CN110075279A - Pancreatin microballoon and its production method - Google Patents
Pancreatin microballoon and its production method Download PDFInfo
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- CN110075279A CN110075279A CN201910337168.4A CN201910337168A CN110075279A CN 110075279 A CN110075279 A CN 110075279A CN 201910337168 A CN201910337168 A CN 201910337168A CN 110075279 A CN110075279 A CN 110075279A
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- pancreatin
- microballoon
- melting point
- low melting
- pharmaceutic adjuvant
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- 108010019160 Pancreatin Proteins 0.000 title claims abstract description 69
- 229940055695 pancreatin Drugs 0.000 title claims abstract description 69
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
- 229920000642 polymer Polymers 0.000 claims abstract description 16
- 230000010148 water-pollination Effects 0.000 claims abstract description 14
- 238000002844 melting Methods 0.000 claims abstract description 13
- 230000008018 melting Effects 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 8
- 239000004005 microsphere Substances 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 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
- 229920002261 Corn starch Polymers 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- 239000008120 corn starch Substances 0.000 claims description 5
- 229940099112 cornstarch Drugs 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 3
- 239000008247 solid mixture Substances 0.000 claims description 3
- 229960004793 sucrose Drugs 0.000 claims description 3
- 239000004382 Amylase Substances 0.000 claims description 2
- 102000013142 Amylases Human genes 0.000 claims description 2
- 108010065511 Amylases Proteins 0.000 claims description 2
- 102000004882 Lipase Human genes 0.000 claims description 2
- 239000004367 Lipase Substances 0.000 claims description 2
- 108090001060 Lipase Proteins 0.000 claims description 2
- 108091005804 Peptidases Proteins 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 239000004365 Protease Substances 0.000 claims description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 2
- 235000019418 amylase Nutrition 0.000 claims description 2
- 230000004927 fusion Effects 0.000 claims description 2
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 2
- 235000019421 lipase Nutrition 0.000 claims description 2
- -1 polyoxyethylene Polymers 0.000 claims description 2
- 235000019419 proteases Nutrition 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 claims 1
- 230000005496 eutectics Effects 0.000 claims 1
- 229920001993 poloxamer 188 Polymers 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 24
- 230000008569 process Effects 0.000 abstract description 15
- 230000002255 enzymatic effect Effects 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 8
- 108090000790 Enzymes Proteins 0.000 description 18
- 102000004190 Enzymes Human genes 0.000 description 18
- 229940088598 enzyme Drugs 0.000 description 18
- 239000002202 Polyethylene glycol Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229920001223 polyethylene glycol Polymers 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000002245 particle Substances 0.000 description 6
- 238000005453 pelletization Methods 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033649 Pancreatitis chronic Diseases 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 210000001953 common bile duct Anatomy 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 235000012438 extruded product Nutrition 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920003113 low viscosity grade hydroxypropyl cellulose Polymers 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
The present invention relates to the productions of the microballoon of pharmaceutical field, disclose a kind of pancreatin microballoon and its production method, the microballoon is made of pancreatin, pharmaceutic adjuvant and one or more hydrophily low melting point polymers, wherein, the weight percent of the pancreatin is 40% ~ 85%, the weight percent of the hydrophily low melting point polymer is 15% ~ 50%, remaining is the pharmaceutic adjuvant；Its production method is to be in the case where solvent is not present, it is granulated by high energy and spheroidizing process produces the pancreatin microballoon, the process of production is not related to the use of solvent, obtained microballoon enzymatic activity with higher, bioavailability and stability, and more more effective than existing production method.
Description
Technical field
The present invention relates to microballoon production technical field, in particular to a kind of pancreatin microballoon and its production method.
Background technique
The reduction of pancreatic secretion enzyme may be to be particularly due to mucus adhesion disease (capsule due to caused by different pathological conditions
Property fibrosis), obstruction of common bile duct, digestive ferment caused by cancer of pancreas and pancreas inflammatory state (chronic pancreatitis) etc. reduction or
Missing.Therefore, food can not be resolved into the molecule that can be absorbed by gastrointestinal tract by the people of these sickness influences.This disease can be led
Weight loss is caused, and may cause fatal consequence.Taking orally animal derived pancreatin is the effective treatment method of such disease.And pancreas
Enzyme is most suitable, most effective preparation is microballoon or bead.Since pancreatin is easy to be inactivated by the acid pH of stomach, and pancreatin must be with
Competence exertion good result when duodenum contacts.Pancreatin is a kind of enzyme with special stability problem, in long-time exposure
It is easy partly or entirely to lose enzymatic activity in the case where simple storage in water environment or high-temperature heating, or at high temperature.Therefore exist
In the case where oral, these preparations not only will be small as far as possible and be equipped with necessary anti-gastric acid coating.In stomach transportational process
In, pancreatin little particle ensures the reasonable layout of enzyme in food, it is often more important that has significant biography when microballoon reaches duodenum
Pass rate.
The production method of pancreatinum mainly uses wet granulation at present, squeezes or dehydrates.Buu (patent TW-A-
310277) it describes and is granulated, dehydration, is granulated again by water, squeezed and the methods of subsequently selected preparing extruded product.JP-A-
08109126 is a kind of based on the production method on liquid bed is applied, i.e., pancreatin powder is by containing bridging agent (hydroxy propyl cellulose
Element) aqueous solution be atomized in sugar ball.A kind of similar method is described in EP-A-277741, which describe application is low
Viscosity hydroxypropylcellulose (Lhpc) aqueous solution, is attached to pancreatin in inert core.All these methods are directed to pancreatin and exist
Under the dynamic condition of particle mixing, with water (or) other solvents mix；Wet granulation will lead to the partial denaturation of pancreatin granules.Pancreas
Enzyme is with the formation of particle, and activity is not as good as native enzyme.
.WO-A-9638169 in, pancreatin is the pelletizing without using solvent, is compressed using extruder, then processes and obtains not
The pelletizing of regular shape.The EP-A-583726 of Boedecker et al. is to produce size 0.7 between 1.4mm by pressurization
Pelletizing.Also extrusion process is used in patent JP-A-04187085, to obtain the particle having a size of 1.5 to 3mm；Squeeze out solvent
For water or the mixture of water and ethyl alcohol.The method that Atzl et al. (WO-A-9107948) uses similar wet granulation obtain partial size for
The spheric granules of 0.3 ~ 4mm.In DE-A-A3422619, obtaining diameter by the extruding after suitably modified is 1-2.5 millimeters,
The microballoon that height is 1-2.5 millimeters.In DE-A-2923279, pancreatin squeezes in the presence of isopropanol or acetone, nodularization, finally
Dehydration.Above-mentioned extrusion process provides irregular surface particles, further of uniform sizeization process is needed, to extend
Production time and bigger enzyme-deactivating risk.This is unfavorable for the stability of enzyme, and is related to higher industrial cost；Moreover,
In extrusion process in the presence of solvent, it there is serious loss of enzyme activity.According to the prior art, lacking one kind at present has
The technique of effect, industrial cost is low, prepares very thin particle size, without causing pancreatin denaturation and enzymatic activity to be lost.
Summary of the invention
Goal of the invention: aiming at the problems existing in the prior art, the present invention provides a kind of pancreatin microballoon and its production method,
The pancreatin Microsphere Size that this method is produced is minimum, enzymatic activity is relatively high and stable.
Technical solution: the present invention provides a kind of pancreatin microballoon, which is by pancreatin, pharmaceutic adjuvant and one kind or more
Kind hydrophily low melting point polymer composition, wherein the weight percent of the pancreatin is 40% ~ 85%, the hydrophily low melting point
The weight percent of polymer is 15% ~ 50%, remaining is the pharmaceutic adjuvant.
Preferably, the pancreatin be it is following any one or combinations thereof: amylase, lipase or protease, preferably
It is powdered.
Preferably, the hydrophily low melting point polymer is that polyethylene glycol, polyoxyethylene or PULLRONIC F68 are total
Polymers.
Preferably, the fusing point of the hydrophily low melting point polymer is 20 ~ 90 DEG C, preferably 30 ~ 70 DEG C.
Preferably, the pharmaceutic adjuvant be it is following any one or combinations thereof: cornstarch, sucrose, microcrystalline cellulose, glue
The lubricants such as body silica, triethyl citrate, talcum powder, gliding agent, plasticizer, colorant or diluent.In general,
All auxiliary materials that can improve or improve nodularization efficiency may be added in ingredient.
The present invention also provides a kind of production methods of pancreatin microballoon, comprising the following steps: S1: pancreatin, hydrophily is low
The solid mixture of melting polymers and auxiliary material is packed into suitable reactor in the solid state；S2: heating heating, and in height
In or equal to the above-mentioned solid mixture of heating stirring at a temperature of the hydrophilic polymer fusion temperature；S3: under agitation
Mixture after cooling down fusing；S4: solidified microsphere obtains the pancreatin microballoon on pelletizer-mixer or fluidized bed.
Preferably, after above-mentioned S4, the spraying of anti-stomach coating can also be carried out in the pancreatin microsphere surface.It is above-mentioned anti-
Stomach coating can for Hydroxypropyl Methylcellulose Phathalate, hydroxypropyl methyl cellulose acetate succinate, acrylate,
The plasticizer such as polyvinyl acetate, triethyl citrate or dibutyl phthalate.
The utility model has the advantages that solvent is not present in pancreatin microballoon in (1) present invention, pass through that high energy is granulated and spheroidizing process is raw
It produces, bioavilability and enzymatic activity with higher.In preparation method, pancreatin is mixed with hydrophily low melting point polymer solid
The direct nodularization of object quickly, inexpensively because not needing to avoid environmental pollution using organic solvent, reduces cost and potential danger,
Water is not needed, drying time is substantially reduced, effectively enzyme is avoided to inactivate yet.And the process of entire above-mentioned nodularization can wait
In or higher than effectively carrying out at a temperature of the fusing point of hydrophily low melting point polymer, the activity of enzyme will not be reduced, is prepared
The enzyme titre of pancreatin microballoon can be equal to or more than 90%.Cooling down under agitation is needed after mixture fusing, to obtain
There must be the microballoon of regular surfaces；Can be realized on pelletizer-mixer or fluidized bed in solidified microsphere process, and can with it is aforementioned
Cooling down carries out simultaneously.
(2) this production method pancreatin microsphere diameter produced is very small, and diameter is put down between 10 microns to 1500 microns
Respectively less than 700 microns, therefore there is very high bioavailability.
(3) coated polymer that the regular surfaces of this production method pancreatin microballoon produced allow usage quantity less obtains
Drug coat form, can reduce in this way coating agent quantity and coating needed for the time, to reduce process costs and enzyme
Inactivate risk.The enzyme titre and native enzyme of these pancreatin microballoons are essentially identical, and activity with higher is lasting under holding conditions
Property, so as to generate the pharmaceutical composition of active pancreatin high, stability is good.
As it can be seen that production method can obtain that size is minimum, enzymatic activity is high and stable pancreatin microballoon in the present invention, do not have to appoint
What solvent (including organic solvent and aqueous solvent) directly solidify nodularization, and at low cost, diameter is small, and surface is regular, activity of pancreatic enzyme height and
Stablize, bioavailability with higher.
Specific embodiment
The present invention is described in detail With reference to embodiment.
Embodiment 1:
Present embodiments provide for a kind of pancreatin microballoon, the pancreatin microballoon be by the mixture of pancreatin, cornstarch and sucrose with
And polyethylene glycol (PEG 4000) composition；Wherein, the weight percent of pancreatin is 56.7%, and the weight percent of polyethylene glycol is
26.7%, the weight percent of the mixture of cornstarch and sucrose is 16.6%.
The production method of above-mentioned pancreatin microballoon is as follows:
Reactor is added in the mixture of 680.0 grams of pancreatin, 320.0 grams of polyethylene glycol and 200.0 grams of cornstarch and sucrose
In be heated to 70 DEG C, mix 40 minutes, be then transferred into the basket of the fluidized bed with rotor insertion.Disk is annular knurl type,
Revolving speed is 1200rpm/min, while hot-air blows to 70 DEG C, is run with the speed of 1-2 meter per second.Filtrate hose shakes in 6 seconds
5 seconds.After heating nodularization in 20 minutes, it is passed through air themperature and is down to 20 DEG C.Make to mix pelletizing hardening, and disc rotary is maintained at 700
Rev/min.In this stage, the shake of filter is 5 seconds/12 seconds.After about 30 minutes cooling, by product from the basket of fluidized bed
It unloads.Whole process total time is 90 minutes.For the pancreatin microsphere diameter prepared between 150 ~ 700 microns, enzyme activity is theoretical
Activity is 18.6u/mg, and actual measurement enzymatic activity is 17.8u/mg, is lost less than 5%.
Embodiment 2:
Present embodiments provide for a kind of pancreatin microballoon, which is by pancreatin, microcrystalline cellulose and polyethylene glycol group
At pharmaceutical composition；The weight percent of pancreatin is 71.8%, and the weight percent of polyethylene glycol is 19%, microcrystalline cellulose
Weight percent is 9.2%.
The production method of above-mentioned pancreatin microballoon is as follows:
717.8 grams of pancreatin, 190.8 grams of polyethylene glycol and 91.4 grams of microcrystalline celluloses are added to the storage tank of a high energy mixers
In.The machine blade speed of service is 900 revs/min, and heating mantle is 70 DEG C.After nodularization 45 minutes, heating is closed, and blade rotational speed is down to
120 revs/min, housing is cooling by pipeline water flow.After 15 minutes cooling, pelletizing is removed.Process total time is 60 minutes.Preparation
The enzyme activity of pancreatin microballoon out is 23.5u/mg, and almost the same with theoretical value 23.6u/mg, pancreatin microballoon enzymatic activity is not damaged
It loses, diameter is at 200 ~ 1000 microns.
Embodiment 3:
Present embodiments provide for a kind of pancreatin microballoon, which is by pancreatin, colloidal silicon dioxide, triethyl citrate
The pharmaceutical composition formed with the mixture and polyethylene glycol of talcum powder；The weight percent of pancreatin is 40%, polyethylene glycol
Weight percent is 50%, and the weight percent of the mixture of colloidal silicon dioxide, triethyl citrate and talcum powder is 10%.
By 400.0 grams of pancreatin, 500.0 grams of polyethylene glycol and 100.0 grams of colloidal silicon dioxides, triethyl citrate and cunning
The mixture of mountain flour is added in reactor, and 70 DEG C of mixing are transferred to after twenty minutes into the basket of the fluidized bed with rotor insertion.
Disk is annular knurl type, and revolving speed 1200rpm/min, while hot-air blows to 70 DEG C is run with the speed of 1-2 meter per second.It filters soft
Pipe shakes 5 seconds in 6 seconds.After nodularization in 20 minutes, it is passed through air themperature and is down to 20 DEG C.Mixing pelletizing is hardened, and disc rotary
It is maintained at 700 revs/min.In this stage, the shake of filter is 5 seconds/12 seconds.After cooling about 30 minutes, by product from fluidisation
It is unloaded in the basket of bed.Whole process total time is 80 minutes.The pancreatin microsphere diameter prepared between 200 ~ 800 microns,
Enzyme activity is 13.1u/mg, and theoretical value 13.2u/mg does not lose substantially.
The technical concepts and features of above embodiment only to illustrate the invention, its object is to allow be familiar with technique
People cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent transformation or modification that Spirit Essence is done, should be covered by the protection scope of the present invention.
Claims (7)
1. a kind of pancreatin microballoon, which is characterized in that the microballoon is by pancreatin, pharmaceutic adjuvant and one or more hydrophily eutectics
Point polymer composition, wherein the weight percent of the pancreatin is 40% ~ 85%, the weight of the hydrophily low melting point polymer
Percentage is 15% ~ 50%, remaining is the pharmaceutic adjuvant.
2. pancreatin microballoon according to claim 1, which is characterized in that the pancreatin is following any one or its group
It closes: amylase, lipase or protease.
3. pancreatin microballoon according to claim 2, which is characterized in that the pancreatin is powdered.
4. pancreatin microballoon according to claim 1, which is characterized in that the hydrophily low melting point polymer is poly- second two
Alcohol, polyoxyethylene or Pluronic F68.
5. pancreatin microballoon according to claim 4, which is characterized in that the fusing point of the hydrophily low melting point polymer is 30
~70℃。
6. pancreatin microballoon according to claim 1, which is characterized in that the pharmaceutic adjuvant is following any one or its group
It closes: cornstarch, sucrose, microcrystalline cellulose, colloidal silicon dioxide, triethyl citrate, talcum powder.
7. the production method of pancreatin microballoon according to any one of claim 1 to 6, which is characterized in that including following step
It is rapid:
S1: it is suitable that the solid mixture of pancreatin, hydrophily low melting point polymer and pharmaceutic adjuvant is packed into the solid state
Reactor；
S2: heating heating, and in the above-mentioned solid of at a temperature of heating stirring for being greater than or equal to the hydrophilic polymer fusion temperature
Mixture；
S3: the mixture after cooling down fusing under agitation；
S4: solidified microsphere obtains the pancreatin microballoon on pelletizer-mixer or fluidized bed.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040101562A1 (en) * | 2000-11-15 | 2004-05-27 | Mario Maio | Microspheres of pancreatic enzymes with high stability and production method thereof |
| CN1933850A (en) * | 2004-03-22 | 2007-03-21 | 索尔瓦药物有限公司 | Oral pharmaceutical compositions of lipase-containing products, in particular of pancreatin, containing surfactants |
| CN101242812A (en) * | 2005-08-15 | 2008-08-13 | 索尔瓦药物有限公司 | Pancreatin micropellets suitable for enteric coating |
| CN102946872A (en) * | 2010-05-03 | 2013-02-27 | 阿普塔利斯制药有限公司 | Micropellet compositions comprising pancreatin containing digestive enzyme mixtures |
-
2019
- 2019-04-25 CN CN201910337168.4A patent/CN110075279A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040101562A1 (en) * | 2000-11-15 | 2004-05-27 | Mario Maio | Microspheres of pancreatic enzymes with high stability and production method thereof |
| CN1933850A (en) * | 2004-03-22 | 2007-03-21 | 索尔瓦药物有限公司 | Oral pharmaceutical compositions of lipase-containing products, in particular of pancreatin, containing surfactants |
| CN101242812A (en) * | 2005-08-15 | 2008-08-13 | 索尔瓦药物有限公司 | Pancreatin micropellets suitable for enteric coating |
| CN102946872A (en) * | 2010-05-03 | 2013-02-27 | 阿普塔利斯制药有限公司 | Micropellet compositions comprising pancreatin containing digestive enzyme mixtures |
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Application publication date: 20190802 |