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WO2007086846A1 - Formules pharmaceutiques utiles pour inhiber la secretion d’acide et procedes de fabrication et d’utilisation correspondants - Google Patents

Formules pharmaceutiques utiles pour inhiber la secretion d’acide et procedes de fabrication et d’utilisation correspondants Download PDF

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Publication number
WO2007086846A1
WO2007086846A1 PCT/US2006/002746 US2006002746W WO2007086846A1 WO 2007086846 A1 WO2007086846 A1 WO 2007086846A1 US 2006002746 W US2006002746 W US 2006002746W WO 2007086846 A1 WO2007086846 A1 WO 2007086846A1
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WO
WIPO (PCT)
Prior art keywords
proton pump
pump inhibitor
pharmaceutical formulation
antacid
formulation according
Prior art date
Application number
PCT/US2006/002746
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English (en)
Inventor
Wareen Hall
Kay Olmstead
Laura Weston
Original Assignee
Santarus, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santarus, Inc. filed Critical Santarus, Inc.
Priority to PCT/US2006/002746 priority Critical patent/WO2007086846A1/fr
Publication of WO2007086846A1 publication Critical patent/WO2007086846A1/fr

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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds

Definitions

  • the present invention is related to pharmaceutical formulations comprising an antacid and a proton pump inhibitor microencapsulated with (1) a material that enhances the shelf-life of the composition, and/or (2) a taste-masking material.
  • pharmaceutical compositions comprising proton pump inhibitor and antacid wherein the proton pump inhibitor is dry coated.
  • methods for manufacture of the pharmaceutical formulations; uses of the pharmaceutical formulations in treating disease; and combinations of the pharmaceutical formulations with other therapeutic agents are described.
  • compositions with enteric-coatings have been designed to dissolve at a pH to ensure that the drug is released in the proximal region of the small intestine
  • enteric-coated compositions due to the pH-dependent attributes of these enteric-coated compositions and the uncertainty of gastric retention time, in- vivo performance as well as both inter- and intra-subject variability are all major set backs of using enteric-coated systems for the controlled release of a drug.
  • Phillips et al. has described non-enteric coated pharmaceutical compositions. These compositions, which allow for the immediate release of the pharmaceutically active ingredient into the stomach, involve the administration of one or more buffering agents with an acid labile pharmaceutical agent, such as a proton pump inhibitor.
  • the buffering agent is thought to prevent substantial degradation of the acid labile pharmaceutical agent in the acidic environment of the stomach by raising the pH. See, e.g., U.S. Patent Nos. 5,840,737; 6,489,346; 6,645,988; and 6,699,885; and U.S. Patent Application No. 10/898,135.
  • a class of acid-labile pharmaceutical compounds that are administered as enteric- coated dosage forms are proton pump inhibiting agents.
  • Exemplary proton pump inhibitors include, omeprazole (Prilosec ® ), lansoprazole (Prevacid ® ), esomeprazole (Nexium ® ), rabeprazole (Aciphex ® ), pantoprazole (Protonix ® ), pariprazole, tentaprazole, and leminoprazole.
  • the drugs of this class suppress gastrointestinal acid secretion by the specific inhibition of the H + /K + -ATPase enzyme system (proton pump) at the secretory surface of the gastrointestinal parietal cell.
  • Omeprazole is one example of a proton pump inhibitor which is a substituted bicyclic aryl-imidazole, 5-methoxy-2-[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-lH-benzimidazole, that inhibits gastrointestinal acid secretion.
  • U.S. Patent No. 4,786,505 to Lovgren et al. teaches that a pharmaceutical oral solid dosage form of omeprazole must be protected from contact with acidic gastrointestinal juice by an enteric- coating to maintain its pharmaceutical activity and describes an enteric-coated omeprazole preparation containing one or more subcoats between the core material and the enteric- coating.
  • Proton pump inhibitors are typically prescribed for short-term treatment of active duodenal ulcers, gastrointestinal ulcers, gastro esophageal reflux disease (GEPJD), severe erosive esophagitis, poorly responsive symptomatic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome. These above-listed conditions commonly arise in healthy or critically ill patients of all ages, and may be accompanied by significant upper gastrointestinal bleeding. It is believed that omeprazole, lansoprazole and other proton pump inhibiting agents reduce gastrointestinal acid production by inhibiting H + ZK + - ATPase of the parietal cell during the final common pathway for gastrointestinal acid secretion.
  • Proton pump inhibitors have the ability to act as weak bases which reach parietal cells from the blood and diffuse into the secretory canaliculi. There the drugs become protonated and thereby trapped. The protonated compound can then rearrange to form a sulfanamide which can covalently interact with sulfhydryl groups at critical sites in the extra cellular (luminal) domain of the membrane-spanning H + ZK + -ATPase. See, e.g.,
  • proton pump inhibitors are prodrugs that must be activated to be effective.
  • the specificity of the effects of proton pump inhibiting agents is also dependent upon: (a) the selective distribution of H + ZK + -ATPaSe; (b) the requirement for acidic conditions to catalyze generation of the reactive inhibitor; and (c) the trapping of the protonated drug and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme. See, e.g., Hardman et al.
  • Figure 1 is a graph comparing the pharmacokinetic release profiles of omeprazole of Prilosec , non-microencapsulated omeprazole with antacid (as described in Example
  • Example 13B omeprazole microencapsulated with Klucel and antacid tablet (as described in Example 13C), and omeprazole microencapsulated with Methocel and antacid tablet (as described in Example 13 D) in human.
  • Figures 2A and 2B are SEM micrographs of micronized omeprazole and omeprazole microencapsulated with Klucel ® Hydroxypropyl Cellulose .
  • Figure 3 is a graph comparing the average pharmacokinetic release profiles of SAN-15 A, SAN- 15B, SAN- 15C, SAN-20D and SAN-20E as compared to Priolosec ® brand enteric coated omeprazole 40 mg. Formulations were prepared as described in Example 13.
  • Figure 4 is a graph comparing the mean peak plasma concentration (Cmax) versus the time at which Cmax is observed (Tmax) for SAN- 15 (20 mg and 40 mg), SAN-20D, SAN- 2OE and Priolosec ® brand enteric coated omeprazole 20 mg and 40 mg, Day 1.
  • the data is from the human clinical trial described in Examples 14B and 15B.
  • Figure 5 is a graph comparing the average pharmacokinetic release profiles for SAN-15 20mg and Priolosec ® brand enteric coated omeprazole 20 mg, Day 1. The data is from the human clinical trial described in Examples 14B.
  • Figure 6 is a graph comparing the average pharmacokinetic release profiles for SAN- 15 40mg and Priolosec ® brand enteric coated omeprazole 40 mg, Day 1. The data is from the human clinical trial described in Examples 15B.
  • Figure 7 is a graph comparing the average pharmacokinetic release profiles for SAN- 15 20mg and Priolosec ® brand enteric coated omeprazole 20 mg, Day 7. The data is from the human clinical trial described in Examples 14B.
  • Figure 8 is a graph comparing the average pharmacokinetic release profiles for SAN- 15 40mg and Priolosec ® brand enteric coated omeprazole 40 mg, Day 7. The data is from the human clinical trial described in Examples 15B.
  • Figure 9 is a graph comparing the mean peak plasma concentration (Cmax) versus the time at which Cmax is observed (Tmax) for SAN-15 (20 mg and 40 mg) and Priolosec ® brand enteric coated omeprazole 20 mg and 40 mg, Day 7. The data is from the human clinical trial described in Examples 14B and 15B.
  • Figure 10 is a graph comparing the mean peak plasma concentration (Cmax) versus the time at which Cmax is observed (Tmax) for SAN- 15 (20 mg and 40 mg) and Priolosec ® brand enteric coated omeprazole 20 mg and 40 mg, Dayl and Day 7. The data is from the human clinical trial described in Examples 14B and 15B.
  • compositions having enhanced shelf-lives comprising, at least one acid labile proton pump inhibitor which is microencapsulated with a material that enhances the shelf-life of the pharmaceutical formulation and at least one antacid; wherein an initial serum concentration of the proton pump inhibitor is greater than about 0.1 ⁇ g/ml at any time within about 30 minutes after administration of the pharmaceutical formulation.
  • taste-masked pharmaceutical formulations comprising at least one acid labile proton pump inhibitor which is microencapsulated with a taste-masking material and at least one antacid; wherein an initial serum concentration of the proton pump inhibitor is greater than about 0.1 ⁇ g/ml at any time within about 30 minutes after administration of the pharmaceutical formulation.
  • the proton pump inhibitor is microencapsulated with one or more compounds selected from cellulose hydroxypropyl ethers; low-substituted hydroxypropyl ethers; cellulose hydroxypropyl methyl ethers; methylcellulose polymers; ethylcelluloses and mixtures thereof; polyvinyl alcohol; hydroxyethylcelluloses; carboxymethylcelluloses and salts of carboxymethylcelluloses; polyvinyl alcohol and polyethylene glycol co-polymers; monoglycerides; triglycerides; polyethylene glycols, modified food starch, acrylic polymers; mixtures of acrylic polymers with cellulose ethers; cellulose acetate phthalate; sepif ⁇ lms, cyclodextrins; and mixtures thereof.
  • the proton pump inhibitor is microencapsulated with one or more additives to enhance the processing or performance of microencapsulation.
  • additives maybe pH modifier, plastersizer, antioxidant, or sweetener or flavor.
  • compositions having enhanced shelf-lives comprising, at least one acid labile proton pump inhibitor and at least one antacid; wherein an initial serum concentration of the proton pump inhibitor is greater than about 0.1 ⁇ g/ml at any time within about 30 minutes after administration of the pharmaceutical formulation, wherein some or all of the proton pump inhibitor is dry coated.
  • the at least one antacid comprises at least one soluble antacid.
  • the soluble antacid is sodium bicarbonate.
  • the at least one buffer is selected from sodium bicarbonate, calcium carbonate, sodium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof.
  • kits for extending the shelf-life of pharmaceutical formulations comprising microencapsulating at least one acid labile proton pump inhibitor with a material that enhances the shelf-life; and combining the microencapsulated acid labile proton pump inhibitor with at least one antacid.
  • methods of masking the taste of a pharmaceutical formulation comprising microencapsulating at least one acid labile proton pump inhibitor with a taste-masking material; and combining the microencapsulated acid labile proton pump inhibitor with an antacid.
  • the proton pump inhibitor is combined with some or all of the antacid to form a slug or sheet of material. This intermediate product is then broken into granular material with is combined with other components present in the pharmaceutical formulation, m other embodiments, the dry coated proton pump inhibitor is combined with additional antacid.
  • the pharmaceutical formulations may further comprise one or more excipients selected from parietal cell activators, organic solvents, erosion facilitators, diffusion facilitators, antioxidants, flavoring agents and carrier materials selected from binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, anti- adherents, and antifoaming agents.
  • excipients selected from parietal cell activators, organic solvents, erosion facilitators, diffusion facilitators, antioxidants, flavoring agents and carrier materials selected from binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, anti- adherents, and antifoaming agents.
  • the present invention is directed to pharmaceutical formulations exhibiting enhanced shelf-life stability and/or improved taste masking properties useful for the treatment of a disease, condition or disorder. Methods of treatment using the pharmaceutical formulations of the present invention are also described.
  • compositions comprising (1) an acid labile proton pump inhibitor which is microencapsulated with a material that enhances the shelf-life of the pharmaceutical composition together with (2) one or more antacid, provide superior performance by enhancing shelf-life stability of the pharmaceutical formulation during manufacturing and storage.
  • compositions comprising (1) an acid labile proton pump inhibitor which has been dry coated and (2) one or more antacids, provide superior performance by enhancing shelf-life stability of the pharmaceutical formulation during manufacturing and storage.
  • the proton pump inhibitor is dry coated with some or all of the antacid.
  • the dry coated proton pump inhibitor is combined with a second antacid which can be the same antacid as used to dry coat the proton pump inhibitor or a different antacid.
  • the dry coated material is combined with one or more pharmaceutical excipients.
  • the proton pump inhibitor is dry coated with a material comprising antacid, sweetener(s), lubricant, and binder.
  • Certain taste-masking materials have also been discovered which, when used in the pharmaceutical formulations provide (1) more palatable forms of the drug by blocking the contact of the unpleasant taste of the pharmaceutical agent from the contact of the taste receptor, thereby increasing patient compliance; and/or (2) require lower amounts of traditional flavoring agents.
  • acid-labile pharmaceutical agent refers to any pharmacologically active drug subject to acid catalyzed degradation.
  • Aftertaste is a measurement of all sensation remaining after swallowing. Aftertaste can be measured, e.g., from 30 seconds after swallowing, 1 minutes after swallowing, 2 minutes after swallowing, 3 minutes after swallowing, 4 minutes after swallowing, 5 minutes after swallowing, and the like.
  • the amplitude scale is 0-none, l-low, 2-moderate, and 3-high.
  • Anti-adherents prevent components of the formulation from aggregating or sticking and improve flow characteristics of a material.
  • Such compounds include, e.g., colloidal silicon dioxide such as Cab-o-sil ® ; tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silicon dioxide (Syloid ® ) and the like.
  • Antifoarning agents reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing.
  • Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate.
  • Antioxidants include, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
  • Binders impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel ® ), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ® ), ethylcellulose (e.g., Ethocel ® ), and microcrystalline cellulose (e.g., Avicel ® ); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as
  • Bioavailability refers to the extent to which an active moiety, e.g., drug, prodrug, or metabolite, is absorbed into the general circulation and becomes available at the site of drug action in the body. Thus, a proton pump inhibitor administered through IV is 100% bioavailable, "Oral bioavailability” refers to the extent to with the proton pump inhibitor is absorbed into the general circulation and becomes available at the site of the drug action in the body when the pharmaceutical formulation is taken orally.
  • Bioequivalence or “bioequivalent” means that the area under the serum concentration time curve (AUC) and the peak serum concentration (C max ) are each within 80% and 125% with a 90% confidence interval.
  • Carrier materials include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with the proton pump inhibitor and the release profile properties of the desired dosage form.
  • Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like.
  • “Pharmaceutically compatible carrier materials” may comprise, e.g., acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like.
  • “Character notes” include, e.g., aromatics, basis tastes, and feeling factors.
  • the intensity of the character note can be scaled from 0-none, 1 -slight, 2-moderate, or 3- strong.
  • a “derivative” is a compound that is produced from another compound of similar structure by the replacement of substitution of an atom, molecule or group by another suitable atom, molecule or group.
  • one or more hydrogen atom of a compound may be substituted by one or more alkyl, acyl, amino, hydroxyl, halo, haloalkyl, aryl, heteroaryl, cycloaolkyl, heterocycloalkyl, or heteroalkyl group to produce a derivative of that compound.
  • diffusion facilitators and “dispersing agents” include materials that control the diffusion of an aqueous fluid through a coating.
  • Exemplary diffusion facilitators/dispersing agents include, e.g., hydrophilic polymers, electrolytes, Tween ® 60 or 80, PEG and the like. Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present invention.
  • “Diluents” increase bulk of the composition to facilitate compression.
  • Such compounds include e.g., lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose such as Avicel ® ; dibasic calcium phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinzed starch; compressible sugar, such as Di-Pac ® (Amstar); mannitol; hydroxypropylmethylcellulose; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrates; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol; bentonite; and the like
  • disintegrate includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid.
  • disintegration agents facilitate the breakup or disintegration of a substance.
  • disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel or Explotab ® ; a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel ® , Avicel ® PHl 01 , Avicel ® PHl 02, Avicel ® PHl 05, Elcema ® PlOO, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka-Floc ® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-
  • Drug absorption or “absorption” refers to the process of movement from the site of administration of a drug toward the systemic circulation, e.g., into the bloodstream of a subject.
  • “Dry coating” is a method of coating the proton pump inhibitor with one or more other components without using water or other solvents.
  • “Dry granulation” is a method of converting powder particles into granules using the application of pressure without the use of a liquid.
  • enteric coating is a substance that remains substantially intact in the stomach but dissolves and releases the drug once the small intestine is reached.
  • the enteric coating comprises a polymeric material that prevents release in the low pH environment of the stomach but that ionizes at a slightly higher pH, typically a pH of 4 or 5, and thus dissolves sufficiently in the small intestines to gradually release the active agent therein.
  • the "enteric form of the proton pump inhibitor” is intended to mean that some or most of the proton pump inhibitor has been enterically coated to ensure that at least some of the drug is released in the proximal region of the small intestine (duodenum), rather than the acidic environment of the stomach.
  • Erosion facilitators include materials that control the erosion of a particular material in gastrointestinal fluid. Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.
  • Filling agents include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • “Flavoring agents” or “sweeteners” useful in the pharmaceutical compositions of the present invention include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, 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, monoammonium glyrrhizinate (MagnaSweet ® ), maltol, mannitol, maple, marshmallow, menthol
  • stomach secretion is the fluid of stomach secretions of a subject or the saliva of a subject after oral administration of a composition of the present invention, or the equivalent thereof.
  • An "equivalent of stomach secretion” includes, e.g., an in vitro fluid having similar content and/or pH as stomach secretions such as a 1% sodium dodecyl sulfate solution or 0.1N HCl solution in water.
  • Hydrof-life refers to the time required for the plasma drug concentration or the amount in the body to decrease by 50% from its maximum concentration.
  • “Lubricants” are compounds that prevent, reduce or inhibit adhesion or friction of materials.
  • Exemplary lubricants include, e.g., stearic acid; calcium hydroxide; talc; sodium stearyl fumerate; a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex ® ); higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet ® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, sodium oleate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as SyloidTM, Carb-0-Sil
  • a “measurable serum concentration” or “measurable plasma concentration” describes the blood serum or blood plasma concentration, typically measured in mg, ⁇ g, or ng of therapeutic agent per ml, dl, or 1 of blood serum, of a therapeutic agent that is absorbed into the bloodstream after administration.
  • One of ordinary skill in the art would be able to measure the serum concentration or plasma concentration of a proton pump inhibitor or other therapeutic agent. See, e.g., Gonzalez H. et al., J. Chromatogr. B. Analyt. Technol. Biomed. Life ScL, vol. 780, pp 459-65, (Nov. 25, 2002).
  • Parietal cell activators or “activators” stimulate the parietal cells and enhance the pharmaceutical activity of the proton pump inhibitor.
  • Parietal cell activators include, e.g., chocolate; alkaline substances such as sodium bicarbonate; calcium such as 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; amino acids (particularly aromatic amino acids such as phenylalanine and tryptophan); and combinations thereof.
  • “Pharmacodynamics” refers to the factors that determine the biologic response observed relative to the concentration of drug at a site of action. “Pharmacokinetics” refers to the factors that determine the attainment and maintenance of the appropriate concentration of drug at a site of action.
  • Plasma concentration refers to the concentration of a substance in blood plasma or blood serum of a subject. It is understood that the plasma concentration of a therapeutic agent may vary many-fold between subjects, due to variability with respect to metabolism of therapeutic agents. In accordance with one aspect of the present invention, the plasma concentration of a proton pump inhibitors and/or other therapeutic agent may vary from subject to subject. Likewise, values such as maximum plasma concentration (C max ) or time to reach maximum serum concentration (T ffla ⁇ ) 5 or area under the serum concentration time curve (AUC) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of proton pump inhibitor or other therapeutic agent, may vary from subject to subject. It is understood that when mean plasma concentrations are disclosed for a population of subjects, these mean values may include substantial variation.
  • Plasticizers are compounds used to soften the microencapsulation material or film, coatings to make them less brittle. Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin.
  • Prevent or "prevention” when used in the context of a gastric acid related disorder means no gastrointestinal disorder or disease development if none had occurred, or no further gastrointestinal disorder or disease development if there had already been development of the gastrointestinal disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the gastrointestinal disorder or disease.
  • prodrug refers to a drug or compound in which the pharmacological action results from conversion by metabolic processes within the body.
  • Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway.
  • Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues.
  • prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210- 218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm.
  • Proton pump inhibitor product refers to a product sold on the market.
  • Proton pump inhibitor products include, for example, Priolosec ® , Nexiurn ® , Prevacid ® , Protonix ® , and Aciphex ® .
  • serum concentration refers to the concentration of a substance such as a therapeutic agent, in blood plasma or blood serum of a subject. It is understood that the serum concentration of a therapeutic agent may vary many-fold between subjects, due to variability with respect to metabolism of therapeutic agents.
  • the serum concentration of a proton pump inhibitors and/or prokinetic agent may vary from subject to subject.
  • values such as maximum serum concentration (C max ) or time to reach maximum serum concentration (T max ), or total area under the serum concentration time curve (AUC) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of proton pump inhibitor, prokinetic agent, or other therapeutic agent, may vary from subject to subject. It is understood that when mean serum concentrations are disclosed for a population of subjects, these mean values may include substantial variation.
  • Solidizers include compounds such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, sodium carbonate and the like.
  • Stabilizers include compounds such as any antioxidation agents, buffers, acids, and the like.
  • “Suspending agents” or “thickening agents” include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone Kl 7, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30; polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400; sodium carboxymethylcellulose; methylcellulose; hydroxy-propylmethylcellulose; polysorbate-80; hydroxyethylcellulose; sodium alginate; gums, such as, e.g., gum tragacanth and gum acacia; guar gum; xanthans, including xanthan gum; sugars; cellulosics, such as, e.
  • “Surfactants” include compounds such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF); and the like.
  • a “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect.
  • the term “therapeutically effective amount” includes, for example, a prophylactically effective amount.
  • An “effective amount” of a proton pump inhibitor is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects.
  • an effective amount of a proton pump inhibitor refers to an amount of proton pump inhibitor that reduces acid secretion, or raises gastrointestinal fluid pH, or reduces gastrointestinal bleeding, or reduces the need for blood transfusion, or improves survival rate, or provides for a more rapid recovery from a gastric acid related disorder.
  • an effect amount or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of therapeutic agents such as proton pump inhibitors and/or prokinetic agents, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
  • Total intensity of aroma is the overall immediate impression of the strength of the aroma and includes both aromatics and nose feel sensations.
  • Total intensity of flavor is the overall immediate impression of the strength of the flavor including aromatics, basic tastes and mouth feel sensations.
  • Treating or “treatment” as used in the context of a gastric acid related disorder refers to any treatment of a disorder or disease associated with a gastrointestinal disorder, such as preventing the disorder or disease from occurring in a subject which 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, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • the term “treat” is used synonymously with the term “prevent.”
  • Weight agents include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, and the like.
  • proton pump inhibitor PPI
  • proton pump inhibiting agent can be used interchangeably to describe any acid labile pharmaceutical agent possessing pharmacological activity as an inhibitor of H+/K+-ATPase.
  • a proton pump inhibitor 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.
  • the proton pump inhibitor can be a substituted bicyclic aryl-imidazole, wherein the aryl group can be, e.g., a pyridine, a phenyl, or a pyrimidine group and is attached to the 4- and 5-positions of the imidazole ring.
  • the aryl group can be, e.g., a pyridine, a phenyl, or a pyrimidine group and is attached to the 4- and 5-positions of the imidazole ring.
  • Proton pump inhibitors comprising a substituted bicyclic aryl-imidazoles include, but are not limited to, omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontop
  • proton pump inhibitors include but are not limited to: soraprazan (Altana); ilaprazole (U.S. Patent No. 5,703,097) (Il-Yang); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO 96/05177) (SB-641257) (2-pyrimidinamine, 4-(3,4-dihydro-l- methyl-2(lH)-isoquinolinyl)-N-(4-fluorophenyl)-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-thienyl) (Shinnippon); 3-hydroxymethyl-2- methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,3-c)-imid
  • Still other proton pump inhibitors contemplated by the present invention include those described in the following U.S. Patent 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
  • “Pharmaceutically acceptable salts,” or “salts,” include, e.g., 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, (3-hydroxybutyric, galactaric and galacturonic acids.
  • acid addition salts are prepared from the free base 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. Patent 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. Patent No. 6,511,996.
  • Other salts of esomeprazole are described in U.S. 4,738,974 and U.S. 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 where R 1 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. Patent 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 al., Acta Cryst. (1989), C45, 1921-1923; U.S. Patent 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. Patent Nos.
  • M mass of drug dissolved
  • t time
  • D diffusion coefficient of drug
  • S effective surface area of drug particles
  • H stationary layer thickness
  • Cs concentration of solution at saturation
  • C concentration of solution at time t.
  • the average particle size of at least about 90% the micronized proton pump inhibitor is less than about 200 ⁇ m, 150 ⁇ m, 100 ⁇ m, 80 ⁇ m, 60 ⁇ m, 40 ⁇ m, or less than about 35 ⁇ m, or less than about 30 ⁇ m, or less than about 25 ⁇ m, or less than about 20 ⁇ m, or less than about 15 ⁇ m, or less than about 10 ⁇ m.
  • At least 80% of the micronized proton pump inhibitor has an average particle size of less than about 200 ⁇ m, 150 ⁇ m, 100 ⁇ m, 80 ⁇ m, 60 ⁇ m, 40 ⁇ m, or less than about 35 ⁇ m, or less than about 30 ⁇ m, or less than about 25 ⁇ m, or less than about 20 ⁇ m, or less than about 15 ⁇ m, or less than about 10 ⁇ m.
  • At least 70% of the micronized proton pump inhibitor has an average particle size of less than about 200 ⁇ m, 150 ⁇ m, 100 ⁇ m, 80 ⁇ m, 60 ⁇ m, 40 ⁇ m, or less than about 35 ⁇ m, or less than about 30 ⁇ m, or less than about 25 ⁇ m, or less than about 20 ⁇ m, or less than about 15 ⁇ m, or less than about 10 ⁇ m.
  • the micronized proton pump inhibitor is of a size that allows greater than 50% of the proton pump inhibitor to be released within about 1 hour or 50 minutes, 40 minutes, 30 minutes, 20 minutes or 10 minutes of dissolution testing. In other embodiments, the micronized proton pump inhibitor allows greater than 25% of the proton pump inhibitor to be released within about 45 minutes, 30 minutes, or 15 minutes of dissolution testing.
  • compositions are provided wherein the micronized proton pump inhibitor is of a size which allows greater than 75% of the proton pump inhibitor to be released within about 1.5 hours, or within about 1.25 hours, or within about 1 hour, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes, or within about 10 minutes, or within about 5 minutes of dissolution testing.
  • the micronized proton pump inhibitor is of a size which allows greater than 90% of the proton pump inhibitor to be released within about 1.5 hours, or within about 1.25 hours, or within about 1 hour, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes, or within about 10 minutes, or within about 5 minutes of dissolution testing. See U.S. Application No. 10/893,092, filed July 16, 2004, which claims priority to U.S. Provisional Application No. 60/488,324 filed July 18, 2003, and any subsequent application claiming priority to these applications, all of which are incorporated by reference in their entirety.
  • the particle size of the proton pump inhibitor, antacid and excipients is an important factor which can effect bioavailability, blend uniformity, segregation, and flow properties.
  • smaller particle sizes of a drug increases the bioabsorption rate of the drug with substantially poor water solubility by increasing the surface area.
  • the particle size of the drug and excipients can also affect the suspension properties of the pharmaceutical formulation. For example, smaller particles are less likely to settle and therefore form better suspensions.
  • the average particle size of the dry powder (which can be administered directly, as a powder for suspension, or used in a solid dosage form) is less than about 500 microns in diameter, or less than about 450 microns in diameter, or less than about 400 microns in diameter, or less than about 350 microns in diameter, or less than about 300 microns in diameter, or less than about 250 microns in diameter, or less than about 200 microns in diameter, or less than about 150 microns in diameter, or less than about 100 microns in diameter, or less than about 75 microns in diameter, or less than about 50 microns in diameter, or less than about 25 microns in diameter, or less than about 15 microns in diameter.
  • the average particle size of the aggregates is between about 25 microns in diameter to about 300 microns in diameter. In still other embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 150 microns in diameter. And, in still further embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 100 microns in diameter.
  • the term "average particle size" is intended to describe the average diameter of the particles and/or agglomerates used in the pharmaceutical formulation.
  • the average particle size of the insoluble excipients is between about 5 ⁇ m to about 500 ⁇ m, or less than about 400 ⁇ m, or less than about 300 ⁇ m, or less than about 200 ⁇ m, or less than about 150 ⁇ m, or less than about 100 ⁇ m, or less than about 90 ⁇ m, or less than about 80 ⁇ m, or less than about 70 ⁇ m, or less than about 60 ⁇ m, or less than about 50 ⁇ m, or less than about 40 ⁇ m, or less than about 30 ⁇ m, or less than about 25 ⁇ m, or less than about 20 ⁇ m, or less than about 15 ⁇ m, or less than about 10 ⁇ m, or less than about 5 ⁇ m.
  • At least about 80% of the particles have a particle size of less than about 300 ⁇ m, or less than about 250 ⁇ m, or less than about 200 ⁇ m, or less than about 150 ⁇ m, or less than about 100 ⁇ m, or less than about 500 ⁇ m.
  • at least about 85% of the dry powder particles have a particle size of less than about 300 ⁇ m, or less than about 250 ⁇ m, or less than about 200 ⁇ m, or less than about 150 ⁇ m, or less than about 100 ⁇ m, or less than about 50 ⁇ m.
  • At least about 90% of the dry powder particles have a particle size of less than about 300 ⁇ m, or less than about 250 ⁇ m, or less than about 200 ⁇ m, or less than about 150 ⁇ m, or less than about 100 ⁇ m, or less than about 50 ⁇ m.
  • at least about 95% of the dry powder particles have a particle size of less than about 300 ⁇ m, or less than about 250 ⁇ m, or less than about 200 ⁇ m, or less than about 150 ⁇ m, or less than about 100 ⁇ m, or less than about 50 ⁇ m.
  • the average particle size of the insoluble material is between about 5 ⁇ m to about 250 ⁇ m in diameter. In other embodiments, the average particle size of the insoluble excipients is between about 5 ⁇ m to about 100 ⁇ m, or between about 5 ⁇ m to about 80 ⁇ m, or between about 5 ⁇ m to about 50 ⁇ m in diameter.
  • the particle size of other excipients is chosen to be about the same as the particle size of the antacid.
  • the particle size of the insoluble excipients is chosen to be about the same as the particle size of the proton pump inhibitor.
  • the excipient should be pharmaceutically acceptable. Also, in some examples, rapid dissolution and neutralization of gastric acid to maintain the gastric pH at about 6.5 for at least one hour.
  • the excipients which will be in contact with the proton pump inhibitor, if any, should also be chemically compatible with the proton pump inhibitor. "Chemically compatible" is intended to mean that the material does not lead to more than 10% degradation of the proton pump inhibitor when stored at room temperature for at least about 1 year.
  • Parietal cell activators are administered in an amount sufficient to produce the desired stimulatory effect without causing untoward side effects to patients.
  • the parietal cell activator is administered in an amount of about 5 mg to about 2.5 grams per 20 mg dose of the proton pump inhibitor.
  • the pharmaceutical composition of the invention comprises one or more antacids.
  • a class of antacids useful in the present invention include, e.g., antacids possessing pharmacological activity as a weak base or a strong base.
  • the antacid when formulated or delivered with an proton pump inhibiting agent, functions to substantially prevent or inhibit the acid degradation of the proton pump inhibitor by gastrointestinal fluid for a period of time, e.g., for a period of time sufficient to preserve the bioavailability of the proton pump inhibitor administered.
  • the antacid can be delivered before, during, and/or after delivery of the Proton Pump Inhibitor.
  • the antacid includes a salt of a Group IA metal, including, e.g., a bicarbonate salt of a Group IA metal (alkali metal), a carbonate salt of a Group IA metal, an alkali earth metal antacid (Group IIA metal), an aluminum antacid, a calcium antacid, or a magnesium antacid.
  • alkali metal a Group IA metal including, but not limited to, lithium, sodium, potassium, rubidium, cesium, and francium
  • alkaline earth metal Group ILA metal including, but not limited to, beryllium, magnesium, calcium, strontium, barium, radium
  • carbonates phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrate, succinates and the like, such as sodium or potassium phosphate, citrate, borate, acetate, bicarbonate and carbonate.
  • an antacid includes, e.g., an amino acid, an alkali salt of an amino acid, aluminum hydroxide, aluminum hydroxide/magnesium carbonate/calcium carbonate co-precipitate, 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, aluminum g
  • the antacids useful in the present invention also include antacids or combinations of antacids 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 antacids produce and maintain a pH greater than the pKa of the proton pump inhibitor.
  • the antacid is selected from sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof.
  • the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 5 mEq of antacid.
  • the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 7 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 10 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 15 mEq of antacid, m other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 20 mEq of antacid.
  • the antacid comprises sodium bicarbonate in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump inhibitor.
  • the antacid comprises a mixture of sodium bicarbonate and magnesium hydroxide, wherein the sodium bicarbonate and magnesium hydroxide are each present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump inhibitor,
  • the antacid comprises a mixture of sodium bicarbonate, calcium carbonate, and magnesium hydroxide, wherein the sodium bicarbonate, calcium carbonate, and magnesium hydroxide are each present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg of the proton pump inhibitor
  • the antacid comprises a mixture of sodium bicarbonate and magnesium oxide, wherein the sodium bicarbonate and magnesium hydroxide are each present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq
  • the antacid is present in an amount of about 0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibitor, or about 0.5 mEq/mg to about 3 mEq/mg of the proton pump inhibitor, or about 0.6 mEq/mg to about 2.5 mEq/mg of the proton pump inhibitor, or about 0.7 mEq/mg to about 2.0 mEq/mg of the proton pump inhibitor, or about 0.8 mEq/mg to about 1.8 mEq/mg of the proton pump inhibitor, or about 1.0 mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor, or at least 0.5 mEq/mg of the proton pump inhibitor.
  • the antacid is present in the pharmaceutical formulations of the present invention in an amount from about 5 to about 50 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount from about 5 to about 40 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount from about 10 to about 30 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount from about 10 to about 20 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount from about 5 to about 15 mEq of antacid.
  • the antacid is present in the pharmaceutical formulations of the present invention in an amount of about 0.1 mEq to about 15 mEq/mg of proton pump inhibitor, or about 0.1 mEq/mg of proton pump inhibitor, or about 0.5 mEq/mg of proton pump inhibitor, or about 1 mEq/mg of proton pump inhibitor, or about 2 mEq/mg of proton pump inhibitor, or about 2.5 mEq/mg of proton pump inhibitor, or about 3 mEq/mg of proton pump inhibitor, or about 3.5 mEq/mg of proton pump inhibitor, or about 4 mEq/mg of proton pump inhibitor, or about 4.5 mEq/mg of proton pump inhibitor, or about 5 mEq/mg of proton pump inhibitor, or about 6 mEq/mg of proton pump inhibitor, or about 7 mEq/mg of proton pump inhibitor, or about 8 mEq/mg of proton pump inhibitor
  • the antacid is present in the pharmaceutical formulations of the present invention in an amount of about 1 niEq to about 160 mEq per dose, or 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 per dose.
  • the antacid is present in an amount of more than about 5 times, or more than about 10 times, or more than about 20 times, or more than about 30 times, or more than about 40 times, or more than about 50 times, or more than about 60 times, or more than about 70 times, or more than about 80 times, or more than about 90 times, or more than about 100 times the amount of the proton pump inhibiting agent on a weight to weight basis in the composition.
  • the amount of antacid present in the pharmaceutical formulation is between 200 and 3500 mg. In other embodiments, the amount of antacid present in the pharmaceutical formulation 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.
  • the at least one buffering agent is a combination of two or more buffering agents
  • the combination comprises 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 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
  • 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.
  • the antacid is sodium bicarbonate and is present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump inhibitor
  • the antacid is a mixture of sodium bicarbonate and magnesium hydroxide, wherein the sodium bicarbonate and magnesium hydroxide are each present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump inhibitor.
  • the antacid is a mixture of sodium bicarbonate and magnesium oxide, wherein the sodium bicarbonate and magnesium oxide are each present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump inhibitor.
  • the term "soluble antacid” as used herein refers to an antacid that has a solubility of at least 500 mg/mL, or 300mg/mL, or 200mg/mL, or lOOmg/mL, or 50 mg/mL in the gastrointestinal fluid.
  • the soluble antacid is sodium bicarbonate. Particle Size of Antacids
  • Particle size of the buffer especially that an insoluble buffer can affect the onset of in- vivo neutralization of the stomach acid. Since decreased particle size increases in surface area, the particle size reduction provides an increase in the rate of acid neutralization, leading to superior protection of PPI from gastric acid degradation. On the other hand, extremely fine particle size of buffer will result in the powder mixture that is difficult to manufacture in commercial scale due to their poor flow and difficulties in processing (i.e., compression and encapsulation).
  • the antacid is a specific particle size.
  • the average particle size is no greater than 20 ⁇ m, or no greater than 30 ⁇ m, or no greater than 40 ⁇ m, or no greater than 50 ⁇ m, or no greater than 60 ⁇ m, or no greater than 70 ⁇ m, or no greater than 80 ⁇ m, or no greater than 90 ⁇ m or no greater than 100 ⁇ m in diameter.
  • At least about 70% of the antacid is no greater than 20 ⁇ m, or no greater than 30 ⁇ m, or no greater than 40 ⁇ m, or no greater than 50 ⁇ m, or no greater than 60 ⁇ m, or no greater than 70 ⁇ m, or no greater than 80 ⁇ m, or no greater than 90 ⁇ m or no greater than 100 ⁇ m in diameter.
  • At least about 85% of the antacid is no greater than 20 ⁇ m, or no greater than 30 ⁇ m, or no greater than 40 ⁇ m, or no greater than 50 ⁇ m, or no greater than 60 ⁇ m, or no greater than 70 ⁇ m, or no greater than 80 ⁇ m, or no greater than 90 ⁇ m or no greater than 100 ⁇ m in diameter.
  • the antacid is micronized.
  • particle size of at least 90% of antacid (D 90 ) is less than about 300 ⁇ m, or less than about 250 ⁇ m, or less than about 200 ⁇ m, or less than about 150 ⁇ m, or less than about 100 ⁇ m.
  • at least 75% of the antacid (D 75 ) has particle size of less than about 300 ⁇ m, or less than about 250 ⁇ m, or less than about 200 ⁇ m, or less than about 150 ⁇ m, or less than about 100 ⁇ m..
  • At least 50% of the antacid has particle size of less than about 300 ⁇ m, or less than about 250 ⁇ m, or less than about 200 ⁇ m, or less than about 150 ⁇ m, or less than about 100 ⁇ m.
  • Spray dried antacid can also facilitate the speed of neutralization by fast reacting with acid upon contact.
  • Sprayed dried antacid typically has spherical particle shape which aids with achieving homogeneous blend during manufacturing process.
  • the antacid is spray dried with at least 15% of coating material such as maltodextrin or starch.
  • the antacid is spray dried with at least 10% of coating material such as maltodextrin or starch.
  • the antacid is spray dried with at least 5% of coating material such as maltodextrin or starch. In still other embodiments, the antacid is spray dried with between about 1% to about 10% of a coating material. In yet other embodiments, the antacid is spray dried with about 5% of a coating material such as maltodextrin or starch.
  • Materials useful for enhancing the shelf-life of the pharmaceutical formulations of the present invention include materials compatible with the proton pump inhibitor of the pharmaceutical formulations which sufficiently isolate the proton pump inhibitor from other non-compatible excipients.
  • Materials compatible with the proton pump inhibitors of the present invention are those that enhance the shelf-life of the proton pump inhibitor, i.e., by slowing or stopping degradation of the proton pump inhibitor.
  • a pharmaceutical formulation of the present invention may have an enhanced shelf-life stability if, e.g., the microencapsulated proton pump inhibitor has less than about 0.5% degradation after one month of storage at room temperature, or less than about 1% degradation after one month at room temperature, or less than about 1.5% degradation after one month of storage at room temperature, or less than about 2% degradation after one month storage at room temperature, or less than about 2.5% degradation after one month of storage at room temperature, or less than about 3% degradation after one month of storage at room temperature.
  • a pharmaceutical formulation of the present invention may have an enhanced shelf-life stability if the pharmaceutical formulation contains less than about 5% total impurities after about 3 years of storage, or after about 2.5 years of storage, or about 2 years of storage, or about 1.5 years of storage, or about 1 year of storage, or after 11 months of storage, or after 10 months of storage , or after 9 months of storage, or after 8 months of storage, or after 7 months of storage, or after 6 months of storage, or after 5 months of storage, or after 4 months of storage, or after 3 months of storage, or after 2 months of storage, or after 1 month of storage.
  • pharmaceutical formulations of the present invention may have enhanced shelf-life stability if the pharmaceutical formulation contains less degradation of the proton pump inhibitor than proton pump inhibitor in the same formulation which is not microencapsulated or dry coated, or "bare". For example, if bare proton pump inhibitor in the pharmaceutical formulation degrades at room temperature by more than about 2% after one month of storage and the microencapsulated or dry coated material degrades at room temperature by less than about 2% after one month of storage, then the proton pump inhibitor has been microencapsulated or dry coated with a compatible material that enhances the shelf-life of the pharmaceutical formulation.
  • the material useful for enhancing the shelf-life of the pharmaceutical formulations increases the shelf-life stability of the pharmaceutical formulation for at least about 5 days at room temperature, or at least about 10 days at room temperature, or at least about 15 days at room temperature, or at least about 20 days at room temperature, or at least about 25 days at room temperature, or at least about 30 days at room temperature or at least about 2 months at room temperature, or at least about 3 months at room temperature, or at least about 4 months at room temperature, or at least about 5 months at room temperature, or at least about 6 months at room temperature, or at least about 7 months at room temperature, or at least about 8 months at room temperature, or at least about 9 months at room temperature, or at least about 10 months at room temperature, or at least about 11 months at room temperature, or at least about one year at room temperature, or at least about 1.5 years at room temperature, or at least about 2 years at room temperature, or at least about 2.5 years at room temperature, or about 3 years at room temperature.
  • Exemplary microencapsulation materials useful for enhancing the shelf-life of pharmaceutical formulations comprising a proton pump inhibitor include, e.g., cellulose hydroxypropyl ethers (HPC) such as EF Klucel ® , Nisso HPC and PrimaFlo HP22; low- substituted hydroxypropyl ethers (L-HPC)] cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat ® , Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Metfiocel ® and Metolose ® ; Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel ® , Aqualon ® -EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol ® ; carboxymethyl
  • the microencapsulation material is selected from hydroxypropylcellulose and cellulose ethers. In still other embodiments, the microencapsulation material is selected from Klucel EF, Klucel EXF 5 Methocel E5, Methocel E15, and Methocel A15. In other embodiments, the material that enhances the shelf-life has a viscosity of 100-800 cps at 10% solution; or a viscosity of 200-600 cps at 10% solution; or a viscosity of 300-400 cps at 10% solution.
  • a buffering agent such as sodium bicarbonate is incorporated into the microencapsulation material
  • an antioxidant such as BHT or BHA is incorporated into the microencapsulation material.
  • plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material.
  • the microencapsulating material useful for enhancing the shelf-life of the pharmaceutical formulations is from the USP or the National Formulary (NF).
  • one or more other compatible materials are present in the microencapsulation material.
  • exemplary materials include, e.g., parietal cell activators, organic solvents, erosion facilitators, diffusion facilitators, anti-adherents, anti-foaming agents, antioxidants, sweetening agents, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filing agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
  • the final formulation of the pharmaceutical formulation will be in the form of a tablet and at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85% or at least about 90%, or at least about 92%, or at least about 95%, or at least about 98%, or at least about 99% of the microspheres survive the tableting process, wherein microspheres that have survived the tableting process are those which provide the desired properties described herein.
  • the final formulation of the pharmaceutical formulation is in the form of a powder for oral suspension and the microencapsulation material surrounding the proton pump inhibitor will sufficiently dissolve in water, with or without stirring, in less than 1 hour, or less than 50 minutes, or less than 40 minutes, or less than 30 minutes, or less than 25 minutes, or less than 20 minutes, or less than 15 minutes, or less than 10 minutes or less than 5 minutes, or less than 1 minute.
  • Sufficiently dissolves means that at least about 50% of the encapsulation material has dissolved.
  • the microencapsulating material useful for enhancing the shelf-life of the pharmaceutical formulation sufficiently disintegrates to release the proton pump inhibitor into the gastrointestinal fluid of the stomach within less than about 1.5 hours, or within about 10 minutes, or within about 20 minutes, or within about 30 minutes, or within about or within about 40 minutes, or within about 50 minutes, or within about 1 hour, or within about 1.25 hours, or within about 1.5 hours after exposure to the gastrointestinal fluid.
  • Sufficiently disintegrates means that at least about 50% of the microencapsulation material has dissolved.
  • the average particle sizes of the microencapsulated drugs range from submicron to less than about 1,000 microns in diameter, or less than about 900 microns in diameter, or less than about 800 microns in diameter, or less than about 700 microns in diameter, or less than about 600 microns in diameter, or less than about 500 microns in diameter, or less than about 450 microns in diameter, or less than about 400 microns in diameter, or less than about 350 microns in diameter, or less than about 300 microns in diameter, or less than about 250 microns in diameter, or less than about 200 microns in diameter, or less than about 150 microns in diameter, or less than about 100 microns in diameter, or less than about 75 microns in diameter, or less than about 50 microns in diameter, or less than about 25 microns in diameter, or less than about 15 microns in diameter.
  • the average particle size of the aggregates is between about 25 microns in diameter to about 300 microns in diameter. In still other embodiments, the average particle size of the aggregates is between about 100 microns in diameter to about 200 microns in diameter. And in still further embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 100 microns in diameter.
  • the term "average particle size" is intended to describe the average diameter of the particles and/or agglomerates used in the pharmaceutical formulation.
  • Proton pump inhibitors are inherently bitter tasting and in one embodiment of the present invention, these bitter proton pump inhibitors are microencapsulated with a taste- masking material.
  • Materials useful for masking the taste of pharmaceutical formulations include those materials capable of microencapsulating the proton pump inhibitor, thereby protecting the senses from its bitter taste.
  • Taste-masking materials of the present invention provide superior pharmaceutical formulations by e.g., creating a more palatable pharmaceutical formulation as compared to pharmaceutical formulations and/or by creating a dosage form requiring less of the traditional flavoring or tastemasking agents.
  • flavor leadership criteria used to develop a palatable product include (1) immediate impact of identifying flavor, (2) rapid development of balanced, full flavor, (3) compatible mouth feel factors, (4) no "off flavors, and (5) short aftertaste. See, e.g., Worthington, A Matter of Taste, Pharmaceutical Executive (April 2001).
  • the pharmaceutical formulations of the present invention improve upon one or more of these criteria.
  • Taste of a pharmaceutical formulation is important for both increasing patient compliance as well as for competing with other marketed products used for similar diseases, conditions and disorders.
  • Taste, especially bitterness is particularly important in pharmaceutical formulations for children since, because they cannot weigh the positive benefit of getting better against the immediate negative impact of the bitter taste in their mouth, they are more likely to refuse a drug that tastes bad. Thus, for pharmaceutical formulations for children, it becomes even more important to mask the bitter taste.
  • Microencapsulation of the proton pump inhibitor can (1) lower the amount of flavoring agents necessary to create a palatable product and/or (2) mask the bitter taste of the proton pump inhibitor by separating the drug from the taste receptors.
  • Taste-masking materials include, e.g., cellulose hydroxypropyl ethers (HPC) such as Klucel ® , Nisswo HPC and PrimaFlo HP22; low-substituted hydroxypropyl ethers (L- HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat ® , Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP 843; methylcellulose polymers such as Methocel ® and Metolose ® ; Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel ® , Aqualon ® -EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol ® ; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aualon ®
  • taste-masking materials contemplated are those described in U.S. Pat. Nos. 4,851,226, 5,075,114, and 5,876,759.
  • taste-masking materials see, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Eastern, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington 's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pennsylvania 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N. Y., 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).
  • a pH modifier such as sodium carbonate or sodium bicarbonate is incorporated into the microencapsulation material.
  • an antioxidant such as BHT or BHA is incorporated into the microencapsulation material.
  • sucrose or sucralose is incorporated into the taste masking material.
  • plasticizers such as polyethylene glycol and/or stearic acid are incorporated into the microencapsulation material.
  • one or more other compatible materials are present in the microencapsulation material.
  • exemplary materials include, e.g., parietal cell activators, organic solvents, erosion facilitators, diffusion facilitators, anti-adherents, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filing agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents.
  • the pharmaceutical formulations of the present invention may also comprise one or more flavoring agents.
  • “Flavoring agents” or “sweeteners” useful in the pharmaceutical formulations of the present invention include, e.g.; acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, 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, monoammonium glyrrhizinate (MagnaSweet®), maltol, marmitol, maple, marshmallow, menthol, mint cream
  • one or more flavoring agents are mixed with the taste-masking material prior to microencapsulating the proton pump inhibitor and, as such, are part of the taste-masking material.
  • the flavoring agent is mixed with the non- compatible excipients during the formulation process and is therefore not in contact with the proton pump inhibitor, and not part of the microencapsulation material.
  • an antacid such as sodium bicarbonate
  • the weight fraction of the taste masking material is, e.g., about 98% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 2%, or about 1% or less of the total weight of the pharmaceutical composition.
  • the amount of flavoring agent necessary to create a palatable product, as compared to a pharmaceutical formulation comprising non-microencapsulated proton pump inhibitor is decreased by 5% or less, or by 5% to 10%, or by 10% to 20%, or by 20% to 30%, or by 30% to 40%, or by 40% to 50%, or by 50% to 60%, or by 60% to 70%, or by 70% to 80%, or by 80% to 90%, or by 90% to 95%, or by greater than 95%.
  • no flavoring agent is necessary to create a more palatable pharmaceutical formulation as compared to a similar pharmaceutical formulation comprising non-microencapsulated proton pump inhibitor.
  • the total amount of flavoring agent present in the pharmaceutical formulation is less than 20 grams, or less than 15 grams, or less than 10 grams, or less than 8 grams, or less than 5 grams, or less than 4 grams, or less than 3.5 grams, or less than 3 grams, or less than 2.5 grams or less than 2 grams, or less than 1.5 grams, or less than 1 gram, or less than 500 mg, or less than 250 mg, or less than 150 mg, or less than 100 mg, or less than 50 mg.
  • the formulation comprises a microencapsulated omeprazole having approximately 37% omeprazole, the remainder being the immediate release coating designed to protect the micronized omeprazole from degradation by flavor components and other excipients.
  • the shelf life of a chewable product is thus improved. Additionally the flavor of the product can be enhanced, as the immediate release coating provides protection against a wide variety of acidic excipients.
  • the proton pump inhibitor may be microencapsulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath.
  • spray drying processes e.g., spray drying processes, spinning disk processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath.
  • several chemical techniques e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used.
  • other methods such as dry granulation (i
  • the spinning disk method allows for: 1) an increased production rate due to higher feed rates and use of higher solids loading in feed solution, 2) the production of more spherical particles, 3) the production of a more even coating, and 4) limited clogging of the spray nozzle during the process.
  • the material used in the spray-dry encapsulation process is emulsified or dispersed into the core material in a concentrated form, e.g., 10-60 % solids.
  • the solid loading is between about 10-20%, or between about 10-40%, or between about 40-60%.
  • the microencapsulation material is, in one embodiment, is emulsified until about 1 to 3 ⁇ m droplets are obtained.
  • the microencapsulation material is emulsified until about 1 to 200 ⁇ m droplets are obtained, or until about 1 to 100 ⁇ m droplets are obtained, hi still other embodiments, the median droplet size of the microencapsulation material is between about 1 to about 300 ⁇ m, or between about 1 to about 200 ⁇ m, or between about 50 to about 150 ⁇ m.
  • Coacervation involves microencapsulation of materials such as active pharmaceutical ingredients and involves a three part process of particle or droplet formation, coacerate wall formation, and capsule isolation. This method can produce very small particle size microcapsules (10-70 microns).
  • Extrusion/spheronization is another method that involves wet massing of active pharmaceutical ingredients, followed by the extrusion of the wet mass through a perforated plate to produce short cylindrical rods. These rods are subsequently placed into a rapidly rotating spheronizer to shape the cylindrical rods into uniform spheres. The spheres are subsequently dried using a fluid bed drier and then coated with a functional coating using a fluid bed equipped with a Wurster insert and spray nozzle. This method produces smooth, uniform spheres that are ideal for receiving a functional coating. Drug loadings as high as 80% are possible (depending on drug characteristics).
  • the microspheres have irregular geometries. In other embodiments, the microspheres are aggregates of smaller particles.
  • the drug loading of the proton pump inhibitor in the microspheres is greater than 1%, greater than 2.5%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80% weight percent of the proton pump inhibitor to the microencapsulated drug.
  • the drug loading of the proton pump inhibitor in the microspheres is between about 5-60 wt%, or about 5-50 wt-%, or about 10-40 wt-%.
  • the stability of the proton pump inhibitors used in the present invention may be increased by alternative methods such as dry coating and nano-particle coating.
  • Dry coating involves the formation of granules of coated proton pump inhibitor which are then mixed with other components. Dry granulation is achieved by forming dense compacts which are subsequently milled to a desired particle size and then blended with other components of the pharmaceutical composition. Dry granulation and nano-particle coating can provide enhanced stability and tastemasking characteristics to active pharmaceutical by diluting and isolating such components in a granulated matrix of compatible ingredients that can enhance the shelf life of proton pump inhibitor products as well as tastemask the bitterness if sweetener or flavors are used in coating material.
  • Typical technique for dry granulation is to use slugging or roller compaction.
  • the dry powders are compressed using a conventional tablet machine, or more usually, a large heavy duty rotary press.
  • the resulting compacts or "slug” are then milled to a desired particle size.
  • Roller compaction is an alternative gentler method, the powder mix being squeezed between two rollers to form a compressed sheet.
  • the sheet normally is weak and brittle and breaks immediately into flakes. These flakes need gentler treatment to break them into granules, and this can be usually be achieved by screening alone. Parikh, D. M., Handbook of Pharmaceutical Granulation Technology, (Marcel Dekker ed. 1997).
  • Nano particle coating is another method that involves a nano particle deposited onto the drug core using Physical Vapour Deposition (PVD) methods.
  • PVD Physical Vapour Deposition
  • This method can coat a 10-20 micro drug core with various thickness of metal, or metal salt (e.g., SB, MgO, MgOH, CaCO 3 , etc).
  • the average particle sizes of the dry coated proton pump inhibitor ranges from submicron to less than about 1,000 microns in diameter, or less than about 900 microns in diameter, or less than about 800 microns in diameter, or less than about 700 microns in diameter, or less than about 600 microns in diameter, or less than about 500 microns in diameter, or less than about 450 microns in diameter, or less than about 400 microns in diameter, or less than about 350 microns in diameter, or less than about 300 microns in diameter, or less than about 250 microns in diameter, or less than about 200 microns in diameter, or less than about 150 microns in diameter, or less than about 100 microns in diameter, or less than about 75 microns in diameter, or less than about 50 microns in diameter, or less than about 25 microns in diameter, or less than about 15 microns in diameter.
  • the average particle size of the aggregates is between about 25 microns in diameter to about 300 microns in diameter. In still other embodiments, the average particle size of the aggregates is between about 100 microns in diameter to about 200 microns in diameter. And in still further embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 100 microns in diameter.
  • the term "average particle size" is intended to describe the average diameter of the particles and/or agglomerates used in the pharmaceutical formulation.
  • the dry coated proton pump inhibitor granules are less than about 2000 microns, or less than about 1500 microns, or less than about 1000 microns.
  • the average particle size of the dry coated proton pump inhibitor granules is between about 100 to about 2000 microns, or between about 100 to about 1000 microns, or between about 200 to about 800 microns, or between about 300 to about 600 microns.
  • the dry coated proton pump inhibitor granules comprise antacid, binder, lubricant and/or sweeteners.
  • the antacid is sodium bicarbonate.
  • the binder is hydroxypropyl cellulose.
  • the sweetener is sucralose and/or xylitab.
  • the lubricant is magnesium stearate.
  • the dry coated proton pump inhibitor is combined with additional antacid.
  • the additional antacid is the same antacid as used in the material used to dry coat the proton pump inhibitor.
  • the antacid is a different antacid.
  • the antacid is a combination of two or more antacids.
  • one or more pharmaceutically acceptable excipients are mixed with the dry coated proton pump inhibitor to form the pharmaceutical composition.
  • the additional pharmaceutical excipients include one or more flavors.
  • one or more other compatible materials are present in the dry coating material.
  • exemplary materials include, e.g., parietal cell activators, organic solvents, erosion facilitators, diffusion facilitators, anti-adherents, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filing agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents.
  • the additional compatible materials are binders, lubricants and sweeteners.
  • one or more sweeteners are incorporated into the material used to dry coat the proton pump inhibitor.
  • one or more flavoring agents are incorporated into the material used to dry coat the proton pump inhibitor, m still other embodiments, the material used to dry coat the proton pump inhibitor comprises a sweetener and/or a flavoring agent. In some embodiments, this dry coated proton pump inhibitor is then mixed with additional sweeteners and/or flavoring agents.
  • “Flavoring agents” or “sweeteners” useful in the pharmaceutical formulations of the present invention include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, 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, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint
  • the weight percent of the proton pump inhibitor in the dry coated granules is about 2-70%. In some embodiments, the weight percent of the proton pump inhibitor in the dry coated granules is about 5-50%, or about 5-30%. In yet other embodiments, the weight percent of the proton pump inhibitor in the granules is about 5%, or about 7%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%.
  • compositions and methods described herein as containing microencapsulated proton pump inhibitors can, in addition to or in the alternative, contain dry coated proton pump inhibitors.
  • the acid neutralizing capacity and pH profile of various antacid combinations can be evaluated by using an in- vitro stomach model.
  • Several of these simulated dynamic models are known in the art. See, e.g., Smyth et al., Correlation of In- Vivo Methodology for Evaluation of Antacids, J. Pharm. Sci. Vol. 65, 1045 (1976); Hobert, Fordham et al., In- Vivo Evaluation of Liquid Antacids, New England Journal of Med.
  • the antacid increases the gastric pH to at least about 3.5 for no more than about 90 minutes as measured by a simulated stomach model such as Fuch's kinetic in- vitro pH model. In other embodiments, the antacid increases the pH to at least about 3.5 for no more than about 60 minutes. In still other embodiments, the antacid increases the pH to at least about 3.5 for no more than 45 minutes. Depending on the buffer system used (i.e., type of antacid and amount) some embodiments of the present invention, the antacid increases the gastric pH to at least about 3.5 for no more than about 30 minutes as measured by a simulated stomach model such as Fuchs' kinetic in-vitro pH model.
  • the antacid increases the gastric pH to at least about 3.5 for less than about 25 minutes as measured by a simulated stomach model such as Fuch's kinetic in-vitro pH model. In yet other embodiments, the antacid increases the gastric pH to at least about 3.5 for less than about 20 minutes, or less than about 15 minutes, or less than about 10 minutes as measured by a stimulated stomach model such as Fuch's kinetic in-vitro pH model. In each of these embodiments, the antacid protects at least some of the proton pump inhibitor and a therapeutically effective amount of the proton pump inhibitor is delivered to the subject.
  • the proton pump inhibiting agent is 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. Patent Nos. 5,840,737, 6,489,346, 6,699,885, and 6,645,988 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, e.g., a gastrointestinal- disorder-effective amount of a proton pump inhibiting agent, is absorbed following administration of the pharmaceutical composition to a subject. It is understood that the amount of proton pump inhibiting agent and/or antacid that is administered to a subject is dependent on, e.g., 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 will require larger dosage units, e.g., 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 e.g., 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, e.g., about 1-2 mg/Kg of body weight, or about 0.5 mg/Kg of body weight, or about 1 mg/Kg of body weight, or 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 subj ect.
  • unit dosage forms for humans contain about 1 mg to about 120 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80, mg, or about 90 mg, or about 100 mg, or about 110 mg, or about 120 mg of a proton pump inhibitor.
  • the pharmaceutical formulation is administered in an amount to achieve a measurable serum concentration of a non-acid degraded proton pump inhibiting agent greater than about 100 ng/ml within about 30 minutes after administration of the pharmaceutical formulation.
  • the pharmaceutical formulation 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 inhibiting agent greater than about 100 ng/ml within about 15 minutes after administration of the pharmaceutical formulation.
  • the pharmaceutical formulation 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 inhibiting agent greater than about 100 ng/ml within about 10 minutes after administration of the pharmaceutical formulation.
  • the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 150 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 to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 250 ng/ml within about 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 to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 350 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 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 to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 150 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 to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 250 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 to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 350 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 to achieve a measurable serum concentration of the proton pump inhibiting agent 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 to achieve a measurable serum concentration of a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 500 ng/ml within 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 a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 300 ng/ml within about 45 minutes after administration of the composition.
  • the composition is administered to the subject in an amount sufficient to achieve a maximum serum concentration (Cmax) at a time (Tmax) that is within about 90, 70, 60, 50, 40, 30 or 20 minutes after administration of the composition according to the present invention.
  • the composition is administered to the subject in an amount sufficient to achieve a maximum serum concentration (Cmax) at a time (Tmax) that is between about 10 and about 90 minutes, between about 10 to about 60 minutes, between about 15 to about 60 minutes or between about 20 to about 60 minutes after administration of the composition according to the present invention.
  • Cmax maximum serum concentration
  • Tmax time
  • the values of Cmax and Tmax are averages over a test population. In other specific embodiments, the values of Cmax and Tmax are the values for an individual.
  • the composition is administered in an amount sufficient to achieve a maximum serum concentration (Cmax) of from about 400 to about 3000 ng/niL, from about 400 to about 2500 ng/niL, from about 400 to about 2000 ng/mL, from about 400 to about 1500 ng/mL, from about 1000 to about 1500 ng/mL , from about 400 to about 1000 ng/mL or from about 400 to about 700 ng/mL.
  • Cmax and Tmax are averages over a test population. In other specific embodiments, the values of Cmax and Tmax are the values for an individual.
  • the composition is administered in an amount sufficient to achieve a maximum serum concentration (Cmax) of greater than 400 ng/mL, greater than 600 ng/mL, greater than 1000 ng/mL.
  • Cmax maximum serum concentration
  • the values of Cmax and Tmax are averages over a test population. In other specific embodiments, the values of Cmax and Tmax are the values for an individual.
  • 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, three times a day, etc. administration if desired.
  • 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, three times a day, etc. administration if desired.
  • one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vivo for a period of time effective to elicit a therapeutic effect. Determination of these parameters is well within the skill of the art. These considerations are well known in the art and are described in standard textbooks.
  • the composition is administered to a subject in a gastrointestinal-disorder-effective amount, that is, the composition is administered in an amount that achieves a therapeutically-effective dose of a proton pump inhibiting agent in the blood serum of a subject for a period of time to elicit a desired therapeutic effect.
  • a therapeutically-effective dose of a proton pump inhibiting agent in the blood serum of a subject for a period of time to elicit a desired therapeutic effect.
  • the composition is administered to achieve a therapeutically-effective dose of a proton pump inhibiting agent in the blood serum of a subject within about 45 minutes after administration of the composition.
  • a therapeutically-effective dose of the proton pump inhibiting agent is achieved in the blood serum of a subject within about 30 minutes from the time of administration of the composition to the subject. In yet another embodiment, a therapeutically-effective dose of the proton pump inhibiting agent is achieved in the blood serum of a subject within about 20 minutes from the time of administration to the subject. In still another embodiment of the present invention, a therapeutically-effective dose of the proton pump inhibiting agent is achieved in the blood serum of a subject at about 15 minutes from the time of administration of the composition to the subject.
  • greater than about 98%; or greater than about 95%; or greater than about 90%; or greater than about 75%; or greater than about 50% of the drug absorbed into the bloodstream is in a non-acid degraded or a non-acid reacted form.
  • the pharmaceutical formulations provide a release profile of the proton pump inhibitor, using USP dissolution methods, whereby greater than about 50% of the proton pump inhibitor is released from the composition within about 2 hours; or greater than 50% of the proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 50% of the proton pump inhibitor is released from the composition within about 1 hour after exposure to gastrointestinal fluid.
  • greater than about 60% of the proton pump inhibitor is released from the composition within about 2 hours; or greater than 60% of the proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 60% of the proton pump inhibitor is released from the composition within about 1 hour after exposure to gastrointestinal fluid.
  • greater than about 70% of the proton pump inhibitor is released from the composition within about 2 hours; or greater than 70% of the proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 70% of the proton pump inhibitor is released from the composition within about 1 hour after exposure to gastrointestinal fluid.
  • the pharmaceutical formulations of the present invention contain desired amounts of microencapsulated proton pump inhibitor and/or dry coated proton pump inhibitor and antacid can be in the form of, e.g., a tablet; including a suspension tablet, a chewable tablet, an effervescent tablet or caplet; a pill; a powder such as a sterile packaged powder, a dispensable powder, and an effervescent powder; a capsule including both soft or hard gelatin capsules such as HPMC capsules; a lozenge; a sachet; a troche; pellets; granules; or aerosol.
  • These pharmaceutical formulations of the present invention can be manufactured by conventional pharmacological techniques.
  • buffers The amount and types of buffers, proton pump inhibitors, and other excipients useful in each of these dosage forms are described throughout the specification and examples. It should be recognized that where a combination of buffer, proton pump inhibitor and/or excipient, including specific amounts of these components, is described with one dosage form that the same combination could be used for any other suitable dosage form. Moreover, it should be understood that one of skill in the art would, with the teachings found within this application, be able to make any of the dosage forms listed above by combining the components (i.e., amounts and types of PPIs, buffers, and other excipients) described in the different sections of the specification.
  • each of the dosage forms may comprise one or more additional materials such as a pharmaceutically compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, surfactant, preservative, lubricant, colorant, diluent, solubilizer, moistening agent, stabilizer, wetting agent, anti- adherent, parietal cell activator, anti-foaming agent, antioxidant, chelating agent, antifungal agent, antibacterial agent, or one or more combination thereof.
  • additional materials such as a pharmaceutically compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, surfactant, preservative, lubricant, colorant, diluent, solubilizer, moistening agent, stabilizer, wetting agent, anti- adherent, parietal cell activator, anti-foaming agent, antioxidant, chelating agent, antifungal agent, antibacterial agent, or one or more combination thereof.
  • Parietal cell activators are administered in an amount sufficient to produce the desired stimulatory effect without causing untoward side effects to patients.
  • the parietal cell activator is administered in an amount of about 5 mg to about 2.5 grams per 20 mg dose of the proton pump inhibitor.
  • compositions of the present invention can be manufactured by conventional pharmacological techniques.
  • Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986).
  • Other methods include, e.g., prilling, spray drying, pan coating, melt granulation, granulation, wurster coating, tangential coating, top spraying, extruding, coacervation and the like.
  • the proton pump inhibitor is microencapsulated or dry coated prior to being formulated into one of the above forms.
  • some or all of the antacid is also microencapsulated prior to being further formulated into one of the above forms.
  • a film coating is provided around the pharmaceutical formulation.
  • compositions wherein some or all of the proton pump inhibitor and some or all of the antacid are microencapsulated or dry coated. In some embodiments, only some of the proton pump inhibitor is microencapsulated or dry coated. In other embodiments, all of the proton pump inhibitor is microencapsulated or dry coated. In still other embodiments, only some of the antacid is microencapsulated or dry coated.
  • one or more layers of the pharmaceutical formulation are plasticized.
  • a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition.
  • Plasticizers include, e.g., diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
  • the pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibiting inhibitor and antacid and are in a solid dosage form. In other embodiments, the pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibitor and antacid and are administered in the form of a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC).
  • Solid compositions e.g., tablets, chewable tablets, effervescent tablets, and capsules, are prepared by mixing the microencapsulated proton pump inhibitor or dry coated proton pump inhibitor with one or more antacid and pharmaceutical excipients to form a bulk blend composition.
  • dry coated proton pump inhibitor mixing with additional antacid is optional.
  • these bulk blend compositions as homogeneous, it is meant that the microencapsulated or dry coated proton pump inhibitor and antacid are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.
  • the individual unit dosages may also comprise film coatings, which disintegrate upon oral ingestion or upon contact with diluent.
  • Compressed tablets are solid dosage forms prepared by compacting the bulk blend compositions described above.
  • compressed tablets of the present invention will comprise one or more flavoring agents.
  • the compressed tablets will comprise a film surrounding the final compressed tablet.
  • the compressed tablets comprise one or more excipients and/or flavoring agents.
  • a capsule may be prepared, e.g., by placing the bulk blend composition, described above, inside of a capsule.
  • the pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibiting inhibitor and antacid and are in a solid dosage form.
  • the pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibitor and antacid and are administered in the form of a capsule (including both soft and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC).
  • the pharmaceutical compositions of the present invention can be manufactured by conventional pharmacological techniques.
  • a chewable tablet may be prepared by compacting bulk blend compositions, described above.
  • the chewable tablet comprises a material useful for enhancing the shelf-life of the pharmaceutical formulation, h ⁇ some embodiments, the proton pump inhibitor is dry coated.
  • microencapsulated material has taste-masking properties.
  • the chewable tablet comprises one or more flavoring agents and one ore more taste-masking materials.
  • the chewable tablet comprises both a material useful for enhancing the shelf- life of the pharmaceutical formulation and one or more flavoring agents.
  • the microencapsulated or dry coated proton pump inhibitor, antacid, and optionally one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the antacid and the proton pump inhibitor into the gastrointestinal fluid.
  • the compressed mass has substantially disintegrated.
  • chewable tablets are prepared using micronized proton pump inhibitor that has been combined with various combinations of potential excipients.
  • micronized omeprazole is combined with various colorants, flavorings and other taste masking excipients.
  • acidity in particular colorants, flavorings or other taste masking excipients can give rise to instability of the proton pump inhibitor.
  • some embodiments provide for encapsulation of micronized proton pump inhibitor in an immediate release coating.
  • the immediate release coating is designed to protect the micronized proton pump inhibitor from degradation by acidic excipients, such as flavor components.
  • a powder for suspension may be prepared by combining microencapsulated proton pump inhibitor and one or more antacid.
  • the powder may comprise one or more pharmaceutical excipients.
  • the proton pump inhibitor is micronized.
  • Other embodiments of the present invention also comprise a suspending agent and/or a wetting agent.
  • Effervescent powders are also prepared in accordance with the present invention.
  • Effervescent salts have been used to disperse medicines in water for oral administration.
  • Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
  • a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
  • Examples of effervescent salts include the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6 or higher.
  • the method of preparation of the effervescent granules of the present invention employs three basic processes: wet granulation, dry granulation and fusion.
  • the fusion method is used for the preparation of most commercial effervescent powders. It should be noted that, although these methods are intended for the preparation of granules, the formulations of effervescent salts of the present invention could also be prepared as tablets, according to known technology for tablet preparation.
  • wet granulation is one of the oldest methods of granule preparation.
  • the individual steps in the wet granulation process of tablet preparation include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation, and final grinding.
  • the microencapsulated omeprazole is added to the other excipients of the pharmaceutical formulation after they have been wet granulated.
  • Dry granulation by slugging 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 or milling operation, usually by passage through an oscillation granulator. The individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation). In a larger scale operation, roller compaction can be used instead of "slugging". Roller compaction procedure is well- known to ones skilled in the art. No wet binder or moisture is involved in any of the dry granulation steps.
  • the microencapsulated omeprazole is dry granulated with other excipients in the pharmaceutical formulation. In other embodiments, the microencapsulated omeprazole is added to other excipients of the pharmaceutical formulation after they have been dry granulated.
  • compositions suitable for buccal (sublingual) administration include, e.g., lozenges in a flavored base, such as sucrose, acacia, tragacanth, and pastilles comprising microencapsulated proton pump inhibitor in an inert base such as gelatin, glycerin, sucrose, and acacia are also provided herein.
  • release delivery systems include, e.g., polymer-based systems, such as polylactic and polyglycolic acid, plyanhydrides and polycaprolactone; nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients partially fused implants and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209- 214 (1990).
  • the pharmaceutical composition comprises (a) microencapsulated proton pump inhibitor; and (b) at least one antacid; wherein the pharmaceutical composition is made by the process of (a) microencapsulating some or all of the proton pump inhibitor; and (b) dry blending the microencapsulated material with some or all of the at least one antacid.
  • the pharmaceutical composition comprises (a) microencapsulated proton pump inhibitor, and (b) at least one antacid, wherein the microencapsulated proton pump inhibitor is made by the process of spray drying the proton pump inhibitor with a microencapsulating material.
  • the pharmaceutical composition comprises (a) microencapsulated proton pump inhibitor, and (b) at least one antacid, wherein the pharmaceutical composition is made by the process of (a) microencapsulating some or all of the proton pump inhibitor, and (b) blending the microencapsulated material with some or all of the at least one antacid.
  • Initial treatment of a subject suffering from a disease, condition or disorder where treatment with an inhibitor of H + /K -ATPase is indicated can begin with the dosages indicated above. Treatment is generally continued as necessary over a period of hours, days, or weeks to several months or years until the disease, condition or disorder has been controlled or eliminated. Subjects undergoing treatment with the compositions disclosed herein can be routinely monitored by any of the methods well known in the art to determine the effectiveness of therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal effective amounts of compounds of the present invention are administered at any point in time, and so that the duration of treatment can be determined as well.
  • the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of an inhibitor of H 4 VK + - ATPase exhibiting satisfactory effectiveness is administered, and so that administration is continued only so ⁇ long as is necessary to successfully treat the disease, condition or disorder.
  • the pharmaceutical formulations are useful for treating a condition, disease or disorder where treatment with a proton pump inhibitor is indicated.
  • the treatment method comprises oral administration of one or more compositions of the present invention to a subject in need thereof in an amount effective at treating the condition, disease, disorder.
  • the disease, condition or disorder is a gastrointestinal disorder.
  • the dosage regimen to prevent, give relief from, or ameliorate the disease, condition or disorder can be modified in accordance with a variety of factors. These factors include the type, age, weight, sex, diet, and medical condition of the subject and the severity of the disorder or disease. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the dosage regimens set forth herein.
  • the pharmaceutical formulation is administered post meal.
  • the pharmaceutical formulation administered post meal is in the form of a chewable tablet.
  • the present invention also includes methods of treating, preventing, reversing, halting or slowing the progression of a gastrointestinal disorder once it becomes clinically evident, or treating the symptoms associated with, or related to the gastrointestinal disorder, by administering to the subject a composition of the present invention.
  • the subject may already have a gastrointestinal disorder at the time of administration, or be at risk of developing a gastrointestinal disorder.
  • the symptoms or conditions of a gastrointestinal disorder in a subject can be determined by one skilled in the art and are described in standard textbooks.
  • the method comprises the oral administration a gastrointestinal-disorder-effective amount of one or more compositions of the present invention to a subject in need thereof.
  • Gastrointestinal disorders include, e.g., duodenal ulcer disease, gastrointestinal ulcer disease, gastroesophageal reflux disease, erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, pathological gastrointestinal hypersecretory disease, Zollinger Ellison Syndrome, and acid dyspepsia.
  • the gastrointestinal disorder is heartburn.
  • the present invention is also useful for other subjects including veterinary animals, reptiles, birds, exotic animals and farm animals, including mammals, rodents, and the like.
  • Mammals include primates, e.g., a monkey, or a lemur, horses, dogs, pigs, or cats.
  • Rodents includes rats, mice, squirrels, or guinea pigs.
  • compositions are designed to produce release of the proton pump inhibitor to the site of delivery (typically the stomach), while substantially preventing or inhibiting acid degradation of the proton pump inhibitor.
  • compositions are designed to produce release of the proton pump inhibitor for immediate release in vitro dissolution profile, which is well accepted to by those in the arts to mean drug release of greater than 70% (Q70) in 45 minutes in a USP dissolution test.
  • In vitro dissolution rate contemplated by the present invention include drug release of greater than 70% (Q70) in 15 minutes in a media with a wide pH range of 1-8.
  • compositions can also be used in combination ("combination therapy") with another pharmaceutical agent that is indicated for treating or preventing a gastrointestinal disorder, such as, e.g., an anti-bacterial agent, an alginate, a prokinetic agent, a H2 antagonist, an antacid, or sucralfate, which are commonly administered to minimize the pain and/or complications related to this disorder.
  • a gastrointestinal disorder such as, e.g., an anti-bacterial agent, an alginate, a prokinetic agent, a H2 antagonist, an antacid, or sucralfate, which are commonly administered to minimize the pain and/or complications related to this disorder.
  • Combination therapies contemplated by the present invention include administration of a pharmaceutical formulation of the present invention in conjunction with another pharmaceutically active agent that is indicated for treating or preventing a gastrointestinal disorder in a subject, as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents for the treatment of a gastrointestinal disorder.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually substantially simultaneously, minutes, hours, days, weeks, months or years depending upon the combination selected).
  • Combination therapies of the present invention are also intended to embrace administration of these therapeutic agents in a sequential manner, that is, where each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, e.g., by administering to the subject a single tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules, or tablets for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route.
  • composition of the present invention can be administered orally or nasogastrointestinal, while the other therapeutic agent of the combination can be administered by any appropriate route for that particular agent, including, but not limited to, an oral route, a percutaneous route, an intravenous route, an intramuscular route, or by direct absorption through mucous membrane tissues.
  • the composition of the present invention is administered orally or nasogastrointestinal and the therapeutic agent of the combination may be administered orally, or percutaneously.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients, such as, but not limited to, a pain reliever, such as a steroidal or nonsteroidal anti-inflammatory drug, or an agent for improving stomach motility, e.g., and with non-drug therapies, such as, but not limited to, surgery.
  • a pain reliever such as a steroidal or nonsteroidal anti-inflammatory drug
  • an agent for improving stomach motility e.g.
  • non-drug therapies such as, but not limited to, surgery.
  • the therapeutic compounds which make up the combination therapy may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration.
  • the therapeutic compounds that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two step administration.
  • a regimen may call for sequential administration of the therapeutic compounds with spaced-apart administration of the separate, active agents.
  • the time period between the multiple administration steps may range from, e.g., a few minutes to several hours to days, depending upon the properties of each therapeutic compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the therapeutic compound, as well as depending upon the effect of food ingestion and the age and condition of the subject.
  • Orcadian variation of the target molecule concentration may also determine the optimal dose interval.
  • the therapeutic compounds of the combined therapies contemplated by the present invention may involve a regimen calling for administration of one therapeutic compound by oral route and another therapeutic compound by an oral route, a percutaneous route, an intravenous route, an intramuscular route, or by direct absorption through mucous membrane tissues, for example.
  • the therapeutic compounds of the combined therapy are administered orally, by inhalation spray, rectally, topically, buccally, sublingualis or parenterally (e.g., subcutaneous, intramuscular, intravenous and intradermal injections, or infusion techniques), separately or together, each such therapeutic compound will be contained in a suitable pharmaceutical formulation of pharmaceutically-acceptable excipients, diluents or other formulations components.
  • the pharmaceutical formulations of the present invention are administered with low strength enteric coated Aspirin.
  • the second active pharmaceutical e.g., Aspirin or an NSAID, used in combination with the pharmaceutical formulations of the present invention, is enteric coated.
  • antacid present in the pharmaceutical formulations of the present invention increase the pH level of the gastrointestinal fluid, thereby allowing part or all of the enteric coating on the second active pharmaceutical to dissolve in the stomach.
  • Example IA Microencapsulation Materials and Methods
  • the basic operation for the spinning disk process used was as follows: An encapsulation solution or suspension was prepared by dissolving the encapsulation (or shell) material in the appropriate solvent. Omeprazole (or the proton pump inhibitor) was dispersed in the coating solution and fed onto the center of the spinning disk or spray dryer which is pre-heated. One of three atomization methods can be used to make droplets of the feed solution/suspension. The microspheres were formed by removal of the solvent using heated airflow inside the drying chamber and collected as a powder using a cyclone separator.
  • Atomization of the feed solution/suspension can be achieved by major methods in a spray dryer, by rotary atomization using a spinning disc, by high pressure-nozzle, or by two fluid nozzles.
  • a thin film was produced across the surface of the disk and atomization occurs as the coating material left the periphery of the disk in a rotary atomization process.
  • the microspheres were formed by removal of the solvent using heated airflow inside the atomization chamber and collected as a free- flowing powder using a cyclone separator.
  • High pressure nozzle utilizes a high pressure pump to feed the solution/suspension through a various size nozzle so droplets form when injected into the drying chamber.
  • the pressure energy is converted to kinetic energy and the feed issues form the orifice as a high speed film that readily disintegrates into droplets.
  • the atomization is created due to high frictional shearing forces between the liquid surface and the air having a high velocity even at sonic velocities and sometimes rotated to obtain maximum atomization.
  • the basic operation for the microencapsulation by spray drying was as follows: An encapsulation solution or suspension was prepared by dissolving the shell material in the appropriate solvent. Proton pump inhibitor was dispersed in the coating solution and fed onto the spray dryer which is pre-heated. One of the three atomization method can be used to make droplet of the feed solution/suspension. The microspheres were formed by removal of the solvent using heated airflow inside the drying chamber and collected as a powder using a cyclone separator.
  • a spray dryer with attached fluid-bed dryer for sizing of dried particles and/or agglomeration if desired can be also used. Recycling of the super-fine particles from the cyclones back to the spray dryer inlet would allow the agglomeration to form desired particle size distribution.
  • the dissolution profiles of the microencapsulated omeprazole were determined by a method similar to the HPLC method outlined in Example 10, described below.
  • the size of the microspheres was determined by using a microscopic optical method similar to the one outlined in Example 11.
  • Example IB Microencapsulation of Omeprazole with Klucel-EF — 37 wt-%
  • a suspension containing Klucel EF, sodium bicarbonate and omeprazole was prepared (total solid content of 16.23%) and spray dried using a rotary atomizer.
  • the pH of the suspension was 8.1.
  • Spray rate was 35 Kg/hour and the resulting outlet temperature was 70-85 0 C.
  • Atomizer speed was 22,000 rpm.
  • the viscosity of the suspension was 680 cps and the pumping system had no difficulty in delivering the suspension to the atomizer.
  • White, fine particles were collected.
  • the median particle size of sample was approximately 80 - 110 ⁇ m.
  • USP No. 2 in vitro dissolution test showed drug release of >90% in 15 minutes. The amounts of each component are shown below:
  • Example 1C Microencapsulation of Omeprazole with Klucel-EF — 28 wt-%
  • a suspension containing Klucel EF, sodium bicarbonate and omeprazole was prepared (total solid content of 16.23%) and spray dried using a rotary atomizer.
  • the pH of the suspension was 8.1.
  • the inlet temperature was 130 0 C and the outlet temperature was 84-85 0 C.
  • Atomizer speed was 27,000 rpm.
  • the viscosity of the suspension was 680 cps and the pumping system had no difficulty in delivering the suspension to the atomizer.
  • White, fine particles were collected.
  • the median particle size of sample was approximately 35-40 ⁇ m.
  • USP No. 2 in vitro dissolution test showed drug release of > 35% in 30 minutes. The amounts of each component are shown below:
  • Example ID Microencapsulation of Omeprazole with Methocel E5
  • omeprazole The microencapsulation of omeprazole consisted of two main steps: 1) suspension preparation and 2) spray drying operation. Methocel E5 was weighed out and added into water extremely slowly until a clear, homogeneous. PEG400 was added to the Methocel E5 polymer solution. Omeprazole and sodium bicarbonate were added to the polymer solution with agitation until a milky white, homogeneous suspension was formed. The finished omeprazole suspension was agitated at a minimum speed to prevent settling. The omeprazole suspension was then sprayed using the parameter shown below. Inlet Temperature 135 0 C
  • Example IE Microencapsulation of Omeprazole using High Pressure Nozzle Spray
  • a suspension containing hydroxypropyl cellulose, sodium bicarbonate and omeprazole was prepared (total solid content of 15.0%) and spray dried using a high pressure nozzle.
  • the pH of the suspension was 8.5.
  • the inlet temperature was 140-150 0 C and the outlet temperature was 79 -85 0 C.
  • Core and the Nozzle size (SK value) used in the spray drying was 72 and 17, respectively.
  • the viscosity of the suspension was in the range of 600 - 700 cps and the pumping system had no difficulty in delivering the suspension to the atomizer.
  • White, fine particles were collected.
  • the median particle size of sample was approximately 60 ⁇ m.
  • the amounts of each component are shown below:
  • the chart below summarizes the wt%, the feed rates used, and the inlet/outlet temperatures for eleven different omeprazole microspheres.
  • the amount of encapsulated omeprazole used in each tablet batch varies based on the actual payload of each set of microcapsules to achieve the theoretical dose of 40 mg.
  • the omeprazole was microencapsulated in a similar manner as that described in Example 1. All ingredients are mixed well to achieve a homogeneous blend.
  • Tablets containing omeprazole microspheres were prepared using a high-speed rotary tablet press (TBCB Pharmaceutical Equipment Group, Model ZPYl 5). Round, convex tablets with diameters of about 10 mm and an average weight of approximately 600 mg per tablet were prepared.
  • Chewable tablets were manufactured using the following materials: Encapsulated omeprazole (varied based on payload, to deliver 40 mg potency), sodium bicarbonate (1260 mg), calcium carbonate (790 mg), croscarmellose sodium (64 mg), Klucel (160 mg), Xylitab 100 (380 mg), microcrystalline cellulose (128 mg), sucralose (162 mg), peppermint flavor (34 mg), peach flavor (100 mg), masking powder (60 mg), FD&C Lake No. 40 Red (3 mg), and magnesium stearate (32 mg).
  • Example 2B Preparation of Microencapsulated PPIs
  • Table 2B summarizes various drug wt%, shell materials, and in-vitro dissolution data for eighteen different proton pump inhibitor microspheres.
  • the atomization method for the spray drying is also listed and is performed in a manner analogous to that listed in Example 1 above.
  • the amount of microencapsulated lansoprazole used in each tablet batch is based on the actual payload of microcapsules to achieve the theoretical dose of 30 mg lansoprazole per tablet.
  • Lansoprazole is microencapsulated in a similar manner as that described in Example 1 and 2. All ingredients are mixed well to achieve a homogenous bulk blend which is then compressed to round tablets.
  • Omeprazole magnesium tablets are manufactured using the following materials: Microencapsulated Omeprazole-Mg salt (45% drug loading-Entry 2B-14 in Table 2B, 89 mg to deliver 40 mg omeprazole), sodium bicarbonate (420 mg), direct-compression grade magnesium hydroxide (contains 5% starch, 337 mg to deliver 320 mg magnesium hydroxide), croscarmellose sodium (50 mg), Klucel-EXF (50 mg), and magnesium stearate (7 mg) [total 16 mEq in swallowable tablet or caplet].
  • omeprazole magnesium salt is microencapsulated in a similar manner as that described in Example 1 and 2. All ingredients are mixed well to achieve a homogenous bulk blend which is then compressed to capsule shaped tablets.
  • Pantoprazole chewable tablets aremanufactured using the following materials:
  • pantoprazole used in each tablet batch is based on the actual payload of microcapsules to achieve the theoretical dose of 40 mg pentoprazole per tablet.
  • Pantoprazole is microencapsulated in a similar manner as that described in Example 1 and 2. All ingredients are mixed well to achieve a homogenous bulk blend which is then compressed to round tablets.
  • Rabeprazole sodium caplets are manufactured using the following materials: Microencapsulated Rabeprazole sodium salt (40% drug loading- Entry 2B-10 Table 2B, 106 mg to deliver 40 mg rabeprazole), sodium bicarbonate (336 mg), Direct-compression grade magnesium hydroxide (contains 5% starch, 307 mg to deliver 292 mg magnesium hydroxide), magnesium oxide (101 mg), croscarmellose sodium (50 mg), Klucel-EXF (40 mg), and magnesium stearate (7 mg) [total 14mEq in swallowable tablet or cap let] .
  • rabeprazole sodium salt is microencapsulated in a similar manner as that described in Example 1 and 2. All ingredients are mixed well to achieve a homogenous bulk blend which is then compressed to tablets.
  • omeprazole used in each capsule batch varies based on the actual payload of each set of microcapsules to achieve the theoretical dose of 30 mg.
  • Example 1 and 2. AU ingredients are mixed well to achieve a homogenous bulk blend which is then filled into a capsule such as a size (00) hard gelatin capsule.
  • Example 2H Preparation of Capsules Containing Lansoprazole Microspheres
  • omeprazole magnesium salt used in each capsule batch varies based on the actual payload of each set of microcapsules to achieve the theoretical dose of 30 mg lansoprazole per capsule.
  • Omeprazole magnesium salt was microencapsulated in a similar manner as that described in Example 1 and 2. All ingredients are mixed well to achieve a homogenous bulk blend which is then filled into a capsule such as a size zero (0) hard gelatin capsule.
  • omeprazole magnesium salt was microencapsulated in a similar manner as that described in Example 1 and 2. All ingredients are mixed well to achieve a homogenous bulk blend which is then filled into a capsule such as a size zero (0) hard gelatin capsule.
  • pentoprazole sodium salt used in each capsule batch varies based on the actual payload of each set of microcapsules to achieve the theoretical dose of 40 mg neutral pentoprazole per capsule.
  • Pentoprazole sodium salt was microencapsulated in a similar manner as that described in Example 1 and 2. All ingredients are mixed well to achieve a homogenous bulk blend which is then filled into a capsule such as a size one hard gelatin capsule.
  • Various chewable tablets are manufactured using the microencapsulate materials described in Examples 1 and 2.
  • the amount of microencapsulated omeprazole used in each chewable tablet batch is based on the actual payload of each set of microcapsules to achieve the theoretical dose. All ingredients are mixed well to achieve a homogenous bulk blend which is then compressed to chewable tablets.
  • caplets are manufactured using the microencapsulate materials described in Examples 1 and 2.
  • the amount of microencapsulated omeprazole used in each caplet batch is based on the actual payload of each set of microcapsules to achieve the theoretical dose. All ingredients are mixed well to achieve a homogenous bulk blend which is then compressed to caplets.
  • microencapsulate materials described in Examples 1 and 2.
  • the amount of microencapsulated omeprazole used in each capsule batch is based on the actual payload of each set of microcapsules to achieve the theoretical dose. All ingredients are mixed well to achieve a homogenous bulk blend which is then filled into a hard gelatin capsule such as a size 00 hard gelatin capsule from Capsugel.
  • Example 6 Analytical Assay for Determining the Amount of Omeprazole Present in Tablets Containing Omeprazole Microspheres The following procedure was used to determine the potency of omeprazole in the tablets. The tablet was accurately weighed and placed into 100 ml volumetric flask. To that, 1.0 ml of Nanopure water was added to wet and soften the tablet. The solution was allowed to stand for 30 minutes. After sitting, the sample was vortexed and sonicated for 30 minutes or until completely dissolved. 1.0 ml of chloroform was then added and the sample was vortexed and sonicated for an additional 15 minutes. The solution was then brought to volume with methanol and vortexed again to mix solution.
  • Microspheres that exhibited dissolution results with greater than 80% omeprazole release after 2 hours were placed on stability.
  • the microspheres were stored in opened vials at 25 0 C.
  • AU samples showed degradation after 4 weeks at elevated temperatures.
  • the open vials stored at 25 0 C were analyzed after 6-8 weeks for potency and for impurities using the Omeprazole EP method.
  • the stability results are summarized in the table 7A below.
  • HPLC samples for the omeprazole assay of various microspheres were prepared as follows: 5 mg of the microsphere were accurately weighed into a screw cap culture tube. To that, 200 ⁇ L of chloroform was added. The microspheres were allowed to dissolve, sonicated and vortex for approximately one minute. Then, 10 ml of methanol was added and the sample was again vortexed for one minute. Once completed, an aliquot of the sample was removed for HPLC analysis.
  • a 5-point calibration curve was prepared in methanol ranging from 20 to 500 ⁇ g/mL to calculate payload.
  • the chromatographic conditions were: Mobile phase: 75.5% Na 2 PO 4 pH 8.0, 24.5% Acetonitrile; Flow Rate: 1.0 mL/min; Run Time: 15 min; Injection Volume: 20 ⁇ L; Detector: U. V., 280 nm; Column: Waters SymmetryShield RP8.
  • HPLC samples for the omeprazole assay of various microspheres were prepared in the following manner: 5 mgs of the omeprazole microspheres were weighed into a screw cap culture tube. To that, 200 ⁇ L of chloroform were added. The microspheres were allowed to dissolve, sonicate and vortex for approximately one minute each. 10 mL of methanol was then added and the sample was again vortexed for 1 minute. Once complete, an aliquot was removed for HPLC analysis.
  • omeprazole concentration 100 ⁇ g/mL concentration of omeprazole in methanol for a marker was prepared. A 0.1 ⁇ g/mL concentration of omeprazole was then prepared to set one-half the minimal detection limit. Then, a 1 ⁇ g/mL concentration of omeprazole impurity D in methanol was prepared.
  • the chromatographic conditions were: Mobile Phase: 75% Na 2 PO 4 pH 7.6, 25% acetonitrile; Flow Rate: 1.0 mL/min; Run Time: 30 min; Injection Volume: 20 ⁇ L; Detector: U. V., 280 irai; Column: Waters SymmetryShield RP8.
  • the omeprazole potency method was used for the dissolution testing.
  • the HPLC samples for the omeprazole assay of various microspheres were prepared according to the following method. 5 mgs of the microspheres were accurately weighed into an 8 ounce amber bottle. To that, 100 ml of pH 7.4 monobasic phosphate buffer was added. The samples were placed in a 37 0 C water bath and vigorously shaken until the end of the release study. Using an Eppendorf pipette, 100 ⁇ L was removed and the outside part of the tip was rinsed with 100 ⁇ L of buffer back into the sample bottle. The sample was then transferred into a limited insert for HPLC analysis using a 1 cc syringe fitted with a 45 micron filter. Samples were then taken at 30, 45, and 120 minutes.
  • a 6-point calibration curve was prepared in diluent (70% sodium phosphate pH 10.0 / 30% acetonitrile) ranging from 1 to 120 ⁇ g/mL to determine sample release rates.
  • the chromatographic conditions were: Mobile phase: 75.5% Na 2 PO 4 pH 8.0, 24.5% Acetonitrile; Flow Rate: 1.0 mL/min; Run Time: 15 min; Injection Volume: 20 ⁇ L; Detector: U. V., 280 nm; Column: Waters SymmetryShield RP8.
  • omeprazole microspheres were observed using an Olympus BX60 optical microscope equipped with an Olympus DPlO digital camera to determine their particle size and morphology characteristics. The microspheres were observed at either IOOX or 200X magnification.
  • the microspheres prepared by spray drying were in the size range of 5 to 30 microns.
  • the microspheres prepared by spinning disk-solvent process were in the size range of 25 to 100 microns.
  • the microspheres prepared by spinning disk-hot melt process were in the size range of 30 to 125 microns.
  • Example 12 Thermal Gravimetric Analysis (TGA)
  • the percent weight loss up to 14O 0 C was recorded to determine the amount of volatiles present. Most samples exhibit a weight loss of less than 1% up to 14O 0 C except the samples that contained sodium bicarbonate which have a greater weight loss, from 7-32%.
  • the following TGA run conditions were used: nitrogen atmosphere; Isothermal for 5 minutes at 25 0 C; ramp 1O 0 C / minute to 25O 0 C; platinum sample pan.
  • Example 13 A Formulation of Placebo Antacid Tablet Used in Example 13G
  • Antacid tablet without any omeprazole was prepared using the components listed in the table below. All ingredients were blended homogeneously in 1 cubic feet V- blender. The resulting blend was compressed into a tablet using a Stokes 16 station rotary tablet press equipped with plain, round 3 A", FFBE punches.
  • Example 13B Preparation of SAN-15A used in Example 13G
  • Micronized, non-microencapsulated omeprazole chewable tablets were prepared using the components listed in the table. All ingredients were blended homogeneously in 1 cubic feet V-blender. The resulting blend was compressed into a tablet using a Stokes 16 station rotary tablet press equipped with plain, round 3 A", FFBE punches.
  • Example 13C Preparationof SAN-15B used in Example 13G
  • Microencapsulated omeprazole powder (40 mg) prepared in Example 1C was coadministered with the antacid chewable tablet prepared in Example 13 A (total ANC of 30.7 mEq).
  • the powder and the placebo chewable tablet were chewed together in the mouth to simulate administration of 40 mg of microencapsulated omeprazole incorporated in the said placebo tablet.
  • Example 13D Preparationof SAN-15C used in Example 13G
  • Microencapsulated omeprazole powder (40 mg) prepared in Example ID was co- administered with an antacid chewable tablet prepared in Example 13A (total ANC of 30.7 mEq).
  • the powder and the placebo chewable tablet were chewed together in the mouth to simulate administration of 40 mg of microencapsulated omeprazole incorporated in the said placebo tablet.
  • Example 13E Preparationof SAN-20D used in Example 13G
  • Microencapsulated omeprazole powder prepared in Example 1C was blended homogeneously with other ingredients shown in the table. The powder blend was then compressed into a capsule shaped tablet using a Stokes rotary press.
  • Example 13F Preparationof S AN-20E used in Example 13G
  • Microencapsulated omeprazole powder prepared in Example 1C was blended homogeneously with other ingredients shown in the table. The powder blend was then compressed into a capsule shaped tablet using a Stokes rotary press.
  • Example 13G Pharmacokinetic Study of Non-Enteric Coated omeprazole 40 mg Chewable Tablets and Prilosec ® Delayed-Release Capsules 40 mg
  • This trial was conducted as an open-label, single-dose, crossover trial, with each subject receiving up to twelve different oral omeprazole formulations, one in each of the twelve treatment periods. Each dose was followed by a minimum 7-day washout. Omeprazole was administered at a dose of 40 mg.
  • the compositions administered are set forth in Examples 13A-13F and Table 13. G.I. All formulations were administered with about 120 ml (4 oz) of water after an overnight fast and 1 hour prior to a standardized, high-fat breakfast. Within a given treatment period, the same treatment was administered to all subjects.
  • the non-enteric coated formulation study drugs were compared to Prilosec ® which contained enteric-coated granules.
  • Table 13.G.1 The pharmacokinetic release trial with omeprazole dosage forms. (All dosage forms contained 40 mg omeprazole)
  • This trial was designed to assess the pharmacokinetics of immediate-release omeprazole chewable tablets and caplets versus the Prilosec ® 40 mg delayed-release formulation.
  • the duration of the trial for each subject was approximately 24 weeks, including up to 14 days for screening and a minimum 7 day wash-out period between omeprazole doses.
  • Data from 12 healthy male subjects were expected to provide adequate power to assess pharmacokinetics and safety using descriptive statistics.
  • the descriptive statistics were assessed using the pharmacokinetic parameters: Tmax, Cmax, AUC(O-t), and AUC(O-inf).
  • the treatments administered to subjects in this trial are listed in Table 13. G.I, above.
  • the treatment protocol entailed a 14 day assessment period, followed by a first period (Period 1) in which Prilosec ® 40 mg delayed release capsule was administered to the subjects, after an overnight fast, and 1 hour prior to a standardized high-fat breakfast.
  • Plasma sampling was conducted for 6 hour post-dose.
  • Period 1 was followed by a 7-14 day washout period, during which the plasma levels of omeprazole were expected to decrease to a steady baseline.
  • the other periods listed in Tablet 13.G.1 were conducted in a similar manner to Period 1, except substituting a dosage form according to the invention for the delayed-release formulation used in Period 1.
  • Blood samples (3 mL) were obtained by venipuncture within 30 minutes before each dose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 300, 360 minutes (6 hours) after delivery of each dose during each trial period.
  • Zero time was the time that the subject swallowed a capsule, caplet or chewable tablet of trial drug.
  • Plasma omeprazole concentrations were measured using a previously validated liquid chromatography mass spectrometry (LC-MSIMS) assay (MDS Pharma Services, Lincoln, NE).
  • LC-MSIMS liquid chromatography mass spectrometry
  • the linear assay range was 5.0 to 750 ng/mL.
  • the following pharmacokinetic parameters were measured for each subject:
  • AUC(O-inf) Area under the plasma drug time-concentration curve calculated from 0 time and extrapolated to infinity [AUC(O-inf)] calculated as AUC(O-t) + Ct/Kel, where Ct is the last measurable plasma concentration (at time t) and KeI is the terminal elimination rate constant defined above.
  • an analysis of variance (ANOVA) model was used to test the bioequivalence of each of the tested drug formulations.
  • the model included the following factors: treatment, period, sequence, and subject nested within sequence.
  • CIs percent confidence intervals
  • Cmax equivalence was declared for each parameter if the bounds of the 90% CIs for the percent mean ratio, comparing a composition according to the invention (Periods 2-12) with Prilosec, were between 80% and 125%.
  • Omeprazole was microencapsulated as described in Example IB.
  • omeprazole pre-blend containing microencapsulated omeprazole, antacid excipients and other formulation components was prepared.
  • a flavor pre-blend containing sensory components was then prepared.
  • the main blend was then prepared by combining the omeprazole and flavor pre-blends. Magnesium stearate was then added to the main blend and mixed to form a final blend. All blending operations were carried out in appropriately sized V-blenders. Blend uniformity was ensured by testing at various stages of blending.
  • the final blend was then compressed on a high speed rotary tablet press to form the final tablets.
  • the tablet press was a Stokes ® instrumented tablet press using less than a full set of tablet tooling in order to conserve powder.
  • a compression force of 50 kN using 3 A" round FFBE tooling gave an acceptable tablet harness and friability in all prototype batches. The amount of each component is listed below in Table 14.A.2.
  • the primary objective was to show that SAN- 15 20 mg Chewable Tablets are pharmacokinetically bioequivalent to Prilosec 20 mg with respect to area under the curve.
  • Subjects who had received SAN- 15 chewable tablets 20 mg in Period 1 were given an eighth dose on Day 8 in Period 1, 1 hour after the start of the standardized high-fat breakfast. Blood samples were collected for 12 hours after the eighth dose. After a 10- to 14-day washout period, subjects returned for Period 2 and received the alternate treatment from that received in Period 1. Procedures in Period 2 were identical to those in Period 1 except that no eighth dose of SAN- 15 chewable tablets 20 mg was given.
  • Treatments The treatments administered to subjects are listed in the table below: Treatment Treatment Description
  • SAN- 15 SAN-15 chewable tablets (omeprazole immediate-release chewable tablets) 20 mg to be administered orally and chewed for 30 seconds, followed by drinking 120 rnL water each morning after an overnight fast, 1 hour before starting breakfast.
  • Prilosec Prilosec Capsules (omeprazole delayed-release capsules) 20 mg to be administered orally with 120 mL water each morning after an overnight fast, 1 hour before starting breakfast.
  • Pharmacokinetic Sampling, Analytical Methods, and Parameters 20 mg to be administered orally with 120 mL water each morning after an overnight fast, 1 hour before starting breakfast.
  • Blood samples (3 mL) were obtained by venipuncture on Days 1 and 7 of both periods and Day 8 of Period 1 (for SAN- 15 chewable tablets) within 30 minutes before each dose, and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, 360, 420, 480, 540, 600, 660, and 720 minutes (12 hours) after each dose.
  • Zero time was the time that the subject ingested a chewable tablet or swallowed a capsule of Prilosec.
  • Plasma omeprazole concentrations were measured using a validated liquid chromatography mass spectrometry (LC-MS/MS) assay (MDS Pharma Services, Lincoln, NE). The linear assay range was 5.0 to 750 ng/mL. The following pharmacokinetic parameters were measured for each subject:
  • Terminal elimination rate constant (kel) determined from a log-linear regression analysis of the terminal plasma omeprazole concentrations
  • AUC(O-M) Area under the plasma drug time-concentration curve from 1 time and extrapolated to infinity [AUC(O-M)] calculated as AUC(O-t) + Ct/Kel, where Ct is the last measurable plasma concentration and KeI is the terminal elimination rate constant defined above.
  • Omeprazole was microencapsulated as described in Example IB. Preparation ofChewable Tablet
  • Example 16A Preparation of Immediate Release Chewable Tablet using dry-coated omeprazole
  • Dry-coated omeprazole are prepared by mixing the ingredients listed in table 16A- 1 and dry-granulate the powder using roller compactor. Resulting granules are screened through a 10-mesh screen.
  • the dry granules are then mixed with the components shown in table 16A-2 until a homogeneous blend is obtained. This blend is then compressed using a 18 mm diameter tooling in a Stokes rotary press.
  • Dry-coated omeprazole are prepared by mixing the ingredients listed in the table 16B-1 and dry-granulate the powder using roller compactor. Resulting granules are screened through a 10-mesh screen.
  • Table 16B-1 Dry Granule Ingredient for dry-coated omeprazole (10% w/w)
  • the dry granules are then mixed with the components shown in table 16B-2 until a homogeneous blend is obtained. This blend is then compressed using a 18 mm diameter tooling in a Stokes rotary press.
  • Dry-coated omeprazole are prepared by mixing the ingredients listed in the table 16C-1 and dry- granulate the powder using roller compactor. Resulting granules are screened through a 10-mesh screen.
  • Example 16C-1 The dry granules prepared in Example 16C-1 are mixed with the ingredients shown in Table 16C-2 until a homogeneous blend is obtained. This blend is then compressed using oval-shaped tooling in a Stokes rotary press.

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Abstract

La présente invention concerne, sous un de ses aspects généraux, des formules pharmaceutiques comprenant un inhibiteur de la pompe à proton microencapsulé ou enrobé à sec comprenant une matière qui améliore la durée de vie de la composition pharmaceutique et au moins un anti-acide. Dans un autre aspect général de la présente invention, des formules pharmaceutiques comprenant un inhibiteur de la pompe à proton microencapsulé ou enrobé à sec accompagné d’une matière déguisant le goût et au moins un anti-acide sont décrits.
PCT/US2006/002746 2006-01-24 2006-01-24 Formules pharmaceutiques utiles pour inhiber la secretion d’acide et procedes de fabrication et d’utilisation correspondants WO2007086846A1 (fr)

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