preventing, slowing or delaying acid-related degradation of the PPI. In another embodiment, therefore, upon administration of a composition of the invention to a human subject, the PPI undergoes reduced gastrointestinal degradation by comparison with administration of PPI alone. This can be determined by any suitable method, for example by sampling and assaying contents of the subjects stomach at various time points after ingestion of a composition of the invention or a comparative PPI composition comprising no protein component (e.g. naked PPI).
In another embodiment, a composition of the invention does not contain an amino acid. In yet another embodiment, a composition of the invention does not contain an alkali earth metal buffering agent. In still another embodiment, a composition of the invention does not contain an alkaline earth metal buffering agent. In another embodiment, a composition of the invention does not contain aluminum and/or aluminum glycinate. Pharmaceutical Excipients
Compositions of the invention can, if desired, include one or more pharmaceutically acceptable excipients. The term "excipient" herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition. Excipients include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, lubricants, glidants, surface modifying agents, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Any such excipients can be used in any dosage forms of according to the present invention, including liquid, solid or semi-solid dosage forms. Excipients optionally employed in compositions of the invention can be solids, semi-solids, liquids or combinations thereof. Compositions of the invention containing excipients can be prepared by any known technique of pharmacy that comprises admixing an excipient with a drug or therapeutic agent.
Compositions of the invention optionally comprise one or more pharmaceutically acceptable diluents as excipients. Suitable diluents illustratively include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., Celutab™ and Emdex™); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of α- and amorphous cellulose (e.g., Rexcel™) and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Such diluents, if present, constitute in total about 5% to about 99%, about 10% to about 85%, or about 20% to about 80%, of the total weight of the composition. The diluent or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
The use of extragranular microcrystalline cellulose (that is, microcrystalline cellulose added to a wet granulated composition after a drying step) can be used to improve hardness (for tablets) and/or disintegration time.
Compositions of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablet formulations. Suitable disintegrants include, either individually or in combination, starches, including sodium starch glycolate (e.g., Explotab™ of PenWest) and pregelatinized corn starches (e.g., National™ 1551, National™ 1550, and Colocorn™ 1500), clays (e.g., Veegum™ HV), celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol™ of FMC), alginates, crospovidone, and gums such as agar, guar, xanthan, locust bean, karaya, pectin and tragacanth gums.
Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to a granulation step or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, about 0.2% to about 10%, or about 0.2% to about 5%, of the total weight of the composition.
Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and, if present, typically constitutes about 0.2% to about 10%, about 0.2% to about 7%, or about 0.2% to about 5%, of the total weight of the composition.
Compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients, particularly for tablet formulations. Such binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion. Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., National™ 1511 and National™ 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., Tylose™); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g., Klucel™); and ethylcellulose (e.g., Ethocel™). Such binding agents and/or adhesives, if present, constitute in total about 0.5% to about 25%, about 0.75% to about 15%, or about 1% to about 10%, of the total weight of the composition.
Compositions of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Non-limiting examples of surfactants that can be used as wetting agents in compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and di glycerides (e.g., Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acid esters, for example propylene glycol laurate (e.g., Lauroglycol™ of Gattefosse), sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate, sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. Such wetting agents, if present, constitute in total about 0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of the total weight of the composition.
Compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients. Suitable lubricants include, either individually or in combination, glyceryl behapate (e.g., Compritol™ 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%, or about 0.25% to about 5%, of the total weight of the composition.
Suitable anti-adherents include talc, cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates. Talc is a anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend. Talc, if present, constitutes about 0.1% to about 10%, about 0.25% to about 5%, or about 0.5% to about 2%, of the total weight of the composition.
Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred.
Compositions of the present invention can comprise one or more anti-foaming agents. Simethicone is an illustrative anti-foaming agent.
Compositions of the present invention can comprise one or more flavoring agents, sweetening agents, and/or colorants. Flavoring agents useful in the present invention include, without limitation, acacia syrup, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butter, butter pecan, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citrus punch, citrus cream, cocoa, coffee, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, MagnaSweet®, maltol, mannitol, maple, menthol, mint, mint cream, mixed berry, nut, orange, peanut butter, pear, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, and combinations thereof, for example, anise-menthol, cherry- anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, etc. Flavoring agents, if present, constitute about 0.001% to about 40%, about 0.001% to about 30%, or about 0.001% to about 20%, of the total weight of the composition.
Sweetening agents that can be used in the present invention include, for example, acesulfame potassium (acesulfame K), alitame, aspartame, cyclamate, cylamate, dextrose, isomalt, MagnaSweet®, maltitol, mannitol, neohesperidine DC, neotame, Prosweet® Powder, saccharin, sorbitol, stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the like. Sweetening agents, if present, constitute about 0.001% to about 40%, about 0.001% to about 30%, or about 0.001% to about 20%, of the total weight of the composition.
In one embodiment, compositions of the invention comprise glycerine, triglycerides, fatty acid esters and/or polyethyleneglycols.
The foregoing excipients can have multiple roles as is known in the art. For example, starch can serve as a filler as well as a disintegrant. The classification of excipients above is not to be construed as limiting in any manner. Pharmaceutical Dosage Forms
Compositions of the present invention can be formulated as solid, liquid or semi-solid dosage forms. In one embodiment, such compositions are in the form of discrete dose units or dosage units. The terms "dose unit" and/or "dosage unit" herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. Such dosage units may be administered one to a small plurality {i.e. 1 to about 4) of times per day, or as many times as needed to elicit a therapeutic response. A particular dosage form can be selected to accommodate any desired frequency of administration to achieve a specified daily dose. Typically one dose unit, or a small plurality (i.e. up to about 4) of dose units, provides a sufficient amount of the active drug to result in the desired response or effect.
Alternatively, compositions of the invention can also be formulated for rectal, topical, or parenteral (e.g. subcutaneous, intramuscular, intravenous and intradermal or infusion) delivery.
In one embodiment, compositions of the invention are suitable for rapid onset of therapeutic effect, particularly with respect to the PPI component. In another embodiment, upon oral administration of a composition of the invention to a subject, at least a therapeutically effective amount of the PPI is available for absorption in the stomach of the subject. As discussed above, most commercially available PPIs require enteric coating to prevent exposure of the PPI to gastrointestinal fluids (and consequent drug degradation) by way of pH dependent coatings. Such coating, in turn, prevents rapid PPI absorption and therapeutic onset of action. In some embodiments, compositions of the present invention, by contrast, do not require enteric coating to maintain drug stability in gastrointestinal fluids and thereby provide for rapid absorption and onset of therapeutic effect.
In one embodiment, a single dosage unit, be it solid or liquid, comprises a therapeutically effective amount or a therapeutically and/or prophylactically effective amount of PPI. The term "therapeutically effective amount" or "therapeutically and/or prophylactically effective amount" as used herein refers to an amount of compound or agent that is sufficient to elicit the required or desired therapeutic and/or prophylactic response, as the particular treatment context may require.
It will be understood that a therapeutically and/or prophylactically effective amount of a drug for a subject is dependent inter alia on the body weight of the subject. A "subject" herein to which a therapeutic agent or composition thereof can be administered includes a human subject of either sex and of any age, and also includes any nonhuman animal, particularly a domestic or companion animal, illustratively a cat, dog or a horse.
Solid Dosage Forms In some embodiments, compositions of the invention are in the form of solid dosage forms. Non-limiting examples of suitable solid dosage forms include tablets (e.g. suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, effervescent tablets, bilayer tablets, etc), caplets, capsules (e.g. a soft or a hard gelatin capsule), powder (e.g. a packaged powder, a dispensable powder or an effervescent powder), lozenges, sachets, cachets, troches, pellets, granules, microgranules, encapsulated microgranules, powder aerosol formulations, or any other solid dosage form reasonably adapted for oral administration.
Tablets are an illustrative dosage form for compositions of the invention. Tablets can be prepared according to any of the many relevant, well known pharmacy techniques. In one embodiment, tablets or other solid dosage forms can be prepared by processes that employ one or a combination of methods including, without limitation, (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion.
The individual steps in the wet granulation process of tablet preparation typically include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation and final grinding. Dry granulation involves compressing a powder mixture into a rough tablet or "slug" on a heavy-duty rotary tablet press. The slugs are then broken up into granular particles by a grinding operation, usually by passage through an oscillation granulator. The individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation). Typically, no wet binder or moisture is involved in any of the steps.
In another embodiment, solid dosage forms such as tablets can be prepared by mixing a PPI with at least one buffering agent as described herein above and, if desired, with one or more optional pharmaceutical excipient to form a substantially homogeneous preformulation blend. The preformulation blend can then be subdivided and optionally further processed (e.g. compressed, encapsulated, packaged, dispersed, etc.) into any desired dosage forms.
Compressed tablets can be prepared by compacting a powder or granulation composition of the invention. The term "compressed tablet" generally refers to a plain, uncoated tablet suitable for oral ingestion, prepared by a single compression or by pre-compaction tapping followed by a final compression. Tablets of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of improved handling or storage characteristics. Preferably, however, any such coating will be selected so as to not substantially delay onset of therapeutic effect of a composition of the invention upon administration to a subject. The term "suspension tablet" as used herein refers to a compressed tablet that rapidly disintegrates after placement in water.
In one embodiment, a composition of the invention comprises a multi-layer tablet having a core comprising a proton pump inhibitor; the core is substantially or completely surrounded by the buffering agent. In one such embodiment, the buffering agent layer completely surrounds the core. In another embodiment, the buffering agent layer partially surrounds the core. In yet another embodiment, the buffering agent layer is in contact with a portion of or with all of the surface area of the core.
In another embodiment, one or more intermediate layers exists in between the core and the buffering agent. The intermediate layers can comprise any pharmaceutically acceptable material, preferably inert and non-pH sensitive coating materials such as polymer based coatings.
In still another embodiment, compositions of the invention can be microencapsulated, for example as is described in U.S. Patent Publication No. 2005/0037070, hereby incorporated by reference herein in its entirety.
In another embodiment, a composition of the invention comprises a proton pump inhibitor and a buffering agent mixed together in powder form and optionally filled into a capsule, for example a hard or soft gelatin or HPMC capsule.
In another embodiment, a composition of the invention is in the form of a molded article, for example a pellet. The term "molded article" herein refers to a discrete dosage form that can be formed by compression, extrusion, or other similar processes. In one embodiment, the molded article is moldable. The term "moldable" in the present context means capable of being shaped or molded by hand. A moldable article herein will therefore have a hardness lower than a conventional pharmaceutical tablet. Such a moldable article will also be capable of being chewed by an animal, for example a horse.
Such an article can comprise, in addition to the PPI and buffering agent, and other excipients described herein, a filler, a sweetener and a flavoring agent. Extrusion is a process of shaping material by forcing it to flow through a shaped opening in a die or other solid. Extruded material emerges as an elongated article with substantially the same profile as the die opening. Liquid Dosage Forms
In another embodiment of the invention, compositions can be in the form of liquid dosage forms or units. Non-limiting examples of suitable liquid dosage forms include solutions, suspension, elixirs, syrups, liquid aerosol formulations, etc.
In one embodiment, a liquid composition comprising water, PPI, a buffering agent and vitamin B12 and/or iron can be prepared. In another embodiment, compositions of the invention are in the form of a powder for suspension that can be suspended in a liquid vehicle prior to administration to a subject. While the powder for suspension itself, can be a solid dosage form of the present invention, the powder dispersed in liquid also comprises a liquid embodiment of the invention.
Generally, a liquid composition of PPI (without a buffering agent) would exhibit a very short period of stability, even when maintained under refrigerated conditions. This is particularly inconvenient in the hospital setting as fresh batches of suspension are continually required. Suspension compositions of the invention comprise at least one PPI, a buffering agent, a liquid media (e.g. water, de-ionized water, etc.), vitamin B12 and or iron, and one or more optional pharmaceutical excipients. Such compositions, upon storage in a closed container maintained at either room temperature, refrigerated (e.g. about 5 -10 °C) temperature, or freezing temperature for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about 90%, at least about 92.5%, at least about 95%, or at least about 97.5% of the original PPI present therein.
Parietal Cell Activators
In one embodiment, a composition of the present invention can further include one or more parietal cell activators. Parietal cell activators such as chocolate, calcium and sodium bicarbonate and other alkaline substances stimulate the parietal cells and enhance the pharmacologic activity of the PPI administered. For the purposes of this application, "parietal cell activator" or "activator" shall mean any compound or mixture of compounds possessing such stimulatory effect including, but not limited to, chocolate, sodium bicarbonate, calcium (for example, calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate and calcium glycerophosphate), peppermint oil, spearmint oil, coffee, tea and colas (even if decaffeinated), caffeine, theophylline, theobromine, and amino acids (particularly aromatic amino acids such as phenylalanine and tryptophan) and combinations thereof. Parietal cell activators, if desired, are typically present in a composition of the invention in an amount sufficient to produce the desired stimulatory effect without causing untoward side effects to patients. For example, chocolate, as raw cocoa, is administered in an amount of about 5 mg to 2.5 g per 20 mg dose of omeprazole (or equivalent pharmacologic dose of another proton pump inhibiting agent). The dose of activator administered to a subject, for example, a horse, in the context of the present invention should be sufficient to result in enhanced effect of a PPI over a desired time frame.
Administration
Compositions of the present invention are useful for treating and/or preventing, inter- alia, gastrointestinal disorders and, in particular, acid related gastrointestinal disorder in a subject in need thereof. The phrase "acid related gastrointestinal disorder" or "acid related gastrointestinal disease" refers generally to a disease or disorder that occurs due to an imbalance between acid and pepsin production on the one hand, so-called aggressive factors, and mucous, bicarbonate, and prostaglandin production on the other hand, so-called defensive factors. The term "subject" means a human or an animal. In one embodiment, the subject is an animal such as a horse, a dog, or a cat.
The term "treat" or "treatment" as used herein refers to any treatment of a disorder or disease associated with a gastrointestinal disorder, and includes, but is not limited to, preventing the disorder or disease from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, for example, arresting the development of the disorder or disease; relieving the disorder or disease, for example, causing regression of the disorder or disease; or relieving the condition caused by the disease or disorder, for example, stopping the symptoms of the disease or disorder.
The term "prevent" or "prevention," in relation to a gastrointestinal disorder or disease, means preventing the onset of gastrointestinal disorder or disease development if none had occurred, or preventing further gastrointestinal disorder or disease development if the gastrointestinal disorder or disease was already present.
In mammals gastrointestinal disorders include, but are not limited to, duodenal ulcer, gastric ulcer, acid dyspepsia, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, (acid reflux), heartburn, nighttime heartburn symptoms, nocturnal acid breakthrough (NAB), and gastrointestinal pathological hypersecretory conditions such as Zollinger Ellison Syndrome. Illustrative acid-related gastrointestinal disorders including duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease (GERD), erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease (acid reflux), pathological gastrointestinal hypersecretory disease, Zollinger Ellison Syndrome, acid dyspepsia, heartburn, and/or NSAED induced ulcer.
Compositions of the invention are to be administered and dosed in accordance with good medical practice, talcing into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration and other factors known to medical practitioners
The percent of intact drug that is absorbed into the bloodstream is not narrowly critical, as long as a therapeutic-disorder-effective amount, for example a gastrointestinal-disorder-effective amount of a proton pump inhibiting agent, is absorbed following administration of the pharmaceutical composition to a subject. It will be understood that the amount of proton pump inhibiting agent and/or antacid that is administered to a subject is dependent on various factors including the sex, general health, diet, and/or body weight of the subject.
In various other embodiments of the present invention, the amount of proton pump inhibitor administered to a subject is about 0.5 to about 3 mg/Kg of body weight or about 1 to about 2.5 mg/Kg of body weight, illustratively about 0.5 mg/Kg of body weight, about 1 mg/Kg of body weight, about 1.5 mg/Kg of body weight, about 2 mg/Kg of body weight or about 2.5 mg/Kg of body weight.
Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for subject administration. Studies in animal models generally may be used for guidance regarding effective dosages for treatment of gastrointestinal disorders or diseases in accordance with the present invention. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route chosen for administration, the condition of the particular subject.
In another embodiment of the present invention, the composition is administered to a subject, for example a horse, in an amount sufficient to achieve a measurable serum concentration of a non-acid degraded or non-acid reacted proton pump inhibitor greater than about 100 mcg/L within about 30 minutes or about 15 minutes or about 10 minutes after administration of the composition.
In another embodiment of the present invention, the composition is administered to a subject, for example a horse, in an amount sufficient to achieve a measurable serum concentration of the proton pump inhibitor greater than about 100 mcg/L within about 15 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 100 mcg/L from about 15 minutes to about 1 hour after administration of the composition. In yet another embodiment of the present invention, the composition is administered to the subject in an amount sufficient to achieve a measurable serum concentration of the proton pump inhibitor greater than about 100 mcg/L within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 100 mcg/L from about 15 minutes to about 1 hour after administration of the composition.
In another embodiment, the composition is administered to a subject, for example a horse, in an amount sufficient to achieve a measurable serum concentration of the proton pump inhibitor greater than about 100 mcg/L within about 30 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 100 mcg/L from about 30 minutes to about 1 hour after administration of the composition. In yet another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibitor greater than about 100 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 100 ng/ml from about 30 minutes to about 1 hour after administration of the composition.
Contemplated compositions of the present invention provide a therapeutic effect as proton pump inhibiting agent medications over an interval of about 5 minutes to about 24 hours after administration, enabling, for example, once-a-day, twice-a-day, or three times a day administration if desired.
In another embodiment, upon oral administration of a composition of the invention to a plurality of subjects, the subjects exhibit an average Tmax of PPI within about 30 seconds to about 90 minutes, within about 1 minute to about 80 minutes, within about 5 minutes to about 60 minutes, within about 10 minutes to about 50 minutes, or within about 15 minutes to about 45 minutes. Those skilled in the art will readily appreciate that numerous other embodiments, modifications and equivalents are contemplated and encompassed by the disclosure of the present invention.
All U.S. Patents and published U.S. patent applications listed herein are hereby incorporated by reference in their entirety. All patents, patent applications and publications referenced herein are hereby incorporated by reference herein to the fullest extend allowed under the law.
EXAMPLES Example 1
Several pellets were prepared, each comprising non-enteric coated omeprazole, sodium bicarbonate, pregelatinized starch, sucrose and flavoring agent (apple). These ingredients were dry blended and compressed in Parr pellet press. The pellets were then administered to a horse as follows.
Little Joe, a 545 kg horse experiencing gastric ulcer, was given several large pellets as described above. The total dose of omeprazole administered was 1090 mg (2 mg/kg). Blood was drawn at several time points over a period of four hours following administration. Plasma was collected from the horse in tubes without anticoagulant. The blood was allowed to clot and was then centrifuged; serum was frozen for later extraction. Extraction was performed using 75 microliter of 0.1 M sodium bicarbonate and 3 microgram/ml of lansoprazole (internal standard) were added to 0.5 ml serum. Five ml of ether: dichloromethane (7:3) were added to each tube. The tubes were mixed by vortexing for 20 seconds, and centrifuged for 10 min at 2500 RPM. A 2.5 ml aliquot of the top organic layer was transferred to a new tube and the solvent was evaporated using a stream of oxygen. The dry samples were reconstituted in 0.25 ml of the HPLC mobile phase.
The HPLC column was an Alltech Prevail Cl 8 5 micron, 15 cm length. The mobile phase consisted of 50% of 15 mM sodium phosphate pH 7.4, 40% methanol and 10% acetonitrile used at a flow rate of 1.1 ml/rαin. A UV detector was used to detect the peaks at 300 nm. Data are shown in Fig. 1, below.

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical composition comprising at least one acid labile proton pump inhibitor, a buffering agent and at least one pharmaceutically acceptable excipient, wherein:
(a) the at least one acid labile proton pump inhibitor is present in the composition in an amount of about 200 mg to about 3000 mg;
(b) a therapeutically effective portion of the at least one acid labile proton pump inhibitor is not enteric coated;
(c) the buffering agent is present in the composition in an amount of about 500 mg to about 5000 mg; and
(d) the composition is in the form of 1 to a small plurality of moldable articles.
2. The composition of Claim 1 wherein the at least one proton pump inhibitor is of Formula (I):
Figure imgf000029_0001
wherein
R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;
R2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl; R3 and R5 are the same or different and each is hydrogen, alkyl, alkoxy, amino, or alkoxyalkoxy;
R4 is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy;
Q is nitrogen, CH, or CR1;
W is nitrogen, CH, or CR1; y is an integer of 0 through 4; and
Z is nitrogen, CH, or CR1; or a free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof.
3. The composition of claim 1 wherein the at least one proton pump inhibitor is omeprazole, tenatoprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, leminoprazole and nepaprazole or a free base, a free acid, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of such compounds.
4. The composition of claim 1 wherein the at least one proton pump inhibitor is omeprazole or lansoprazole.
5. The composition of claim 1 wherein the at least one proton pump inhibitor is present in an amount of about 1 mg to about 3000 mg on a dry weight basis.
6. The composition of claim 1 wherein the at least one proton pump inhibitor is present in an amount of about 50 mg to about 3000 mg on a dry weight basis.
7. The composition of claim 1 wherein the at least one proton pump inhibitor is present in an amount of about 100 mg to about 2000 mg on a dry weight basis.
8. The composition of claim 1 wherein the buffering agent is present in an amount of about 250 mg to about 100 g on a dry weight basis.
9. The composition of claim 1 wherein the buffering agent is present in an amount of about 500 mg to about 10 g on a dry weight basis.
10. The composition of claim 1 wherein the buffering agent is present in an amount of about 500 mg to about 5 g on a dry weight basis.
11. The composition of claim 1 wherein the excipient is selected from starch, pregelatinized starch, flavoring agents and sweetening agents.
12. An orally deliverable pharmaceutical composition in the form of a moldable article comprising omeprazole, a buffering agent, pregelatinized starch, a sweetening agent and a flavoring agent.
13. The composition of claim 12 wherein the moldable article is prepared by direct compression or extrusion.
14. A method of treating a gastric acid related disorder in a horse in need thereof, the method comprising administering to the horse one to a small plurality of moldable articles comprising at least one acid labile proton pump inhibitor, a buffering agent and at least one pharmaceutically acceptable excipient, wherein:
(a) the at least one proton pump inhibitor is present in said one to a small plurality of molded articles in an amount of about 200 mg to about 3000 mg;
(b) a therapeutically effective portion of the at least one proton pump inhibitor is not enteric coated; and
(c) the buffering agent is present in said one to a small plurality of molded articles in an amount of about 500 mg to about 5000 mg.
15. The method of claim 14 wherein said one to a small plurality of moldable articles comprises one or more compressed or extruded pellets.
16. The method of claim 15 wherein the at least one proton pump inhibitor is of Formula (I):
Figure imgf000031_0001
wherein R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;
R is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralky], carboaikoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;
R3 and R5 are the same or different and each is hydrogen, alkyl, alkoxy, amino, or alkoxyalkoxy;
R4 is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy;
Q is nitrogen, CH, or CR1;
W is nitrogen, CH, or CR1; y is an integer of 0 through 4; and
Z is nitrogen, CH, or CR1 ; or a free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof.
17. The method of claim 14 wherein the at least one proton pump inhibitor is omeprazole, tenatoprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, leminoprazole and nepaprazole or a free base, a free acid, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of such compounds.
18. The method of claim 14 wherein the at least one proton pump inhibitor is omeprazole or lansoprazole.
19. The method of claim 14 wherein the at least one proton pump inhibitor is present in an amount of about ϊ mg to about 3000 mg on a dry weight basis.
20. The method of claim 14 wherein the at least one proton pump inhibitor is present in an amount of about 50 mg to about 3000 mg on a dry weight basis.
21. The method of claim 14 wherein the at least one proton pump inhibitor is present in an amount of about 100 mg to about 2000 mg on a dry weight basis.
22. The method of claim 14 wherein the buffering agent is present in an amount of about 250 mg to about 100 g on a dry weight basis.
23. The method of claim 14 wherein the buffering agent is present in an amount of about 500 mg to about 10 g on a dry weight basis.
24. The method of claim 14 wherein the buffering agent is present in an amount of about 500 mg to about 5 g on a dry weight basis.
25. The method of claim 14 wherein the excipient is selected from starch, pre gelatinized starch, flavoring agents and sweetening agents.
PCT/US2006/015939 2005-04-26 2006-04-25 Composition comprising proton pump inhibitor and buffer WO2006116556A2 (en)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2008057802A2 (en) * 2006-10-27 2008-05-15 The Curators Of The University Of Missouri Compositions comprising at least one acid labile proton pump inhibiting agents, optionally other pharmaceutically active agents and methods of using same
US9351966B2 (en) 2008-02-20 2016-05-31 The Curators Of The University Of Missouri Composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008057802A2 (en) * 2006-10-27 2008-05-15 The Curators Of The University Of Missouri Compositions comprising at least one acid labile proton pump inhibiting agents, optionally other pharmaceutically active agents and methods of using same
WO2008057802A3 (en) * 2006-10-27 2008-11-06 Univ Missouri Compositions comprising at least one acid labile proton pump inhibiting agents, optionally other pharmaceutically active agents and methods of using same
US9351966B2 (en) 2008-02-20 2016-05-31 The Curators Of The University Of Missouri Composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same

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