WO2007013752A1 - Processes for preparing spherical pancreatin-containing granules - Google Patents
Processes for preparing spherical pancreatin-containing granules Download PDFInfo
- Publication number
- WO2007013752A1 WO2007013752A1 PCT/KR2006/002904 KR2006002904W WO2007013752A1 WO 2007013752 A1 WO2007013752 A1 WO 2007013752A1 KR 2006002904 W KR2006002904 W KR 2006002904W WO 2007013752 A1 WO2007013752 A1 WO 2007013752A1
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- WIPO (PCT)
- Prior art keywords
- pancreatin
- spherical
- containing granules
- enteric
- process according
- Prior art date
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- 108010019160 Pancreatin Proteins 0.000 title claims abstract description 114
- 229940055695 pancreatin Drugs 0.000 title claims abstract description 114
- 239000008187 granular material Substances 0.000 title claims abstract description 93
- 238000000034 method Methods 0.000 title claims description 48
- 239000006185 dispersion Substances 0.000 claims abstract description 68
- 238000005507 spraying Methods 0.000 claims abstract description 33
- 238000002360 preparation method Methods 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 239000002702 enteric coating Substances 0.000 claims description 23
- 238000009505 enteric coating Methods 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 17
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000454 talc Substances 0.000 claims description 8
- 229910052623 talc Inorganic materials 0.000 claims description 8
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 6
- 239000001069 triethyl citrate Substances 0.000 claims description 6
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 6
- 235000013769 triethyl citrate Nutrition 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 229920001688 coating polymer Polymers 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000004408 titanium dioxide Substances 0.000 claims description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 4
- 239000004014 plasticizer Substances 0.000 claims description 3
- VOJUXHHACRXLTD-UHFFFAOYSA-N 1,4-dihydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC(O)=C21 VOJUXHHACRXLTD-UHFFFAOYSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 239000000975 dye Substances 0.000 claims description 2
- 239000001087 glyceryl triacetate Substances 0.000 claims description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 229960002622 triacetin Drugs 0.000 claims description 2
- 229920003176 water-insoluble polymer Polymers 0.000 claims description 2
- 229920003169 water-soluble polymer Polymers 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims 1
- 239000008213 purified water Substances 0.000 description 15
- 239000002245 particle Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000009826 distribution Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 4
- 230000002779 inactivation Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 108090001060 Lipase Proteins 0.000 description 3
- 102000004882 Lipase Human genes 0.000 description 3
- 239000004367 Lipase Substances 0.000 description 3
- 238000011109 contamination Methods 0.000 description 3
- 239000002612 dispersion medium Substances 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 235000019421 lipase Nutrition 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000000879 optical micrograph Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 240000008791 Antiaris toxicaria Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 235000019626 lipase activity Nutrition 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- XRHVZWWRFMCBAZ-UHFFFAOYSA-L Endothal-disodium Chemical compound [Na+].[Na+].C1CC2C(C([O-])=O)C(C(=O)[O-])C1O2 XRHVZWWRFMCBAZ-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108010067035 Pancrelipase Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 229940025131 amylases Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- -1 e.g. Substances 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940045258 pancrelipase Drugs 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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
-
- 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
- A61K9/1682—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
-
- 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
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- 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
- A61K9/5078—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 with drug-free core
-
- 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
- A61K9/5089—Processes
Definitions
- the present invention relates to a process for preparing spherical pancreatin- containing granules and/or a process for preparing enteric-coated spherical pancreatin- containing granules using the same.
- Pancreatin is a digestive enzyme extracted from the pancreas of animals (e.g., pigs), and contains amylases, Upases and proteases. Since pancreatin shows its enzymatic activities under neutral or weak alkaline conditions, oral formulations thereof require protecting this vulnerable enzyme from inactivation by gastric acid. In addition, the three-dimensional structure of pancreatin is likely to deform by heat, thereby losing its enzymatic activities. Particularly, instability of pancreatin in water makes it difficult to prepare pancreatin formulations.
- pancreatin when pancreatin is formulated into granules by a conventional method using water as a dispersion medium, the activities of enzymes (e.g., Upases) in pancreatin can be significantly reduced up to 50%.
- enzymes e.g., Upases
- organic solvents such as isopropanol and acetone, have been employed to prepare pancreatin-containing formulations (See, e.g., U. S. Patent No. 4,280,971).
- the use of organic solvents may result in problems associated with residual solvents in the formulation, such as toxicity problems.
- enteric coating techniques are conventionally employed for the purpose of protecting active ingredients from gastric acid.
- thickness and uniformity of the resultant enteric coating layer are important factors in determining the quality of the enteric coatings.
- Un-uniform thickness of an enteric coating layer is an obstacle to effective protection of active ingredients from gastric acid, making active ingredients vulnerable to in vivo environmental changes, thereby causing significant deviations in activities of the active ingredients between individuals as well as in an individual.
- CF granulator centrifugal fluidized-bed coating granulator
- the present invention provides a process for preparing spherical pancreatin- containing granules where water is employed as a dispersion medium, thereby causing no environmental contamination.
- the process may be carried out in a simple manner and can minimize inactivation of enzymes in pancreatin.
- the present invention also provides a process for preparing enteric-coated spherical pancreatin-containing granules using the same.
- a process for preparing spherical pancreatin-containing granules which comprises: dispersing one or more divided portions of pancreatin in water to prepare one or more dispersions; and spraying the dispersions on spherical granular cores while fluidizing the spherical granular cores in a fluidized-bed granulator, wherein the spraying is conducted within 20 to 90 minutes since the preparation of respective dispersions.
- a process for preparing enteric-coated spherical pancreatin-containing granules which comprises spraying an enteric-coating solution or dispersion on the spherical pancreatin-containing granules prepared by the process mentioned above while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator.
- FlG. 1 is an optical micrograph of spherical pancreatin-containing granules prepared by a process of the present invention
- FlG. 2 is an optical micrograph of enteric-coated spherical pancreatin-containing granules prepared by a process of the present invention.
- FlG. 3 is an optical micrograph showing the cross section of an enteric-coated spherical pancreatin-containing granule prepared by a process of the present invention.
- the present invention provides a process for preparing spherical pancreatin-containing granules, which comprises: dispersing one or more divided portions of pancreatin in water to prepare one or more dispersions; and spraying the dispersions on spherical granular cores while fluidizing the spherical granular cores in a fluidized-bed granulator, wherein the spraying is conducted within 20 to 90 minutes since the preparation of respective dispersions.
- the use of the fluidized-bed granulator makes it possible to minimize damages to granules and to prepare spherical granules with a uniform particle size in a simple manner.
- water is used as a medium of the pancreatin-containing dispersions
- the process of the present invention is safe and causes no environmental contamination problems.
- pancreatin is water-labile
- spraying the dispersion prepared using water as a dispersion medium at a high speed i.e. within 20-90 minutes
- enteric-coated pancreatin-containing granules can be prepared in a simple manner by using the spherical pancreatin-containing granules.
- the pancreatin used as an active ingredient in the process of the present invention can be used in an amount necessary to produce a formulation containing a therapeutically effective amount of the pancreatin, and the amount of the pancreatin used may vary depending on batch sizes used in the production.
- the pancreatin can be used in an amount of 30 to 80% by weight and preferably 50 to 70% by weight, based on the total weight of the granules.
- pancreatin is dispersed in water to prepare one or more dispersions.
- the pancreatin may be divided into three to ten and preferably five to eight portions.
- the pancreatin can be appropriately divided depending on the batch sizes by those skilled in the art.
- the amount of the water in the dispersions is not restricted so long as the divided pancreatin portions can be suitably sprayed through a nozzle of the fluidized-bed granulator.
- the water may be used in an amount of 1 to 8 parts by weight and preferably 3 to 6 parts by weight, based on one part by weight of each of the divided pancreatin portions.
- the dispersions are sprayed on granular cores in a fluidized-bed granulator within
- the process of the present invention comprises spraying the dispersions on spherical granular cores while fluidizing the spherical granular cores in a fluidized-bed granulator.
- spherical granular cores used in the field of pharmaceutics may be used in the present invention.
- the spherical granular cores include celluloses, starches, saccharides, and a mixture thereof.
- Sugar sphere commercially available from IPS Inc. (Italy) can be used as the granular cores.
- the mean diameter of the granular cores may be in the range of 200 to 1,000 um, but not limited to this range.
- the fluidized-bed granulator can be operated under the conditions that are routinely employed in the filed of pharmaceutics.
- the internal temperature of the fluidized-bed granulator is maintained at about 60 C or lower and preferably about 40 °C or lower.
- the pressure for spraying the dispersions may be in the range of about 1 to about 4 bars.
- the dispersions may further comprise a binder.
- Suitable binders are those conventionally used in the field of pharmaceutics, such as hydroxypropyl cellulose, (hydroxypropyl)methyl cellulose, carboxymethyl- cellulose, and a mixture thereof.
- the dispersions may further comprise one or more additives selected from, but not limited to, talc, magnesium stearate, silicon dioxide, and combinations thereof, in order to prevent sticking or adhesion of the particles to the fluidized-bed granulator as well as adhesion between the particles.
- additives selected from, but not limited to, talc, magnesium stearate, silicon dioxide, and combinations thereof, in order to prevent sticking or adhesion of the particles to the fluidized-bed granulator as well as adhesion between the particles.
- the present invention provides a process for preparing enteric- coated spherical pancreatin-containing granules, which comprises spraying an enteric- coating solution or dispersion on the spherical pancreatin-containing granules prepared by the process mentioned above while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator.
- the enteric-coating solution or dispersion comprises an enteric coating polymer, e.g., a water-soluble polymer that does not dissolve at pH 3.0 or lower, a water- insoluble polymer, or a mixture thereof.
- enteric coating polymers include polyvinyl acetate phthalate, acrylic polymers, acrylic copolymers (e.g., Eudragit L30 D-55, (hoem GmbH, Germany)), and cellulose acetate phthalates.
- the enteric-coating solution or dispersion may be prepared by dissolving or dispersing the enteric coating polymer in water.
- the enteric-coating solution or dispersion may further comprise a plasticizer, e.g., triethyl citrate, triacetin, polyethylene glycol, and a mixture thereof. These plasticizers may be used alone or as a mixture thereof.
- the enteric-coating solution or dispersion may further comprise a colorant, such as talc, titanium dioxide, iron oxide, tar dyes and their lakes, and mixtures thereof.
- talc titanium dioxide
- iron oxide iron oxide
- tar dyes and their lakes and mixtures thereof.
- the use of colorants such as talc, titanium dioxide, and a mixture thereof serves to prevent sticking or adhesion of the particles to the fluidized-bed granulator as well as adhesion between the particles.
- the spherical pancreatin-containing granules and/or the enteric-coated spherical pancreatin-containing granules prepared by the respective processes of the present invention may be used without any additional processing.
- the granules may be filled in capsules to produce capsule formulations or pressed to produce tablet formulations.
- a dispersion of 100 g of pancreatin in 400 ml of purified water was completely sprayed on 200 g of Sugar sphereTM (IPS Inc., Italy) that has a mean diameter of 600 to 710 um (25-30 mesh). Spraying was performed within 60 minutes since the preparation of respective dispersions, while fluidizing the Sugar sphere in a fluidized-bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
- Example 1 except for using 200 g of Sugar sphere (IPS Inc., Italy) that has a mean diameter of 355 to 425 um (40-45 mesh).
- Example 1 except for using 200 g of Sugar sphereTM (IPS Inc., Italy) that has a mean diameter of 212 to 250 um (60-70 mesh).
- a dispersion of 100 g of pancreatin and 1.9 g of hydroxypropyl cellulose in 400 ml of purified water was completely sprayed on 200 g of Sugar sphere (IPS Inc., Italy) that has a mean diameter of 355 to 425 um (40-45 mesh). Spraying was performed within 60 minutes since the preparation of respective dispersion while fluidizing the Sugar sphere in a fluidized-bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and the spraying pressure of the dispersion at about 2 bars or lower.
- Example 1 except for the fact that the dispersions were completely sprayed within 90 minutes since the preparation of respective dispersions.
- a dispersion of 300 g of Eudragit L30 D-55 (hoem GmbH, Germany), 33 g of triethyl citrate and 98.4 g of talc in 1.95 liter of purified water was sprayed on 1,000 g of the spherical pancreatin-containing granules prepared in Example 2 while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator to prepare enteric-coated pancreatin-containing granules.
- the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
- Example 9 Preparation of enteric-coated spherical pancreatin-containing granules
- a dispersion of 200 g of Eudragit L30 D-55 (hoem GmbH, Germany), 22 g of triethyl citrate, 45.6 g of titanium dioxide, and 65.6 g of talc in 1.3 liter of purified water was sprayed on 1,000 g of the spherical pancreatin-containing granules prepared in Example 1 while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator to prepare enteric-coated pancreatin-containing granules having white color.
- the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
- a dispersion of 200 g of pancreatin in 800 ml of purified water was completely sprayed on 200 g of Sugar sphere (IPS Inc., Italy) that has a mean diameter of 600 to 710 um (25-30 mesh) within 120 minutes since the preparation of respective dispersion while fluidizing the Sugar sphereTM in a fluidized-bed granulator.
- the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
- a dispersion of 266.66 g of pancreatin in 1066.66 ml of purified water was completely sprayed on 200 g of Sugar sphereTM (IPS Inc., Italy) that has a mean diameter of 600 to 710 um (25-30 mesh). Spraying was performed within 150 minutes since the preparation of respective dispersion while fluidizing the Sugar sphere in a fluidized-bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
- a dispersion of 400 g of pancreatin in 1600 ml of purified water was completely sprayed on 200 g of Sugar sphereTM (IPS Inc., Italy) that has a mean diameter of 600 to 710 um (25-30 mesh). Spraying was performed within 180 minutes since the preparation of respective dispersion while fluidizing the Sugar sphereTM in a fluidized- bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and the spraying pressure of the dispersion at about 2 bars or lower.
- a dispersion of 800 g of pancreatin in 3200 ml of purified water was completely sprayed on 200 g of Sugar sphere (IPS Inc., Italy) that has a mean diameter of 600 to 710 um (25-30 mesh). Spraying was performed within 240 minutes since the preparation of respective dispersion while fluidizing the Sugar sphereTM in a fluidized- bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and the spraying pressure of the dispersion at about 2 bars or lower.
- Test Example 2 Acid resistance test
- An acid resistance test was conducted on the enteric-coated pancreatin-containing granules prepared in Examples 6-9. The granules were added to 900 mL of a first solution specified in the Korean pharmacopoeia, and then stirred at 100 rpm at 37 °C for 2 hours. The content of lipase dissolved was measured, and the results are shown in Table 2. [84] Table 2
- Test Example 3 Test for degree of enzyme activity
- the spherical pancreatin-containing granules prepared in Examples 1 and 2 and Comparative Examples 1-4 were measured for the degree of enzymatic activities in accordance with the pancrelipase test method described in the US pharmacopoeia. The results are shown in Table 3.
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- Animal Behavior & Ethology (AREA)
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- Epidemiology (AREA)
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- General Health & Medical Sciences (AREA)
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- Medicinal Preparation (AREA)
Abstract
The present invention provides a process for preparing spherical pancreatin-containing granules, which comprises dispersing one or more divided portions of pancreatin in water to prepare one or more dispersions and spraying the dispersions on spherical granular cores while fluidizing the spherical granular cores in a fluidized-bed granulator, wherein the spraying is conducted within 20 to 90 minutes since the preparation of respective dispersions; and a process for preparing enteric-coated pancreatin-containing granules using the same.
Description
Description
PROCESSES FOR PREPARING SPHERICAL PANCREATIN-
CONTAINING GRANULES
Technical Field
[1] The present invention relates to a process for preparing spherical pancreatin- containing granules and/or a process for preparing enteric-coated spherical pancreatin- containing granules using the same. Background Art
[2] Pancreatin is a digestive enzyme extracted from the pancreas of animals (e.g., pigs), and contains amylases, Upases and proteases. Since pancreatin shows its enzymatic activities under neutral or weak alkaline conditions, oral formulations thereof require protecting this vulnerable enzyme from inactivation by gastric acid. In addition, the three-dimensional structure of pancreatin is likely to deform by heat, thereby losing its enzymatic activities. Particularly, instability of pancreatin in water makes it difficult to prepare pancreatin formulations. Specifically, when pancreatin is formulated into granules by a conventional method using water as a dispersion medium, the activities of enzymes (e.g., Upases) in pancreatin can be significantly reduced up to 50%. In view of this problem of pancreatin, organic solvents, such as isopropanol and acetone, have been employed to prepare pancreatin-containing formulations (See, e.g., U. S. Patent No. 4,280,971). However, the use of organic solvents may result in problems associated with residual solvents in the formulation, such as toxicity problems.
[3] Meanwhile, enteric coating techniques are conventionally employed for the purpose of protecting active ingredients from gastric acid. In enteric-coating particles or tables, thickness and uniformity of the resultant enteric coating layer are important factors in determining the quality of the enteric coatings. Un-uniform thickness of an enteric coating layer is an obstacle to effective protection of active ingredients from gastric acid, making active ingredients vulnerable to in vivo environmental changes, thereby causing significant deviations in activities of the active ingredients between individuals as well as in an individual.
[4] Since powder has different sizes and shapes with large surface area, it is difficult to prepare enteric-coated particles that have constant level of coating layer. Generally, granulation of powder for the preparation of spherical granules that have a uniform particle size is required in order to make uniform enteric coating layers.
[5] Processes involving vacuum drying by extrusion molding and the use of extruder- granulators are conventionally employed to prepare granules. According to these processes, granules are prepared through a series of complicated steps, e.g. kneading,
granulating, screening, drying and sieving. Further, the granules thus prepared are not completely spherical and have a broad particle size distribution. Therefore, it is difficult to apply the above methods to the processes for the preparation of pancreatin- containing granules having a uniform enteric coating layer.
[6] The use of a centrifugal fluidized-bed coating granulator (CF granulator) enables preparing spherical granules with an improved particle size distribution to some extent, but has drawbacks in that considerable damage to spherical granules occurs during preparation and that the surface of granules is roughed, thus making it difficult to achieve uniform enteric coating.
[7] There is thus a need in the art to develop a process for formulating water-labile pancreatin into spherical granules in a simple manner and a process for preparing enteric-coated spherical pancreatin-containing granules using the spherical granules. Disclosure of Invention Technical Problem
[8] The present invention provides a process for preparing spherical pancreatin- containing granules where water is employed as a dispersion medium, thereby causing no environmental contamination. The process may be carried out in a simple manner and can minimize inactivation of enzymes in pancreatin. The present invention also provides a process for preparing enteric-coated spherical pancreatin-containing granules using the same.
[9] Therefore, it is an object of the present invention to provide a process for preparing spherical pancreatin-containing granules.
[10] It is another object of the present invention to provide a process for preparing enteric-coated spherical pancreatin-containing granules using the same. Technical Solution
[11] In accordance with an aspect of the present invention, there is provided a process for preparing spherical pancreatin-containing granules, which comprises: dispersing one or more divided portions of pancreatin in water to prepare one or more dispersions; and spraying the dispersions on spherical granular cores while fluidizing the spherical granular cores in a fluidized-bed granulator, wherein the spraying is conducted within 20 to 90 minutes since the preparation of respective dispersions.
[12] In accordance with another aspect of the present invention, there is provided a process for preparing enteric-coated spherical pancreatin-containing granules, which comprises spraying an enteric-coating solution or dispersion on the spherical pancreatin-containing granules prepared by the process mentioned above while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator.
Brief Description of the Drawings
[13] The above and other objects, features and other advantages of the present invention will be more clearly understood from the following illustrative and non-limiting embodiments taken in conjunction with the accompanying drawings, in which:
[14] FlG. 1 is an optical micrograph of spherical pancreatin-containing granules prepared by a process of the present invention;
[15] FlG. 2 is an optical micrograph of enteric-coated spherical pancreatin-containing granules prepared by a process of the present invention; and
[16] FlG. 3 is an optical micrograph showing the cross section of an enteric-coated spherical pancreatin-containing granule prepared by a process of the present invention. Mode for the Invention
[17] In one aspect, the present invention provides a process for preparing spherical pancreatin-containing granules, which comprises: dispersing one or more divided portions of pancreatin in water to prepare one or more dispersions; and spraying the dispersions on spherical granular cores while fluidizing the spherical granular cores in a fluidized-bed granulator, wherein the spraying is conducted within 20 to 90 minutes since the preparation of respective dispersions.
[18] In the process of the present invention, the use of the fluidized-bed granulator makes it possible to minimize damages to granules and to prepare spherical granules with a uniform particle size in a simple manner. In addition, since water is used as a medium of the pancreatin-containing dispersions, the process of the present invention is safe and causes no environmental contamination problems. Particularly, it is surprising that, although pancreatin is water-labile, spraying the dispersion prepared using water as a dispersion medium at a high speed (i.e. within 20-90 minutes) can minimize inactivation of enzymes contained in pancreatin. In addition, enteric-coated pancreatin-containing granules can be prepared in a simple manner by using the spherical pancreatin-containing granules.
[19] The pancreatin used as an active ingredient in the process of the present invention can be used in an amount necessary to produce a formulation containing a therapeutically effective amount of the pancreatin, and the amount of the pancreatin used may vary depending on batch sizes used in the production. The pancreatin can be used in an amount of 30 to 80% by weight and preferably 50 to 70% by weight, based on the total weight of the granules.
[20] According to the process of the present invention, one or more divided portions of pancreatin are dispersed in water to prepare one or more dispersions. The pancreatin may be divided into three to ten and preferably five to eight portions. The pancreatin can be appropriately divided depending on the batch sizes by those skilled in the art. The amount of the water in the dispersions is not restricted so long as the divided
pancreatin portions can be suitably sprayed through a nozzle of the fluidized-bed granulator. The water may be used in an amount of 1 to 8 parts by weight and preferably 3 to 6 parts by weight, based on one part by weight of each of the divided pancreatin portions.
[21] The dispersions are sprayed on granular cores in a fluidized-bed granulator within
20 to 90 minutes and preferably 40 to 70 minutes since the preparation of respective dispersions. If the spraying is conducted for over 90 minutes since the preparation of respective dispersions, the activities of enzymes contained in the pancreatin may be reduced (for example, over 20% of lipase activities could be reduced.). Meanwhile, spraying time shorter than 20 minutes is too short to conduct the spraying step.
[22] The process of the present invention comprises spraying the dispersions on spherical granular cores while fluidizing the spherical granular cores in a fluidized-bed granulator.
[23] Conventional spherical granular cores used in the field of pharmaceutics may be used in the present invention. Examples of the spherical granular cores include celluloses, starches, saccharides, and a mixture thereof. Sugar sphere commercially available from IPS Inc. (Italy) can be used as the granular cores. The mean diameter of the granular cores may be in the range of 200 to 1,000 um, but not limited to this range.
[24] The fluidized-bed granulator can be operated under the conditions that are routinely employed in the filed of pharmaceutics. For example, the internal temperature of the fluidized-bed granulator is maintained at about 60 C or lower and preferably about 40 °C or lower. The pressure for spraying the dispersions may be in the range of about 1 to about 4 bars.
[25] For better coating on the granular cores, the dispersions may further comprise a binder. Suitable binders are those conventionally used in the field of pharmaceutics, such as hydroxypropyl cellulose, (hydroxypropyl)methyl cellulose, carboxymethyl- cellulose, and a mixture thereof.
[26] The dispersions may further comprise one or more additives selected from, but not limited to, talc, magnesium stearate, silicon dioxide, and combinations thereof, in order to prevent sticking or adhesion of the particles to the fluidized-bed granulator as well as adhesion between the particles.
[27] In another aspect, the present invention provides a process for preparing enteric- coated spherical pancreatin-containing granules, which comprises spraying an enteric- coating solution or dispersion on the spherical pancreatin-containing granules prepared by the process mentioned above while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator.
[28] The enteric-coating solution or dispersion comprises an enteric coating polymer,
e.g., a water-soluble polymer that does not dissolve at pH 3.0 or lower, a water- insoluble polymer, or a mixture thereof. Examples of such enteric coating polymers include polyvinyl acetate phthalate, acrylic polymers, acrylic copolymers (e.g., Eudragit L30 D-55, (hoem GmbH, Germany)), and cellulose acetate phthalates.
[29] The enteric-coating solution or dispersion may be prepared by dissolving or dispersing the enteric coating polymer in water.
[30] The enteric-coating solution or dispersion may further comprise a plasticizer, e.g., triethyl citrate, triacetin, polyethylene glycol, and a mixture thereof. These plasticizers may be used alone or as a mixture thereof. And, in order to enhance the quality of the enteric-coated pancreatin-containing granules, the enteric-coating solution or dispersion may further comprise a colorant, such as talc, titanium dioxide, iron oxide, tar dyes and their lakes, and mixtures thereof. Especially, the use of colorants such as talc, titanium dioxide, and a mixture thereof serves to prevent sticking or adhesion of the particles to the fluidized-bed granulator as well as adhesion between the particles.
[31] The spherical pancreatin-containing granules and/or the enteric-coated spherical pancreatin-containing granules prepared by the respective processes of the present invention may be used without any additional processing. Alternatively, the granules may be filled in capsules to produce capsule formulations or pressed to produce tablet formulations.
[32] Hereinafter, the present invention will be explained in more detail with reference to the following examples and test examples. However, these examples and test examples are given for the purpose of illustration and are not intended to limit the present invention.
[33]
[34] Example 1: Preparation of spherical pancreatin-containing granules
[35] A dispersion of 100 g of pancreatin in 400 ml of purified water was completely sprayed on 200 g of Sugar sphere™ (IPS Inc., Italy) that has a mean diameter of 600 to 710 um (25-30 mesh). Spraying was performed within 60 minutes since the preparation of respective dispersions, while fluidizing the Sugar sphere in a fluidized-bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
[36] Seven additional dispersions of 100 g of pancreatin in 400 ml of purified water were prepared and sprayed in accordance with the procedures mentioned above, to prepare spherical pancreatin-containing granules with 800 g of pancreatin in total. The spherical pancreatin-containing granules thus prepared were observed under an optical microscope (FIG. 1).
[37]
[38] Example 2: Preparation of spherical pancreatin-containing granules
[39] Spherical pancreatin-containing granules were prepared in the same manner as in
Example 1, except for using 200 g of Sugar sphere (IPS Inc., Italy) that has a mean diameter of 355 to 425 um (40-45 mesh).
[40]
[41] Example 3: Preparation of spherical pancreatin-containing granules
[42] Spherical pancreatin-containing granules were prepared in the same manner as in
Example 1, except for using 200 g of Sugar sphere™ (IPS Inc., Italy) that has a mean diameter of 212 to 250 um (60-70 mesh).
[43]
[44] Example 4: Preparation of spherical pancreatin-containing granules
[45] A dispersion of 100 g of pancreatin and 1.9 g of hydroxypropyl cellulose in 400 ml of purified water was completely sprayed on 200 g of Sugar sphere (IPS Inc., Italy) that has a mean diameter of 355 to 425 um (40-45 mesh). Spraying was performed within 60 minutes since the preparation of respective dispersion while fluidizing the Sugar sphere in a fluidized-bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and the spraying pressure of the dispersion at about 2 bars or lower.
[46] Seven additional dispersions of 100 g of pancreatin and 1.9 g of hydroxypropyl cellulose in 400 ml of purified water were prepared and sprayed in accordance with the procedures mentioned above, to prepare spherical pancreatin-containing granules with 800 g of pancreatin and about 15 g of hydroxypropyl cellulose in total.
[47]
[48] Example 5: Preparation of spherical pancreatin-containing granules
[49] Spherical pancreatin-containing granules were prepared in the same manner as in
Example 1, except for the fact that the dispersions were completely sprayed within 90 minutes since the preparation of respective dispersions.
[50]
[51] Example 6: Preparation of enteric-coated spherical pancreatin-containing granules
[52] A dispersion of 200 g of Eudragit L30 D-55 (hoem GmbH, Germany), 22 g of triethyl citrate and 65.6 g of talc in 1.3 liter of purified water was sprayed on 1,000 g of the spherical pancreatin-containing granules prepared in Example 1 while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator to prepare enteric-coated pancreatin-containing granules. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower. The enteric-coated spherical pancreatin-containing granules thus prepared were observed under an optical
microscope (FlG. 2). The cross section of one of the granules was observed under an optical microscope (FlG. 3).
[53]
[54] Example 7: Preparation of enteric-coated spherical pancreatin-containing granules
[55] A dispersion of 300 g of Eudragit L30 D-55 (hoem GmbH, Germany), 33 g of triethyl citrate and 98.4 g of talc in 1.95 liter of purified water was sprayed on 1,000 g of the spherical pancreatin-containing granules prepared in Example 2 while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator to prepare enteric-coated pancreatin-containing granules. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
[56]
[57] Example 8: Preparation of enteric-coated spherical pancreatin-containing granules
[58] A dispersion of 500 g of Eudragit L30 D-55 (hoem GmbH, Germany), 55 g of triethyl citrate and 164 g of talc in 3.25 liter of purified water was sprayed on 1,000 g of the spherical pancreatin-containing granules prepared in Example 3 while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator to prepare enteric-coated pancreatin-containing granules. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
[59]
[60] Example 9: Preparation of enteric-coated spherical pancreatin-containing granules
[61] A dispersion of 200 g of Eudragit L30 D-55 (hoem GmbH, Germany), 22 g of triethyl citrate, 45.6 g of titanium dioxide, and 65.6 g of talc in 1.3 liter of purified water was sprayed on 1,000 g of the spherical pancreatin-containing granules prepared in Example 1 while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator to prepare enteric-coated pancreatin-containing granules having white color. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
[62]
[63] Comparative Example 1: Preparation of spherical pancreatin-containing granules
[64] A dispersion of 200 g of pancreatin in 800 ml of purified water was completely sprayed on 200 g of Sugar sphere (IPS Inc., Italy) that has a mean diameter of 600 to
710 um (25-30 mesh) within 120 minutes since the preparation of respective dispersion while fluidizing the Sugar sphere™ in a fluidized-bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
[65] Three additional dispersions of 200 g of pancreatin in 800 ml of purified water were prepared and sprayed in accordance with the above procedures, to prepare spherical pancreatin-containing granules with 800 g of pancreatin in total.
[66]
[67] Comparative Example 2: Preparation of spherical pancreatin-containing granules
[68] A dispersion of 266.66 g of pancreatin in 1066.66 ml of purified water was completely sprayed on 200 g of Sugar sphere™ (IPS Inc., Italy) that has a mean diameter of 600 to 710 um (25-30 mesh). Spraying was performed within 150 minutes since the preparation of respective dispersion while fluidizing the Sugar sphere in a fluidized-bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and spraying pressure of the dispersion at about 2 bars or lower.
[69] Two additional dispersions of 266.66 g of pancreatin in 1066.66 ml of purified water were prepared and sprayed in accordance with the above procedures, to prepare spherical pancreatin-containing granules with 800 g of pancreatin.
[70]
[71] Comparative Example 3: Preparation of spherical pancreatin-containing granules
[72] A dispersion of 400 g of pancreatin in 1600 ml of purified water was completely sprayed on 200 g of Sugar sphere™ (IPS Inc., Italy) that has a mean diameter of 600 to 710 um (25-30 mesh). Spraying was performed within 180 minutes since the preparation of respective dispersion while fluidizing the Sugar sphere™ in a fluidized- bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and the spraying pressure of the dispersion at about 2 bars or lower.
[73] Additional dispersions of 400 g of pancreatin in 1600 ml of purified water were prepared and sprayed in accordance with the above procedures, to prepare spherical pancreatin-containing granules with 800 g of pancreatin in total.
[74]
[75] Comparative Example 4: Preparation of spherical pancreatin-containing granules
[76] A dispersion of 800 g of pancreatin in 3200 ml of purified water was completely sprayed on 200 g of Sugar sphere (IPS Inc., Italy) that has a mean diameter of 600 to
710 um (25-30 mesh). Spraying was performed within 240 minutes since the preparation of respective dispersion while fluidizing the Sugar sphere™ in a fluidized- bed granulator. During the procedure, the internal temperature of the fluidized-bed granulator was maintained at 40 °C or lower and the spraying pressure of the dispersion at about 2 bars or lower.
[77] [78] Test Example 1: Measurement of particle size distribution [79] The particle size distributions of the spherical pancreatin-containing granules prepared in Examples 1-4 and those of the enteric-coated spherical pancreatin-containi ng granules prepared in Examples 6-9 were evaluated using a sieve shaker. The results are shown in Table 1.
[80] Table 1
[81] [82] Test Example 2: Acid resistance test [83] An acid resistance test was conducted on the enteric-coated pancreatin-containing granules prepared in Examples 6-9. The granules were added to 900 mL of a first solution specified in the Korean pharmacopoeia, and then stirred at 100 rpm at 37 °C for 2 hours. The content of lipase dissolved was measured, and the results are shown in Table 2.
[84] Table 2
Example 6 Example 7 Example 8 Example 9
Dissolution of lipase (%) 4.2 3.5 3.3 3.6
[85] As can be seen from the results of Table 2, dissolution of the lipase was rarely occurred.
[86] [87] Test Example 3: Test for degree of enzyme activity [88] The spherical pancreatin-containing granules prepared in Examples 1 and 2 and Comparative Examples 1-4 were measured for the degree of enzymatic activities in accordance with the pancrelipase test method described in the US pharmacopoeia. The results are shown in Table 3.
[89] Table 3
[90] The results of Table 3 indicate that there was no significant change in enzymatic activities in the pancreatin-containing granules prepared in Examples 1 and 2. However, the enzymatic activities (particularly, lipase activity) in the pancreatin- containing granules prepared in Comparative Examples 1-4 were greatly decreased.
[91]
Industrial Applicability [92] As apparent from the above description, according to the processes of the present invention, damage to granules can be minimized and spherical granules having a uniform particle size can be prepared in a simple manner. In addition, the processes of the present invention can minimize inactivation of enzymes contained in pancreatin while still using water as a solvent, thereby causing no environmental contamination problems. Furthermore, enteric-coated pancreatin-containing granules can be prepared in a simple manner by using the spherical pancreatin-containing granules thus obtained.
Claims
[I] A process for preparing spherical pancreatin-containing granules, which comprises: dispersing one or more divided portions of pancreatin in water to prepare one or more dispersions; and spraying the dispersions on spherical granular cores while fluidizing the spherical granular cores in a fluidized-bed granulator, wherein the spraying is conducted within 20 to 90 minutes since the preparation of respective dispersions.
[2] The process according to claim 1, wherein the pancreatin is divided into three to ten portions.
[3] The process according to claim 1, wherein the spraying is conducted within 40 to
70 minutes since the preparation of respective dispersions.
[4] The process according to claim 1, wherein the spherical granular cores have a mean diameter of 200 to 1,000 um.
[5] The process according to claim 1, wherein the spherical granular cores are selected from the group consisting of celluloses, starches, saccharides, and a mixture thereof.
[6] The process according to claim 1, wherein the dispersions further comprises a binder.
[7] The process according to claim 6, wherein the binder is hydroxypropyl cellulose,
(hydroxypropyl)methyl cellulose, carboxymethylcellulose, or a mixture thereof.
[8] A process for preparing enteric-coated spherical pancreatin-containing granules, which comprises spraying an enteric-coating solution or dispersion on the spherical pancreatin-containing granules prepared by the process according to any one of claims 1 to 7 while fluidizing the spherical pancreatin-containing granules in a fluidized-bed granulator.
[9] The process according to claim 8, wherein the enteric-coating solution or dispersion is prepared by dissolving or dispersing an enteric coating polymer in water.
[10] The process according to claim 9, wherein the enteric coating polymer is a water- soluble polymer that does not dissolve at pH 3.0 or lower, a water-insoluble polymer, or a mixture thereof.
[II] The process according to claim 8, wherein the enteric-coating solution or dispersion further comprises a plasticizer selected from the group consisting of triethyl citrate, triacetin, polyethylene glycol, and a mixture thereof.
[12] The process according to claim 8, wherein the enteric-coating solution or
dispersion further comprises an additive selected from the group consisting of talc, titanium dioxide, iron oxide, tar dyes or lakes thereof, and a mixture thereof.
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| KR10-2005-0067227 | 2005-07-25 | ||
| KR1020050067227A KR101199196B1 (en) | 2005-07-25 | 2005-07-25 | Manufacturing method for spheric granule of pancreatin |
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Cited By (8)
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| US7658918B1 (en) | 2007-02-20 | 2010-02-09 | Eurand Pharmaceuticals Ltd. | Stable digestive enzyme compositions |
| US9259393B2 (en) | 2000-11-15 | 2016-02-16 | Aptalis Pharma S.R.L. | Microspheres of pancreatic enzymes with high stability and production method thereof |
| US9976171B2 (en) | 2011-08-08 | 2018-05-22 | Allergan Pharmaceuticals International Limited | Method for dissolution testing of solid compositions containing digestive enzymes |
| US10087493B2 (en) | 2008-03-07 | 2018-10-02 | Aptalis Pharma Canada Ulc | Method for detecting infectious parvovirus in pharmaceutical preparations |
| US10184121B2 (en) | 2013-06-28 | 2019-01-22 | Allergan Pharmaceuticals International Limited | Methods for removing viral contaminants from pancreatic extracts |
| US10993996B2 (en) | 2013-08-09 | 2021-05-04 | Allergan Pharmaceuticals International Limited | Digestive enzyme composition suitable for enteral administration |
| US11364205B2 (en) | 2010-10-01 | 2022-06-21 | Societe Des Produits Nestle S.A. | Stable low digestive enzyme content formulation |
| CN114767639A (en) * | 2022-05-13 | 2022-07-22 | 天津博菲德科技有限公司 | Acid-resistant enzyme preparation granule and preparation method thereof |
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| KR101028168B1 (en) * | 2010-05-17 | 2011-04-08 | 주식회사엠엠엘바이오테크 | Nano-microcapsul of fibrinase |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US9259393B2 (en) | 2000-11-15 | 2016-02-16 | Aptalis Pharma S.R.L. | Microspheres of pancreatic enzymes with high stability and production method thereof |
| US9884025B2 (en) | 2000-11-15 | 2018-02-06 | Aptalis Pharma S.R.L. | Microspheres of pancreatic enzymes with high stability and production method thereof |
| EP2754437A3 (en) * | 2007-02-20 | 2015-07-01 | Aptalis Pharma Limited | Stable digestive enzyme compositions |
| US8221747B2 (en) | 2007-02-20 | 2012-07-17 | Aptalis Pharma Limited | Stable pancreatic enzyme compositions |
| US8562979B2 (en) | 2007-02-20 | 2013-10-22 | Aptalis Pharma Limited | Stable digestive enzyme compositions |
| US8562981B2 (en) | 2007-02-20 | 2013-10-22 | Aptalis Pharma Limited | Stable digestive enzyme compositions |
| US8562978B2 (en) | 2007-02-20 | 2013-10-22 | Aptalis Pharma Limited | Stable digestive enzyme compositions |
| US8562980B2 (en) | 2007-02-20 | 2013-10-22 | Aptalis Pharma Limited | Stable digestive enzyme compositions |
| US7658918B1 (en) | 2007-02-20 | 2010-02-09 | Eurand Pharmaceuticals Ltd. | Stable digestive enzyme compositions |
| EP2079445B1 (en) * | 2007-02-20 | 2015-11-04 | Aptalis Pharma Limited | Stable digestive enzyme compositions |
| US8246950B2 (en) | 2007-02-20 | 2012-08-21 | Aptalis Pharma Limited | Stable digestive enzyme compositions |
| US8293229B2 (en) | 2007-02-20 | 2012-10-23 | Aptalis Pharma Limited | Methods of producing stable pancreatic enzyme compositions |
| US10206882B2 (en) | 2007-02-20 | 2019-02-19 | Allergan Pharmaceuticals International Limited | Stable digestive enzyme compositions |
| US10087493B2 (en) | 2008-03-07 | 2018-10-02 | Aptalis Pharma Canada Ulc | Method for detecting infectious parvovirus in pharmaceutical preparations |
| US11364205B2 (en) | 2010-10-01 | 2022-06-21 | Societe Des Produits Nestle S.A. | Stable low digestive enzyme content formulation |
| US9976171B2 (en) | 2011-08-08 | 2018-05-22 | Allergan Pharmaceuticals International Limited | Method for dissolution testing of solid compositions containing digestive enzymes |
| US10184121B2 (en) | 2013-06-28 | 2019-01-22 | Allergan Pharmaceuticals International Limited | Methods for removing viral contaminants from pancreatic extracts |
| US10993996B2 (en) | 2013-08-09 | 2021-05-04 | Allergan Pharmaceuticals International Limited | Digestive enzyme composition suitable for enteral administration |
| CN114767639A (en) * | 2022-05-13 | 2022-07-22 | 天津博菲德科技有限公司 | Acid-resistant enzyme preparation granule and preparation method thereof |
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|---|---|
| KR101199196B1 (en) | 2012-11-07 |
| KR20070012955A (en) | 2007-01-30 |
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