WO2006116583A2 - Compositions comprenant un benzimidazole polymerise et un tampon et procedes permettant de les utiliser - Google Patents

Compositions comprenant un benzimidazole polymerise et un tampon et procedes permettant de les utiliser Download PDF

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WO2006116583A2
WO2006116583A2 PCT/US2006/015983 US2006015983W WO2006116583A2 WO 2006116583 A2 WO2006116583 A2 WO 2006116583A2 US 2006015983 W US2006015983 W US 2006015983W WO 2006116583 A2 WO2006116583 A2 WO 2006116583A2
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composition
agent
sodium
magnesium
calcium
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WO2006116583A3 (fr
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Jeffrey Phillips
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The Curators Of The University Of Missouri
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom

Definitions

  • the present invention relates to pharmaceutical compositions comprising a polymerized benzimidazole and a buffering agent, to methods for manufacture of such compositions, and to use of such compositions in treating various diseases and/or disorders.
  • Gastrointestinal disorders such as active duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome represent a major global health concern impacting millions of people globally. In fact, it is estimated that as many as 60 million Americans experience reflux at least once a month, while approximately 19 million Americans suffer from GERD.
  • H 2 histamine antagonists and antacids have been treated with H 2 histamine antagonists and antacids.
  • many such available treatments are not completely effective in ameliorating the disorders themselves or their symptoms; additionally, many produce adverse side effects including, among others, constipation, diarrhea, and thrombocytopenia.
  • H 2 antagonists such as ranitidine and cimetidine are relatively costly modes of therapy generally requiring multiple daily doses to produce some control of acid secretion.
  • tolerance to H 2 antagonists increases with continued use thus prohibiting clinical utility in chronic dosing settings.
  • PPIs proton pump inhibitors
  • H + , K + -ATPase of the parietal cell the final common pathway for gastric acid secretion.
  • PPIs proton pump inhibitors
  • One particular class of PPIs includes substituted benzimidazole compounds that contain a sulfinyl group bridging substituted benzimidazole and pyridine rings. At neutral pH, these PPIs are chemically stable, lipid-soluble compounds that have little or no inhibitory activity. It is believed that the neutral PPIs reach parietal cells from the blood and diffuse into the secretory canaliculi where they become protonated and thereby trapped.
  • the protonated agent is then believed to rearrange to form a sulfenic acid and a sulfenamide.
  • the sulfenamide in turn, is thought to interact covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane-spanning H + , K + -ATPase. See e.g. Hardman et ah, Goodman & Gilman's The Pharmacological Basis of Therapeutics, p. 907, 9 th ed. (1996).
  • commercially available substituted benzimidazole compounds 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, which coating protects the drug from contact with acidic stomach secretions.
  • enteric coated solid dosage forms for example enteric coated tablets, which coating protects the drug from contact with acidic stomach secretions.
  • enteric coating 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 is particularly undesirable for patients in need of rapid relief from one or more of the above described disorders or symptoms.
  • enteric coated PPIs include omeprazole (Prilosec®), lansoprazole (Prevacid®), perprazole (also referred to as esomeprazole; Nexium®), rabeprazole (Aciphex®), and pantoprazole (Protonix®).
  • Omeprazole a substituted benzimidazole, has the following chemical name: 5-methoxy-2-[ (4- methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl]-lH-benzimidazole.
  • U.S. Patent No. 4,786,505 to Lovgren et al. discloses that a pharmaceutical oral solid dosage form of omeprazole must be protected from contact with acidic gastric juice by an enteric coating to maintain its pharmaceutical activity. That patent describes an enteric coated omeprazole preparation containing an alkaline core comprising omeprazole, a subcoating over the core, and an enteric coating over the subcoating.
  • the present invention provides pharmaceutical compositions comprising at least one polymerized benzimidazole, for example a polymerized proton pump inhibitor, one or more buffering agents and one or more optional pharmaceutical excipients.
  • Such compositions can further comprise a protein component.
  • the present invention provides pharmaceutical compositions comprising at least one polymerized benzimidazole, for example a PPI, a protein component and one or more optional pharmaceutical excipients. Such compositions can further comprise a buffering agent.
  • the present invention provides an orally deliverable pharmaceutical composition comprising a polymerized PPI and one or more buffering agents (and/or a protein component) wherein upon oral administration of the composition to a plurality of fasted adult human subjects, the subjects exhibit an average plasma concentration of the PPI moiety of at least about 0.1 mg/ml at any time within about 30 minutes after administration.
  • Also provided by the present invention are methods of treating acid related gastrointestinal disorders by administering to a subject one or more compositions described herein.
  • 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 benzimidazole moiety is present in a composition of the invention in an amount of about 1 to about 2000 mg; in another embodiment, a buffering agent is present in a composition of the invention
  • 9065024.1 4 invention in an amount of about 200 mg to about 3500 nig.
  • a composition has a benzimidazole:buffering agent weight ratio of less than or greater than 1:200, less than or greater than 1:3500, less than or greater than 10: 1 (2000/200), less than or greater than 1 :3500, less than or greater than about 200:3500, or in ranges of about 1:200 to about 1:3500, about 1:3500 to about 10:1, 1:200 to about to about 200:3500, 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 present invention comprise a polymeric benzimidazole, also referred to herein as "polymer-based benzimidazoles", or “polymerized benzimidazoles”.
  • polymeric benzimidazole and the interchangeable terms listed immediately above refer to a compound comprising a benzimidazole moiety, wherein the compound is bonded or linked to a least one pharmaceutically acceptable polymer.
  • benzimidazole moiety refers to the benzimidazole moiety of formulas (II) and (III) as shown herein below, not including any pharmaceutically acceptable polymer substituted at the N position of the benzimidazole ring.
  • Benzimidazole moiety-containing compounds or drugs useful in the present invention include any pharmacologically active benzimidazole compounds that are susceptible to acid catalyzed degradation and that can be substituted at the N position of the benzimidazole ring.
  • pharmacologically active benzimidazole compound includes any such compound or drug which is capable of producing a pharmacological response in a subject, irrespective of whether therapeutic, diagnostic, or prophylactic in nature.
  • pharmacologically active agents useful in the present invention are those which are degraded by acids, even organic acids, or are degraded in acid catalyzed reactions.
  • a particularly preferred class of benzimidazole moiety-containing acid- labile compounds suitable for polymeric N-substitution and preparation of polymeric benzimidazoles useful in the present invention include substituted benzimidazole compounds possessing pharmacological activity as an inhibitor of H + , K + -ATPase (i.e. proton pump inhibitors).
  • proton pump inhibitors can, if desired, be in the form of a free base, a free acid, a salt, an ester, a hydrate, an amide, an enantiomer, an isomer, a tautomer, a prodrug, a polymorph, a derivative or the like, and can be in racemic or enantiomeric form.
  • Polymeric benzimidazoles suitable for use in the present invention can be prepared by any process known in the art.
  • otherwise acid-labile benzimidazole compounds can be used as starting agents for formation of polymeric benzimidazoles by polymeric N-substitution as described in U.S. Patent No. 6,617,338, which is hereby incorporated by reference in its entirety.
  • a buffering agent or protein component as descirbed herein, enzymes and chemicals in the gastrointestinal fluid cleave at the hydrolysable group (e.g.
  • N-substituted benzimidazole derivative that may or may not be the original starting benzimidazole moiety (e.g. moiety B below) having a portion of the polymer remaining attached thereto.
  • the N-substituted benzimidazole derivative in the presence of the buffering agent or protein component, maintains its pharmacological activity as an inhibitor of H + , K + -ATPase, while the cleaved portion of the polymer becomes an inert, non-toxic and/or non-absorbable metabolite that is excreted from the body.
  • suitable polymeric benzimidazoles are those compounds of formula (I):
  • R 7 , R 8 , R 9 , and R 10 are independently H or a lower alkyl (preferably methyl or ethyl), for example a C 1-4 alkyl; U is OCOCH 2 COO
  • R 11 is H, CH 3 , C 2 H 5 , or CONH 2 ;
  • Y and V are independently OH or NH 2 ;
  • R 1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which may optionally be fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;
  • Q is nitrogen, CH, or CR 1 ;
  • W is nitrogen, CH, or CR 1 ; and y is an integer of 0 through 4; or a salt, an ester, a hydrate, an amide, an enantiomer, an isomer, a tautomer, a polymorph, a polymorph, a prodrug, or a derivative thereof.
  • (B) is a benzimidazole moiety of formula (III):
  • R 1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which may optionally be fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;
  • R 3 and R 5 are independently hydrogen, alkyl, alkoxy, amino, or alkoxyalkoxy;
  • R 4 is hydrogen, alkyl, 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 salt, an ester, a hydrate, an amide, an enantiomer, an isomer, a tautomer, a polymorph, a prodrug, or a derivative thereof.
  • suitable PPIs for use as the benzimidazole moiety (B) include esomeprazole (also referred to as S-omeprazole), ilaprazole (U.S. Pat. No.
  • lansoprazole omeprazole
  • pantoprazole pariprazole
  • rabeprazole tenatoprazole
  • nepaprazole or a free base, a free acid, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of such compounds.
  • 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 can be prepared from 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.
  • Acid addition salts can be 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 inhibitors 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. 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
  • 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
  • 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.
  • An exemplary "isomer" of a substituted bicyclic aryl-imidazole is the isomer of omeprazole including but not limited to isomers described in: Oishi et al, Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. Patent
  • polymorphs include, but are not limited to, those described in
  • compositions of the invention comprise at least one polymeric benzimidazole.
  • at least one polymeric benzimidazole is present in a composition of the invention in an amount corresponding to a benzimidazole moiety weight of about 0.0005% to about 80%, about 0.005% to about 70%, about 0.05% to about 60%, or about 0.5% to about 50%, by weight of the composition.
  • the benzimidazole moiety itself (without regard for the weight of the polymer portion) is present in a composition of the invention in a total amount of about 1 to about 2000 mg, about 2.5 to about 1700 mg, about 5 to about 1500 mg, about 7.5 to about 1250 mg, about 7.5 to about 1000 mg, about 7.5 to about 750 mg, about 7.5 to about 500 mg, or about 7.5 mg to about 250 mg, for example about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50
  • compositions of the invention comprise at least one polymeric benzimidazole in an amount of about 0.0005% to about 80%, about
  • At least one polymeric benzimidazole is present in the composition in a total amount of about 5 to about 2500 mg, about 7.5 to about 2000 mg, about 10 to about 1500 mg, or about 15 to about 1000 mg, for example about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg,
  • no portion of the polymeric benzimidazole is enteric coated. In another embodiment, at least a portion of the polymeric benzimidazole is not enteric coated. In another embodiment, at least a therapeutically effective portion of the polymeric benzimidazole 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 polymeric benzimidazole is not enteric coated.
  • the amount of benzimidazole moiety that is administered to a subject is dependent on, inter alia, the type of subject, the sex, age, general health, diet, and/or body weight of the subject.
  • a composition of the invention comprises a benzimidazole moiety such as omeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole or pariprazole, and the subject is a child or a small animal ⁇ e.g. a dog)
  • a relatively low amount of the benzimidazole moiety in the dose range provided herein is likely to provide blood serum concentrations consistent with therapeutic effectiveness.
  • compositions of the invention can also optionally comprise one or more non-polymeric benzimidazoles.
  • non-polymeric benzimidazoles are those of formula (IV): wherein
  • 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 are the same or different and each is hydrogen, alkyl, alkoxy, amino, or alkoxyalkoxy;
  • R 4 is hydrogen, alkyl, 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 salt, an ester, a hydrate, an amide, an enantiomer, an isomer, a tautomer, a prodrug, a polymorph, or a derivative thereof.
  • Illustrative optional non-polymeric benzimidazoles include omeprazole, tenatoprazole, lansoprazole, rabeprazole, esomeprazole (also referred to as S- omeprazole), pantoprazole, pariprazole, and nepaprazole or a free base, a free acid, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of these compounds, as well as all those substituted benzimidazoles described herein above. Buffering Agent
  • compositions of the invention comprise one or more pharmaceutically acceptable 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.
  • 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 niEq/mg to about 5 mEq/mg of the benzimidazole moiety, about 0.5 mEq/mg to about 3 mEq/mg of the benzimidazole moiety, about 0.6 mEq/mg to about 2.5 mEq/mg of the benzimidazole moiety, about 0.7 mEq/mg to about 2.0 mEq/mg of the benzimidazole moiety, about 0.8 mEq/mg to about 1.8 mEq/mg of the benzimidazole moiety, about 1.0 mEq/mg to about 1.5 mEq/mg of the benzimidazole moiety.
  • the buffering agent is present in an amount of at least about 0.5 mEq/mg of the benzimidazole moiety, at least about 0.75 mEq/mg of the benzimidazole moiety, or at least about 1 mEq/mg of the benzimidazole moiety on a dry weight basis.
  • one or more buffering agents are present in a total amount of about 0.5 mEq to about 160 mEq, about 1 mEq to about 150 mEq, about 10 mEq to about 150 mEq, about 10 mEq to about 75 mEq, about 10 mEq to about 60 mEq, or about 10 mEq to about 50 mEq.
  • a composition of the invention can comprise about 1 mEq, or about 5 mEq, or about 10 mEq, or about 15 mEq, or about 20 mEq, or about 25 mEq, or about 30 mEq, or about 35 mEq, or about 40 mEq, or about 45 mEq, or about 50 mEq, or about 60 mEq, or about 70 mEq, or about 80 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 160 mEq of buffering agent.
  • one or more buffering agents are present in a total amount of at least about 10 mEq, at least about 11 mEq, at least about 12 mEq, at least about 13 mEq, at least about 14 mEq, or at least about 15 mEq.
  • one or more buffering agents and the benzimidazole moiety 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 200 to about 3500 mg, about 300 to about 3000 mg, about 400 to about 2500 mg, or about 500 to about 2200 mg.
  • the amount of buffering agent present in a composition of the invention is about 200 mgs, or about 300 mgs, or about 400 mgs, or about 500 mgs, or about 600 mgs, or about 700 mgs, or about 800 mgs, or about 900 mgs, or about 1000 mgs, or about 1100 mgs, or about 1200 mgs, or about 1300 mgs, or about 1400 mgs, or about 1500 mgs, or about 1600 mgs, or about 1700 mgs, or about 1800 mgs, or about 1900 mgs, or about 2000 mgs, or about 2100 mgs, or about 2200 mgs, or about 2300 mgs, or about 2400 mgs, or about 2500 mgs, or about 2600 mgs, or about 2700 mgs, or about 2800 mgs, or about 2900 mgs, or about 3000 mgs, or about 3200 mgs, or about 3500 mgs.
  • one or more buffering agents are present in a composition of the invention in a total amount that is greater than 800 mg, for example at least about 920 mg or at least about 1000 mg.
  • the buffering agent and PPI are present in a weight ratio greater than 20:1, not less than about 21:1, not less than about 22:1, not less than about 23:1, not less than about 24:1, not less than about 25:1, not less than about 26:1, not less than about 27:1, not less than about 28:1, not less than about 29:1, not less than about 30:1, not less than about 31:1, not less than about 32:1, not less than about 33:1, not less than about 34:1, not less than about 35:1, not less than about 36:1, not less than about 37:1, not less than about 38:1, not less than
  • a composition in another embodiment, comprises a combination of 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 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.
  • 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 not include amino acid buffering agents.
  • a composition of the invention comprises at least one non-amino acid buffering agent wherein the non-amino acid buffering agent is present in the composition in a total amount greater than 800 mg.
  • 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[ ⁇ hosphoryl/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.
  • a composition is provided that comprises at least one buffering agent in a total amount of at least about 10 mEq.
  • an amino acid buffering agent if an amino acid buffering agent is present in the composition, at least one of the following conditions is met: (1) the weight ratio of amino acid buffering agentproton pump inhibitor is greater than 20: 1; (2) the composition comprises at least two non-amino acid buffering agents; (3) the composition comprises at least one non-amino acid buffering agent wherein the weight ratio of the at least one non-amino acid buffering agentproton pump inhibitor is greater than 20:1; and/or (4) the weight ratio of total buffering agentproton pump inhibitor is greater than 40:1.
  • 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 buffering agent comprises 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.
  • compositions comprising at least one soluble buffering agent.
  • soluble buffering agent refers to an antacid that has a solubility of at least about 500 mg/mL, or at least about 300 mg/mL, or at least about 200 mg/mL, or at least about 100 mL/mL in gastrointestinal fluid or simulated gastrointestinal fluid.
  • the buffering agent has a defined particle size distribution.
  • the D 50 , D 70> Ds 5 , 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.
  • a protein component can replace a buffering agent in any embodiment of the invention described herein.
  • 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.
  • compositions of the invention optionally 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 optionally comprise a protein component in a total amount of about 1 mg to about 100 g, about 1 mg to about 20 g, about 1 mg to about 1O g, about 5 mg to about 5 g, about 10 mg to about 2.5 g, about 10 mg to about 1.0 g, or about 10 mg to about 0.5 g on a dry weight basis.
  • the weight ratio of protein component (if desired) to benzimidazole moiety, 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 optional 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 optional 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
  • compositions of the invention can, if desired, comprise 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 unit dose 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 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 macrocrystalline cellulose, food grade sources of a- 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.
  • Lactose and macrocrystalline cellulose are preferred diluents.
  • 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 Pen West) 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 Pen West) 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, preferably 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).
  • acacia tragacanth
  • sucrose gelatin
  • glucose starches
  • starches such as, but not limited to, pregelatinized starches (e.g., NationalTM 1511 and NationalTM 1500)
  • 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 diglycerides ⁇ e.g., LabrasolTM 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,
  • 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, 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 5%, of the
  • Magnesium stearate is a preferred lubricant used, for example, to reduce friction between the equipment and granulated mixture during compression of tablet formulations.
  • Suitable anti-adherents include talc, cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates.
  • Talc is a preferred 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 a preferred 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, MagnaSwee
  • 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.
  • 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 (e.g. benzimidazole moiety) to result in the desired response or effect.
  • active drug e.g. benzimidazole moiety
  • 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 drag 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.
  • a therapeutically effective amount or a therapeutically and/or prophylactically effective amount of PPI.
  • therapeutically and/or prophylactically effective amount 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 or units.
  • 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, micro granules, 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.
  • 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.
  • 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.) and one or more optional pharmaceutical excipients.
  • a liquid media e.g. water, de-ionized water, etc.
  • 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.
  • compositions of the invention are in the form of a powder for suspension that is ultimately to be suspended in a liquid vehicle prior to administration to a subject.
  • Liquid compositions comprising an acid labile PPI suspended in a liquid vehicle, without more, would typically exhibit short periods 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 are believed to exhibit improve storage stability.
  • Illustrative suspension compositions of the invention comprise at least one PPI, at least one buffering agent, vitamin B 12 , water, and one or more optional pharmaceutical excipients.
  • Such compositions upon storage in a closed container maintained at room temperature, refrigerated (e.g. about 5 to about 5 -10 °C) temperature, or frozen for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, preferably exhibit at least about 90%, more preferably at least about 92.5%, still more preferably at least about 95%, and yet more preferably at least about 97.5% of the original benzimidazole moiety present therein.
  • a composition of the present invention can further include one or more parietal cell activators.
  • Parietal cell activators are particularly preferred where the benzimidazole moiety is a PPI.
  • 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 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).
  • the dose of activator administered to a subject, for example, a human, in the context of the present invention should be sufficient to result in enhanced effect of a PPI over a desired time frame.
  • the approximate effective ranges for various parietal cell activators per 20 mg dose of omeprazole include, Chocolate (raw cocoa) - 5 mg to 2.5 g; Sodium bicarbonate - 7 mEq to 25 mEq; Calcium carbonate - 1 mg to 1.5 g; Calcium gluconate - 1 mg to 1.5 g; Calcium lactate - 1 mg to 1.5 g; Calcium hydroxide - 1 mg to 1.5 g; Calcium acetate - 0.5 mg to 1.5 g; Calcium glycerophosphate - 0.5 mg to 1.5 g; Peppermint oil - (powdered form) 1 mg to 1 g; Spearmint oil - (powdered form) 1 mg to 1 g; Coffee - 20 ml to 240 ml; Tea - 20 ml to 240 ml; Cola - 20 ml to 240 ml; Caffeine - 0.5 mg to 1.5 g; The
  • compositions of the present invention are useful for treating and/or preventing, inter alia, gastrointestinal disorders and, in particular, acid related gastrointestinal disorders.
  • 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.
  • 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 NSAE) induced ulcer.
  • the heartburn can be meal-related or induced, sleep-related or induced, and/or nighttime-related or induced heartburn.
  • Sleep-related heartburn and/or nighttime-related heartburn can be caused, for example, by breakthrough gastritis between conventional doses of a therapeutic agent, such as while sleeping or in the early morning hours after a night's sleep.
  • Treatment of these conditions is accomplished by administering to a subject a gastrointestinal-disorder-effective amount (or a therapeutically-effective amount) of a pharmaceutical composition according to the present invention.
  • a subject may be experiencing one or more of the above conditions or disorders or related symptoms.
  • compositions of the invention can be administered to a subject at any suitable time, for example upon waking, prior to a meal, during the day, or at night time (e.g. before bed).
  • a composition of the invention is useful for treating and/or preventing nighttime heartburn or nighttime heartburn symptoms, nocturnal acid breakthrough (NAB), and/or for providing nighttime pH control.
  • NAB herein refers to intragastric pH less than 4 for more than 1 hour in the overnight period.
  • a composition of the invention is administered to a subject between about 6:00 pm and about 1:00 am, about 7:00 pm and about 1:00 am, about 8:00 pm and about 12:00 am, about 8:00 pm and about ll:pm, about
  • composition of the invention is administered to a subject within about 3 hours before or after the subject has eaten dinner, within about 2 hours before or after the subject has eaten dinner, within about 1 hour before or after the subject has eaten dinner or within about 30 minutes before or after the subject has eaten dinner.
  • a composition of the invention is administered to a subject at such a time to result in a blood serum concentration of the proton pump inhibitor of at least about 0.1 micromolar, at least about 0.2 micromolar, at least about 0.3 micromolar, at least about 0.4 micromolar, at least about 0.5 micromolar, at least about 0.6 micromolar, at least about 0.7 micromolar, at least about 0.8 micromolar, at least about 0.9 micromolar that occurs at any time during the subject's typical period of nocturnal acid breakthrough.
  • the subject's typical period of nocturnal acid breakthrough refers to a period of time at night during which a subject tends to experiences intragastric pH not greater than 4 for a continuous period of about one hour. This can be determined, for example, by measuring a subject's intragastric pH for 1 to 3 nights and calculating the beginning and ending times (of pH less than 4), or the average beginning and ending times if pH is measured during more than 1 night.
  • the subject's typical period of nocturnal acid breakthrough could be characterized as 1:30 am to 4:30 am.
  • a composition of the invention could be administered to the subject at such a time so as to provide a blood serum concentration of the proton pump inhibitor of at least about 0.1 micromolar, at least about 0.2 micromolar, at least about 0.3 micromolar, at least about 0.4 micromolar, at least about 0.5 micromolar, at least about 0.6 micromolar, at least about 0.7 micromolar, at least about 0.8 micromolar, or at least about 0.9 micromolar at any time during the period of about 12:00 am to about 6:00 am, about 12:30 am to about 5:30 am, about 1:00 am to about 5:00 am, or about 2:00 am to about 4:00 am.
  • a composition of the invention is administered to a subject at such a time to result in a blood serum concentration of the proton pump inhibitor of at least about 0.1 micromolar, at least about 0.2 micromolar, at least about 0.3 micromolar, at least about 0.4 micromolar, at least about 0.5 micromolar, at least about 0.6 micromolar, at least about 0.7 micromolar, at least about 0.8 micromolar, at least about 0.9 micromolar or at least about 1 micromolar continuously throughout the subject's typical period of nocturnal acid breakthrough.
  • a composition of the invention is administered to a subject at such a time to result in a blood serum concentration of the proton pump inhibitor of at least about 0.1 micromolar, at least about 0.2 micromolar, at least about 0.3 micromolar, at least about 0.4 micromolar, at least about 0.5 micromolar, at least about 0.6 micromolar, at least about 0.7 micromolar, at least about 0.8 micromolar, at least about 0.9 micromolar, or at least about 1 micromolar at any time point during the period of about 12:00 am to about 6:00 am, about 12:30 am to about 5:30 am, about 1:00 am to about 5:00 am, or about 2:00 am to about 4:00 am.
  • a composition of the invention is administered to a subject at such a time to result in a blood serum concentration of the proton pump inhibitor of at least about 0.1 micromolar, at least about 0.2 micromolar, at least about 0.3 micromolar, at least about 0.4 micromolar, at least about 0.5 micromolar, at least about 0.6 micromolar, at least about 0.7 micromolar, at least about 0.8 micromolar, at least about 0.9 micromolar or at least about 1 micromolar continuously from about 12:00 am to about 6:00 am, from about 12:30 am to about 5:30 am, from about 1:00 am to about 5:00 am, or from about 2:00 am to about 4:00 am.
  • a composition of the invention is administered to a subject at such a time to result in a blood serum concentration of the proton pump inhibitor of about 0.1 micromolar to about 5 micromolar, about 0.2 micromolar to about 2.5 micromolar, or about 0.3 micromolar to about 2 micromolar continuously from about 12:00 am to about 6:00 am, from about 12:30 am to about 5:30 am, from about 1:00 am to about 5:00 am, or from about 2:00 am to about 4:00 am.
  • a composition of the invention is administered to a subject at such a time to result in a blood serum concentration of the proton pump inhibitor of about 0.1 micromolar to about 5 micromolar, about 0.2 micromolar to about 2.5 micromolar, or about 0.3 micromolar to about 2 micromolar from about 12:00 am to about 6:00 am, from about 12:30 am to about 5:30 am, at any time during the period of about 1:00 am to about 5:00 am, or from about 2:00 am to about 4:00 am.
  • a composition of the invention is administered to a subject at such a time to result in a C max of the proton pump inhibitor that occurs during the subject's typical period of nocturnal acid breakthrough.
  • a composition of the invention is administered to a subject at such a time to result in a C max of the proton pump inhibitor that occurs about 0.1 to about 5 hours, about 0.1 to about 4 hours, about 0.1 to about 3 hours, or about 0.1 to about 2 hours before the subject's typical period of nocturnal acid breakthrough.
  • compositions of the invention are to be administered and dosed in accordance with good medical practice, taking 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.
  • human therapy it is important to provide a dosage form that delivers the required therapeutic amount of the drug in vivo, and renders the drug bioavailable in a rapid manner.
  • the dosage forms described by Phillips et al. in U.S. Pat. No. 6,489,346 are incorporated herein by reference.
  • 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.
  • a relatively low amount of the proton pump inhibitor e.g., about 1 mg to about 30 mg, will often provide blood serum concentrations consistent with therapeutic effectiveness.
  • achievement of a therapeutically effective blood serum concentration may require larger dosage units, for example about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 80 mg, or about 120 mg dose for an adult human, or about 150 mg, or about 200 mg, or about 400 mg, or about 800 mg, or about 1000 mg dose, or about 1500 mg dose, or about 2000 mg dose, or about 2500 mg dose, or about 3000 mg dose, or about 3200 mg dose, or about 3500 mg dose for an adult horse.
  • larger dosage units for example about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 80 mg, or about 120 mg dose for an adult human, or about 150 mg, or about 200 mg, or about 400 mg, or about 800 mg, or about 1000 mg dose, or about 1500 mg dose, or about 2000 mg dose, or about 2500 mg dose, or about 3000 mg dose, or about 3200 mg dose, or about 3500 mg dose for an adult horse.
  • the amount of proton pump inhibitor administered to a subject is about 1-2 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, or about 2 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 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 ng/ml within about 30 minutes or about 15 minutes or about 10 minutes after administration of the composition.
  • the composition is administered to a subject in an amount sufficient to achieve a measurable serum concentration of the proton pump inhibitor greater than about 150 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 150 ng/ml 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 250 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 150 ng/ml 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 350 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 150 ng/ml 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 inhibiting agent greater than about 450 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 150 ng/ml 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 150 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 150 ng/ml 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 250 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 150 ng/ml from about 30 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 350 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibitor of greater than about 150 ng/ml from about 30 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 450 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 150 ng/ml from about 30 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 a non-acid degraded or non-acid reacted proton pump inhibitor greater than about 500 ng/ml within 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 a non-acid degraded or non-acid reacted proton pump inhibitor greater than about 300 ng/ml within about 45 minutes 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 fasted human subjects, the 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.
  • the subjects upon administration of a composition of the invention to a plurality of fasted human subjects, the subjects exhibit an average plasma concentration of the PPI of at least about 0.1 ⁇ g/ml, at least about 0.15 ⁇ g/ml, at least about 0.2 ⁇ g/ml, at least about 0.3 ⁇ g/ml, at least about 0.4 ⁇ g/ml, at least about 0.5 ⁇ g/ml, at least about 0.6 ⁇ g/ml, at least about 0.7 ⁇ g/ml, at least about 0.8 ⁇ g/ml, at least about 0.9 ⁇ g/ml, at least about 1 ⁇ g/ml, at least about 1.5 ⁇ g/ml, or at least about 2.0 ⁇ g/ml at any time within about 90 minutes, within about 75 minutes, within about 60 minutes, within about 55 minutes, within about 50 minutes, within about 45 minutes, within about 40 minutes, within about 35 minutes, within about 30 minutes, within about 25 minutes, within about 20 minutes, within about 17 minutes, within
  • the subjects upon administration of a composition of the invention to a plurality of fasted human subjects, the subjects exhibit a plasma concentration of PPI of at least about 0.1 ⁇ g/ml, at least about 0.15 ⁇ g/ml, at least about 0.2 ⁇ g/ml, at least about 0.3 ⁇ g/ml, at least about 0.4 ⁇ g/ml, at least about 0.5 ⁇ g/ml, at least about 0.6 ⁇ g/ml, at least about 0.7 ⁇ g/ml, at least about 0.8 ⁇ g/ml, at least about 0.9 ⁇ g/ml, at least about 1.0 ⁇ g/ml, at least about 1.5 ⁇ g/ml or at least about 2.0 ⁇ g/ml, maintained from at latest about 15 minutes to at earliest about 60 minutes after administration, preferably at latest about 15 minutes after administration to at earliest about 90 minutes after administration, more preferably at latest about 15 minutes to at earliest about 120 minutes after administration, and still more preferably at latest about 15 minutes
  • the subjects upon administration of a composition of the invention to a plurality of fasted human subjects, exhibit at least one of: a mean C ma ⁇ of PPI of about 500 ⁇ g/ml to about 2000 ⁇ g/ml, about 600 ⁇ g/ml to about 1900 ⁇ g/ml, or about 700 ng/ml to about 1800 ⁇ g/ml; a mean T max of PPI of about 0.15 to about 2 hours, about 0.25 to about 1.75 hours, or about 0.3 hours to about 1 hour; and/or a mean AUQo-inf) of PPI of about 1000 to about 3000 ⁇ gihr/ml, about 1500 to about 2700 ⁇ g-hr/ml, or about 1700 to about 2500 ⁇ g*hr/ml.
  • a mean C ma ⁇ of PPI of about 500 ⁇ g/ml to about 2000 ⁇ g/ml, about 600 ⁇ g/ml to about 1900 ⁇ g/ml, or about 700 ng/m
  • the subjects upon administration of a composition of the invention to a plurality of fasted adult human subjects, the subjects exhibit: a mean C max of PPI of about 500 ⁇ g/ml to about 2000 ⁇ g/ml, about 600 ⁇ g/ml to about 1900 ⁇ g/ml, or about 700 ⁇ g/ml to about 1800 ⁇ g/ml; a mean T max of PPI of about 0.15 to about 2 hours, about 0.25 to about 1.75 hours, or about 0.3 hours to about 1 hour; and a mean AUQo- mf ) of PPI of about 1000 to about 3000 ng ⁇ hr/ml, about 1500 to about 2700 ng+hr/ml, or about 1700 to about 2500 ngAr/ml.
  • Compositions of the present invention are particularly useful for treating and/or preventing gastrointestinal disorders.
  • gastrointestinal disorders are acid-caused gastrointestinal disorders including duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease (GERD), erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, pathological gastrointestinal hypersecretory disease, Zollinger Ellison Syndrome, acid dyspepsia, heartburn, nocturnal acid breakthrough (NAB), and/or NSAID induced ulcer.
  • the disorder is heartburn
  • the heartburn can be meal related or induced, sleep related or induced, and/or nighttime related or induced.
  • Sleep related or induced heartburn and/or nighttime related or induced heartburn can be caused, for example, by breakthrough gastritis between conventional doses of a therapeutic agent, such as while sleeping or in the early morning hours after a night's sleep.
  • Treatment of these conditions is accomplished by administering to a subject a gastrointestinal-disorder-effective amount (or a therapeutically-effective amount) of a pharmaceutical composition according to the present invention.
  • a subject may be experiencing one or more of these conditions or disorders.
  • 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.
  • compositions shown in Table 1, can be prepared as tablets, capsules, or other solid dosage forms.

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Abstract

Cette invention concerne des compositions pharmaceutiques comprenant au moins un benzimidazole polymérisé; au moins un tampon et/ou un composant protéique, et un ou plusieurs excipients pharmaceutiques éventuels. Les compositions décrites dans cette invention sont utiles pour traiter, entre autres, des maladies gastro-intestinales et des troubles gastro-intestinaux.
PCT/US2006/015983 2005-04-26 2006-04-25 Compositions comprenant un benzimidazole polymerise et un tampon et procedes permettant de les utiliser WO2006116583A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008110070A1 (fr) * 2007-03-09 2008-09-18 Shanghai Allist Pharmaceuticals, Inc. Comprimé double comprenant un médicament labile sous l'action d'un acide

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Publication number Priority date Publication date Assignee Title
US5840737A (en) * 1996-01-04 1998-11-24 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6617338B2 (en) * 2000-02-24 2003-09-09 Kopran Research Laboratories Limited Orally administrable acid stable antiulcer benzimidazole derivatives
US20040028737A1 (en) * 2002-08-12 2004-02-12 Kopran Research Laboratories Limited Enteric coated stable oral pharmaceutical composition of acid unstable drug and process for preparing the same
WO2004041923A2 (fr) * 2002-11-05 2004-05-21 Kopran Research Laboratories Limited Composes actifs sur le plan biologique hydrolysables chimio-enzymatiquement
WO2004041869A2 (fr) * 2002-11-05 2004-05-21 Kopran Research Laboratories Limited Polymeres reactifs ayant des groupes fonctionnels hydrolysables par chimie chimioenzymatique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5840737A (en) * 1996-01-04 1998-11-24 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6617338B2 (en) * 2000-02-24 2003-09-09 Kopran Research Laboratories Limited Orally administrable acid stable antiulcer benzimidazole derivatives
US20040028737A1 (en) * 2002-08-12 2004-02-12 Kopran Research Laboratories Limited Enteric coated stable oral pharmaceutical composition of acid unstable drug and process for preparing the same
WO2004041923A2 (fr) * 2002-11-05 2004-05-21 Kopran Research Laboratories Limited Composes actifs sur le plan biologique hydrolysables chimio-enzymatiquement
WO2004041869A2 (fr) * 2002-11-05 2004-05-21 Kopran Research Laboratories Limited Polymeres reactifs ayant des groupes fonctionnels hydrolysables par chimie chimioenzymatique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008110070A1 (fr) * 2007-03-09 2008-09-18 Shanghai Allist Pharmaceuticals, Inc. Comprimé double comprenant un médicament labile sous l'action d'un acide
CN101626755B (zh) * 2007-03-09 2011-11-30 上海艾力斯医药科技有限公司 包含酸不稳定药物的双单元片剂

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