EP1651193A2 - Pharmaceutical compositions having a swellable coating - Google Patents

Pharmaceutical compositions having a swellable coating

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Publication number
EP1651193A2
EP1651193A2 EP04778421A EP04778421A EP1651193A2 EP 1651193 A2 EP1651193 A2 EP 1651193A2 EP 04778421 A EP04778421 A EP 04778421A EP 04778421 A EP04778421 A EP 04778421A EP 1651193 A2 EP1651193 A2 EP 1651193A2
Authority
EP
European Patent Office
Prior art keywords
dosage form
pharmaceutical dosage
coating
pharmaceutical
core
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04778421A
Other languages
German (de)
English (en)
French (fr)
Inventor
Irukulla Dr. Reddy's Laboratories Ltd. SRINIVAS
Akhilesh A. Dr. Reddy's Laboratories Ltd DIXIT
Pallempalli V.S. Dr. Reddy's Labs. Ltd. REDDY
Billa P. Dr. Reddy's Laboratories Ltd. REDDY
Mailatur S. Dr.Reddy's Laboratories Ltd. MOHAN
Kodipyaka Dr.Reddy's Laboratories Ltd. RAVINDER
Vijay Dr.Reddy's Laboratories Ltd. NASARE
Edward D. Pergament
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Original Assignee
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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Filing date
Publication date
Application filed by Dr Reddys Laboratories Ltd, Dr Reddys Laboratories Inc filed Critical Dr Reddys Laboratories Ltd
Publication of EP1651193A2 publication Critical patent/EP1651193A2/en
Withdrawn legal-status Critical Current

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2873—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin

Definitions

  • the invention relates to solid pharmaceutical dosage forms having coatings that protect contained pharmaceutical active ingredients against degradation by acidic gastric fluid.
  • the dosage forms have coatings comprising substances that swell upon contact with aqueous fluids.
  • a number of pharmaceutical active ingredients are not chemically stable in acidic environments. For this reason, oral administration cannot be effective without some means for protecting the substances against contact with gastric fluid. This, however, also has the generally undesired effect of delaying availability of the substance to the body, since systemic absorption will not commence until the substance has been released from its dosage form.
  • Patent 5,160,742 discloses a sustained release system for an acid-sensitive drug such as a -lactam antibiotic.
  • Coated drug particles suitable for inclusion in syrups or other formulations are prepared by forming a core that contains the drug, coating the core with a prolamine, and applying a final exterior coating of an enteric substance such as a methacrylic acid copolymer.
  • an additional coating of prolamine can be applied onto the enteric coating layer. The drug is released over a prolonged time, beginning after the coated particles enter a high-pH environment.
  • Patent 6,346,269 to Hsiao et al. teaches oral formulations for acid- sensitive drugs, where the drug substance is mixed with an alkaline material such as trisodium phosphate and coated onto a core, such as a tablet, then an enteric coating is applied over the drug substance layer.
  • an alkaline material such as trisodium phosphate
  • a core such as a tablet
  • enteric coating is applied over the drug substance layer.
  • a pharmaceutical dosage form comprising: a solid core comprising an acid-sensitive pharmaceutical active and a disintegrant; a swellable coating comprising a hydrocolloid-forming component, surrounding the core; and an enteric coating surrounding the swellable coating.
  • the invention further includes a pharmaceutical dosage form comprising: a solid core comprising a benzimidazole and a disintegrant; a swellable coating comprising one or more hydrocolloid-formers selected from zein, crospovidone, and a hydroxypropyl cellulose, surrounding the core: and an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate, surrounding the swellable coating.
  • the invention includes a method of preparing a pharmaceutical dosage form, comprising the steps of: combining components comprising a pharmaceutical active and a disintegrant, and forming a solid core; coating the core with a swellable coating comprising a hydrocolloid-forming component; and applying an outer coating comprising an acid-resistant enteric substance.
  • Preferred swelling agents in the swellable coating include prolamines; vinylpyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates; pectins; agar; and gums. Zein, crospovidone, or a hydroxypropyl cellulose are more preferred for use as the swelling agent.
  • the subject invention provides a pharmaceutical dosage form comprising a core that comprises a pharmaceutical active ingredient, and a swellable coating surrounding the core.
  • the core comprises at least 50%, at least 60%, at least 70%, preferably at least 80%, preferably at least 82.5%, preferably at least 85%, preferably at least 87%, preferably at least 88%, preferably at least 89% of the total pharmaceutical composition.
  • the core may also comprise at least 90%, at least 91 %, at least 92% or at least 93% of the total pharmaceutical composition.
  • the terms "pharmaceutical active ingredient” "pharmaceutical active” and “active” are used interchangeably to refer to a component of a pharmaceutical dosage form that provides a therapeutic effect upon administration to a subject.
  • This invention is particularly applicable to acid- sensitive pharmaceutical actives, which exhibit instability in a low-pH environment, such as the benzimidazole derivatives, including their optically active isomers.
  • useful benzimidazole compounds include rabeprazole, omeprazole, esomeprazole, lansoprazole, and pantoprazole.
  • Other drugs for which the invention will be useful include, without limitation thereto: pharmaceutical actives that react with enteric coating components, examples being drugs that form insoluble complexes with the enteric coatings, such as fluoxetine and duloxetine; and highly alkaline drugs that can react with acidic groups to reduce the acid-insolubility of the coating, such as diclofenac sodium and piroxicam.
  • a “swellable coating” is a coating that increases in volume upon contact with' aqueous fluids. This swelling usually occurs through imbibition of water.
  • the swellable coating adds 0.1-10%, 0.5-8%, 0.7-7%, 1-5%, 1.3-3%, 1.5-2%, about 2%, or about 1.5% to the weight of the core.
  • the swellable coating adds 0.1- 5%, 0.1- 4%, 0.1- 3%, 0.1-2%, or 0.1-1 % to the weight of the core.
  • the swellable coating upon wetting, becomes a hydrocolloid, which is a gelatinous suspension of microscopic particles in water.
  • the hydrocolloid is formed from a prolamine, such as gliadan, hordein, or, more preferably, zein.
  • a prolamine such as gliadan, hordein, or, more preferably, zein.
  • Zein is extracted from corn as a granular, straw to pale yellow colored amorphous powder or fine flakes and various commercial extracts have molecular weights in the range of 25,000-35,000. Zein is insoluble in water and insoluble in alcohols, but soluble in aqueous alcohol solutions. Chemically, zein is fairly abundant in glutamine and devoid of lysine and tryptophan.
  • Zein comprises about 20-22% glutamic acid and glutamine, 17-20% leucine, 5-9% proline, 8-10% alanine, 4-7% phenylalanine, 3-7% isoleucine, 4-6% serine, 4-5% asparginine and 3-5% tyrosine. All of the other amino acids in zein each comprise less than 3%. Zein has been generally recognized as safe (GRAS) by the United States Food and Drug Administration since March, 1985 for use in food and pharmaceutical products.
  • GRAS general recognized as safe
  • Zein is available commercially from several sources, including Freeman Industries LLC, Tuckahoe, New York USA; among the commercial zein products sold by this company are those designated Zein F4000, Zein 4400, Zein F6000, Zein G-10, Aqua Zein, and Aqua Zein Neutral.
  • a presently preferred zein for the present invention is the Zein F6000, which has been re-extracted to reduce its color (from xanthophyll) level.
  • Zein F6000 is a very light yellow granular powder with an approximate molecular weight of 35,000 and a bulk density of 0.125-0.21 g/ml. It contains 90-96% zein protein, calculated on a dry basis.
  • the hydrocolloid can also be formed from a hydroxypropyl methylcellulose.
  • the viscosity of a 2 weight percent aqueous solution of various hydroxypropyl methylcellulose products ranges from about 4,000 mPa-s to about 100,000 mPa-s.
  • the hydroxypropyl methylcellulose is United States Pharmacopeia Substitution Type 2208, also called hypromellose 2208, with a viscosity of about 15,000 mPa-s, which is commercially available as Methocel K15M.
  • the hydroxypropyl methylcellulose is United States Pharmacopeia Substitution Type 2910, also known as hypermellose 2910, with a viscosity of about 4,000 mPa-s, which is marketed as Methocel E4M.
  • METHOCEL is a trademark of Dow Chemical Company, Midland, Michigan U.S.A.
  • crospovidone croscarmellose sodium
  • cellulose derivatives such as hydroxyethylcellulose, hydroxypropyl cellulose, or methylcellulose
  • gums such as seaweed extracts, plant extracts, plant exudates, plant seed extracts, and microbial fermentation products
  • starches including pregelatinized and modified starches
  • synthetics such as carboxyvinyl polymers, including carbopols.
  • Additional specific examples include alginates, pectins, low methoxy pectins, agar, carrageenan, plus arabic, tragacanth, karaya, ghatti, locust bean (carob), guar, dextran, xanthan, carrageenan, tara, Khaya grandfolia, gellan, Konjac mannan, galactomannan, funoran, acetan, welan, rhamsan, furcelleran, succinoglycan, scieroglycan, schizophylan, curdlan, pullulan, karaya and tamarind gums.
  • the core further comprises a disintegrant that, in an aqueous environment, assists in the physical fragmentation of any material with which is it combined.
  • a disintegrant does not promote dissolution or a chemical change in the material being fragmented.
  • useful disintegrants starches such as potato or tapioca starch, modified starches (such as sodium starch glycolate) and partially pregelatinized starches (such as Starch 1500); polyvinylpyrrolidones, including modified polyvinylpyrrolidones (such as crospovidone, polymerized under conditions that promote crosslinking); celluloses such as microcrystalline cellulose, modified celluloses (such as low substituted hydroxypropyl cellulose, croscarmellose sodium and calcium carboxymethyl cellulose); formaldehyde-casein compounds (such as Esma-Spreng.RTM); resins, such as the polacrilin potassium sold by Rohm and Haas Company, Philadelphia, Pennsylvania U.S.A., using
  • the pharmaceutical dosage form further comprises an enteric coating surrounding the swellable coating.
  • An "enteric coating” is a coating that is substantially insoluble at the acidic pH conditions of the stomach but is substantially soluble or water-permeable at the higher pH conditions of the intestines. In this invention, the enteric coating protects the swellable coating against contact with the acidic stomach environment but permits contact of the swellable coating with the more alkaline intestinal fluid.
  • Eudragit L100-55 is especially preferred.
  • Eudragit L 100-55 is a powder, spray-dried Eudragit L 30 D- 55 which can be reconstituted.
  • Eudragit L 30 D-55 is an aqueous dispersion of a pH dependent polymer soluble at or above pH 5.5 for targeted delivery in the duodenum.
  • Eudragit L 100-55 retains the pH dependency of Eudragit L 30 D-55 and thus, is soluble at or above pH 5.5 and provides delivery to the duodenum.
  • Eudragit L 100-55 and Eudragit L 30 D-55 are copolymers of methacrylic acid and ethyl acrylate in a 1:1 ratio. They have the molecular formula: (C5H2 ⁇ 2 -C H6 ⁇ 2 ) x and have been assigned the Chemical Abstracts Registry No. 25212-88-8. Eudragit L100-55 also meets the United States Pharmacopeia specificiation for Methacrylic Acid Copolymer Type C.
  • the enteric coating comprises 1-40%, 3-35%, 5-30%,
  • the enteric coating comprises at most 20%, at most 17.5%, at most 15%, at most
  • an excipient that modulates the release of the pharmaceutical active is added to the swellable coating. Modulation may be achieved by facilitating or impeding the access of water to the core.
  • Useful excipients include plasticizers such as lactic acid, lactic acid acetamide, glycerin, glyceryl monostearate, triacetin, sorbitol, triethyl citrate, polyvinylpyrrolidone, triethylene glycol, tricresyl phosphate, dibutyl tartrate, ethylene glycol monooleate, palmitic acid, stearic acid, oleic acid, dibutyl sebacate, aceylated monoglycerides, and other oils and waxes, as well as polyethylene glycol 300, 400, 600, 1450, 3350 and 8000.
  • Additional excipients that modulate the rate of release of the active include water soluble surfactants, such as sodium lauryl sulfate and docusate sodium, and enteric coating materials, such as Eudragit L 100-55, which are mixed into the swellable coating.
  • enteric coating material incorporated in the swellable coating dissolves upon contact with the intestinal fluid and forms channels in the swellable coating, which facilitate the entry of the intestinal fluids into the core.
  • the enteric coating material constitutes about 0.1-30%, 0.5-20%, 1-17.5%, preferably 5-15%, or more preferably 5-10% of the swellable coating.
  • the enteric coating material comprises 10-50%, 15-40%, preferably 20-30% of the swellable coating.
  • the water soluble surfactant causes rapid wetting of the swellable coating upon exposure to the intestinal fluids, thereby assisting entry of fluid into the core.
  • the water soluble surfactant when present, it constitutes about 0.001-30%, 0.005-20%, 0.01- 10%, 0.03-8%, 0.05-6%, 0.07-4%, 0.09-2%, or 0.1-1% by weight of the swellable coating. A preferred range is 0.01-10%.
  • This permeability affects the amount of intestinal fluid that contacts the core and leads to fragmentation. It is hypothesized that the fragments puncture the swellable coating upon fragmentation, thereby affecting the release of the pharmaceutical active. It is further believed that the openings created in the swellable coating provide conduits for the entry of additional intestinal fluid into the core, further accelerating fragmentation.
  • a third factor is the use of a disintegrant in the core. The employment of a disintegrant increases the rate of fragmentation of the core, which is thought to raise the frequency with which fragments create voids in the swellable coating. The sheer increase in fragments exiting through the swellable coating raises the rate of release of the pharmaceutical active.
  • the higher number of voids created in the swellable coating is believed to allow more water to enter the core, causing an even greater fragmentation of the active.
  • the disintegrant may augment the force at which the core fragments impact the swellable coating, which may result in more fragments successfully creating voids in the swellable coating. These more forceful disintegrations further raise the rate of release of the pharmaceutical active by allowing a greater number of core fragments to pass through the swellable coating.
  • this invention does not have an objective of producing sustained release formulations whereby the pharmaceutical active is released at a controlled rate over an extended period of time, such as 12 or 24 hours. Rather, a feature of this invention is a delayed release of ingested pharmaceutical active until the dosage form has reached the intestinal tract, where the alkaline pH conditions will not affect an acid-sensitive pharmaceutical active, then facilitation of a rapid, essentially complete release of the pharmaceutical active for systemic absorption.
  • pantoprazole Tablets containing either 20 or 40 mg of pantoprazole were prepared using the following components and procedure:
  • Tablet cores were prepared by granulating a dry mix of pantoprazole sodium, mannitol, crospovidone and sodium carbonate with an aqueous solution of hydroxypropyl cellulose (Klucel LF) and sodium carbonate anhydrous. The granulates were dried using conventional drying techniques. The dried granules were then lubricated with crospovidone, talc and calcium stearate. The lubricated granules were compressed into cores. The cores were subcoated with a mixture of zein, Eudragit L 100-55, water, and isopropyl alcohol, and dried.
  • Enteric coating on top of the subcoat was performed using Eudragit L 100-55 with isopropyl alcohol as the solvent and triethyl citrate as the plasticizer. Talc and titanium dioxide were used as the lubricant and the opaquent, respectively. After drying, the enteric coated tablet was film-coated using Opadry Yellow OY-52945 and printed with Opacode Black S-1-8152 HV.
  • pantoprazole Tablets containing either 20 or 40 mg of pantoprazole were prepared using the following components and procedure.
  • Tablet cores were prepared by granulating a dry mix of pantoprazole sodium, mannitol, crospovidone and sodium carbonate with an aqueous solution of hydroxypropyl cellulose (Klucel LF) and sodium carbonate anhydrous. The granulates were dried using conventional drying techniques. The dried granules were lubricated with crospovidone, talc and calcium stearate. The lubricated granules were then compressed into cores. The cores were subcoated with a mixture of zein, Eudragit L 100-55, water, and isopropyl alcohol.
  • an enteric coating on top of the subcoat was performed using Eudragit L 100-55 with isopropyl alcohol as the solvent and triethyl citrate as the plasticizer. Talc and titanium dioxide were used as the lubricant and the opaquent, respectively. Then, the dried enteric coated tablet was film-coated using Opadry Yellow OY- 52945 and printed upon with Opacode Black S-1-8152 HV.
  • Omeprazole core pellets were prepared by mixing omeprazole, mannitol, crospovidone, meglumine and polaxomer and granulating this mixture with hydroxypropyl methylcellulose as a binder. The granules thus obtained were subjected to extrusion and spheronization to produce spherical pellets. The pellets were then dried by conventional drying techniques. The pellets were coated with a swellable coating containing zein and sodium lauryl sulphate dissolved in a mixture of isopropyl alcohol and water, then dried.
  • the enteric coat was prepared by dissolving hydroxypropyl methylcellulose phthalate and triethyl citrate in a mixture of isopropyl alcohol and acetone and dispersing talc in this solution, which was then layered upon intermediate coating.
  • Core tablets were prepared by blending pantoprazole sodium sesquihydrate with mannitol, crospovidone, Plasdone S630, talc, and magnesium stearate, and direct compressing into tablets. These core tablets were coated with a swellable coating solution containing zein and sodium lauryl sulphate dissolved in a mixture of isopropyl alcohol and water, then dried.
  • the enteric coat was prepared by dissolving hydroxypropyl methylcellulose phthalate and triethyl citrate in a mixture of isopropyl alcohol and acetone and dispersing talc in this solution, which was then layered upon intermediate coating.
  • the core was prepared by mixing esomeprazole magnesium trihydrate, mannitol, crospovidone and sodium lauryl sulphate and granulating this mixture with an aqueous solution of copovidone. The granules were then subjected to extrusion and spheronization to obtain spherical pellets. The pellets were dried by conventional drying techniques. The dried pellets were coated with intermediate coating solution containing zein and sodium lauryl sulphate dissolved in a mixture of isopropyl alcohol and water, then dried. The enteric coat was prepared by dissolving Methacrylic Acid Copolymer Type C and triethyl citrate in isopropyl alcohol and dispersing talc and titanium dioxide in this solution. Coated pellets are filled into gelatin capsules, giving 4000 capsules that each contain 40 mg of esomeprazole.
  • Esomeprazole tablets were prepared, using the following ingredients and procedure.
  • Esomeprazole magnesium trihydrate, magnesium oxide, copovidone, crospovidone, mannitol, and silicon dioxide were blended, then sodium stearyl fumarate was added with further blending. This mixture was compressed into core tablets. The tablets were coated with an aqueous alcohol solution of zein, then dried. Finally, the enteric coating ingredients were dispersed in water and coated onto the zein-coated tablets, followed by a final drying.
  • Tablets containing rabeprazole sodium were prepared using the following components and procedure: O 2005 0 21
  • Rabeprazole sodium, crospovidone, Plasdone S630 and mannitol were mixed with mannitol (Pearlitol DC 400) for 20 minutes.
  • Talc and magnesium stearate were then added to the mixture and mixed for 5 minutes.
  • This lubricated blend was then compressed into tablets.
  • the core tablets were subcoated with a water-alcohol solution of zein (weight increase 2.5 ⁇ 0.5%) and dried.
  • the subcoated tablets were coated with enteric coating solution (weight increase 8-9%).
  • Rabeprazole sodium tablets were prepared using the following components and procedure:
  • the sifted granules were blended with L- HPC in a double cone blender for 5 minutes. Magnesium stearate (sifted through a 60 mesh sieve) was added to the blend and mixed for 5 minutes. The lubricated blend was then compressed into core tablets.
  • the core tablets were coated with a water-alcohol zein coating solution (weight increase 2.5 ⁇ 0.5%) and dried.
  • the coated tablets were further coated with enteric coating solution (weight increase 8.0 ⁇ 1.0%).
  • the enteric coated tablets were additionally coated with Opadry solution until the weight increase was 2.0 ⁇ 0.5%. Then, the film coated tablets were imprinted with Opacode black ink.
  • Pantoprazole sodium tablets prepared according to Example 5, were tested according to Method 724 "Drug Release" of The United States Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville, Maryland U.S.A., pp. 1944-1947, 2000, using Method B and Apparatus 1 (described in Method 711 "Dissolution," on page 1942).
  • a tablet was first immersed in 0.1 N hydrochloric acid, with stirring, for two hours at 37°C.
  • the tablet was then immersed in the pH 6.8 phosphate buffer, with stirring, and samples of the buffer solution were taken at intervals for analysis to determine the amount of drug released from the tablet. Following are the data obtained from testing six tablets.
  • the amount of drug released into the acid is not shown, but was small. In general, release of up to 10% of the drug into the acid is considered acceptable for enteric coated dosage forms.
  • a pharmaceutical active is considered to be substantially retained within the dosage form if less than about ten percent by , weight is released into 0.1 N hydrochloric acid, under the conditions of the USP test.
  • Example 10 tablets of rabeprazole sodium prepared according to Example 9 were tested by USP Drug Release Method 724. However, the alkaline solution for the second part of the test was a phosphate buffer adjusted to pH 8.0 24 and also containing 0.5 weight percent of sodium lauryl sulfate. Results were obtained, as follows.
  • EXAMPLE 12 Esomeprazole tablets were prepared using the following ingredients and the procedure described below.

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EP04778421A 2003-07-17 2004-07-16 Pharmaceutical compositions having a swellable coating Withdrawn EP1651193A2 (en)

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IN580CH2003 2003-07-17
IN1064CH2003 2003-12-30
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PCT/US2004/022910 WO2005009410A2 (en) 2003-07-17 2004-07-16 Pharmaceutical compositions having a swellable coating

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JP (1) JP2007524646A (pt)
KR (1) KR20060065632A (pt)
AU (1) AU2004259226B2 (pt)
BR (1) BRPI0412697A (pt)
CA (1) CA2532310A1 (pt)
HR (1) HRP20060016A2 (pt)
IL (1) IL173053A0 (pt)
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US20050147663A1 (en) * 2003-07-17 2005-07-07 Mohan Mailatur S. Method of treatment for improved bioavailability
FR2878159B1 (fr) * 2004-11-24 2008-10-17 Flamel Technologies Sa Medicament oral a liberation modifiee d'au moins un principe actif sous forme multimicrocapsulaire
AR054358A1 (es) * 2005-05-13 2007-06-20 Combino Pharm Sl Formulaciones que contienen pantoprazol libre de acido y sus sales
EA015535B1 (ru) * 2005-07-11 2011-08-30 Никомед Данмарк Апс Формуляция бензимидазола
BRPI0621024A2 (pt) * 2006-01-16 2011-11-29 Jubilant Organosys Ltd formulação farmacêutica estável de um composto de ácido lábil e o processo para preparação do mesmo
EP2254556A2 (en) 2008-03-11 2010-12-01 Takeda Pharmaceutical Company Limited Orally-disintegrating solid preparation
EP2319504A1 (en) * 2009-11-07 2011-05-11 Laboratorios Del. Dr. Esteve, S.A. Pharmaceutical solid dosage form
US20130216617A1 (en) * 2010-06-29 2013-08-22 Cadila Healthcare Limited Pharmaceutical compositions of (r)-lansoprazole
EP3158995B1 (en) * 2012-08-09 2018-05-23 Dynamis Therapeutics, Inc. Meglumine for reducing high triglyceride levels
JP6856326B2 (ja) * 2016-07-15 2021-04-07 富士化学工業株式会社 腸放出粒子組成物
KR101907116B1 (ko) * 2016-07-25 2018-10-11 한미약품 주식회사 에스오메프라졸, 또는 약학적으로 허용 가능한 그의 염을 포함하는, pH-의존성 약물 방출 특성이 개선된 제형
KR101877350B1 (ko) * 2016-10-28 2018-08-09 한미약품 주식회사 에스오메프라졸 함유 복합 캡슐제 및 그 제조방법
JP6336651B1 (ja) * 2016-12-15 2018-06-06 大原薬品工業株式会社 化学的安定性が改善されたエソメプラゾール塩を含有する錠剤
WO2019066555A1 (en) * 2017-09-28 2019-04-04 Hanmi Pharm. Co., Ltd. PHARMACEUTICAL COMPOSITION COMPRISING MULTI-UNIT SPHEREOIDAL TABLET CONTAINING ESOMEPRAZOLE AND PHARMACEUTICAL QUALITY SALT THEREOF, AND PROCESS FOR PREPARING THE PHARMACEUTICAL COMPOSITION
JP7026510B2 (ja) * 2018-01-11 2022-02-28 株式会社Ｓｃｒｅｅｎホールディングス 印刷物、読取装置、読取方法、印刷方法、および印刷装置
JP7652406B2 (ja) * 2019-09-30 2025-03-27 備前化成株式会社 多糖類を含有する固形経口組成物
CN111728124A (zh) * 2020-07-08 2020-10-02 江苏宏远药业有限公司 一种安全性较高的食品级白色素
US12409145B2 (en) 2020-09-10 2025-09-09 Sawai Pharmaceutical Co., Ltd. Granule, preparation containing the granule, production method of the granule, and production method of preparation containing the granule
JP7808937B2 (ja) * 2020-09-10 2026-01-30 沢井製薬株式会社 顆粒、顆粒を含む製剤、顆粒の製造方法、及び顆粒を含む製剤の製造方法
CN115998705A (zh) * 2022-08-26 2023-04-25 苏州弘森药业股份有限公司 一种非布司他纳米包合物的制备方法
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BRPI0412697A (pt) 2006-10-03
AU2004259226B2 (en) 2009-09-24
KR20060065632A (ko) 2006-06-14
NZ544608A (en) 2008-07-31
WO2005009410A2 (en) 2005-02-03
HRP20060016A2 (en) 2006-02-28
AU2004259226A1 (en) 2005-02-03
JP2007524646A (ja) 2007-08-30
CA2532310A1 (en) 2005-02-03
NO20060786L (no) 2006-04-10
MXPA06000577A (es) 2006-07-03
IL173053A0 (en) 2006-06-11

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