CN109125282A - A kind of omeprazole enteric-coated capsules and preparation method thereof - Google Patents
A kind of omeprazole enteric-coated capsules and preparation method thereof Download PDFInfo
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- CN109125282A CN109125282A CN201811031732.1A CN201811031732A CN109125282A CN 109125282 A CN109125282 A CN 109125282A CN 201811031732 A CN201811031732 A CN 201811031732A CN 109125282 A CN109125282 A CN 109125282A
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
The invention discloses a kind of omeprazole enteric-coated capsules and preparation method thereof, the capsule is filled in gelatine capsule shell by omeprazole enteric-coated micro-pill and forms.Omeprazole enteric-coated micro-pill is successively that Omeprazole carries pill core, separation layer and enteric layer from inside to outside.Omeprazole is carried pill core and is prepared using extrusion spheronization method, and separation layer and enteric layer are prepared using fluidized bed coating.Unlike grinding product from original, Omeprazole carries pill core on the basis of Omeprazole, Lactis Anhydrous, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, hydroxypropylcellulose, lauryl sodium sulfate, increases Tween 80 and low-substituted hydroxypropyl cellulose.Omeprazole enteric-coated capsules prepared by the present invention are not only without the stability and reproducibility of change product, also improve the dissolution in vitro of drug, in particular improve homogeneity between individual, different health volunteer's peak reaching time of blood concentration more tends to unanimously, has good application value in terms of clinical application.
Description
Technical field
The present invention relates to field of medicine preparations, and in particular to a kind of omeprazole enteric-coated micro-pill and by the enteric-coated micro-pill system
The preparation method of standby omeprazole enteric-coated capsules and affiliated omeprazole enteric-coated capsules.
Background technique
Proton pump inhibitor is benzimidazoles compound, comprehensive for peptic ulcer, esophageal reflux disease, gastrinoma
The treatment of disease and helicobacter pylori.So far, the external proton pump inhibitor listed have Omeprazole, esomeprazole,
Pantoprazole, Lansoprazole, Rabeprazole, dextral-rabeprazole, Dexlansoprazole etc., the proton pump inhibitor of country's listing
There are Omeprazole, esomeprazole, Pantoprazole, Lansoprazole, Rabeprazole etc., that is declaring registration has dextrorotation Lei Beila
Azoles, Dexlansoprazole etc..Omeprazole was listed in 1988 in the U.S., was that the earliest benzimidazole proton pump of listing inhibits
Agent.
According to Thomson Newport database displaying, on March 31st, 1988, Astrazeneca AB had listed entirely in Luxembourg
The first omeprazole enteric-coated capsules of ball (delayed-release capsules) preparation (trade name " LOSEC ", Losec),
Specification is 20mg.On January 30th, 1989, AstraZeneca is in Britain's Initial Public Offering omeprazole enteric-coated capsules (trade names
" LOSEC ", specification 20mg).On June 30th, 1989, AstraZeneca have listed omeprazole enteric-coated capsules (rule in Spain
Lattice: 20mg).April 30 nineteen ninety, AstraZeneca have listed omeprazole enteric-coated capsules (specification: 20mg) in Greece.1989
September 14 days, the enteric coated omeprazole pellets capsule of AstraZeneca obtained FDA approval listing, specification 10mg, 20mg, 40mg, commodity
Entitled " PRILOSEC "；On March 20th, 2008, the magnesium omeprazole oral sustained-release dry suspension of AstraZeneca get the Green Light,
U.S.'s listing, specification 2.5mg, 10mg, trade name is all " PRILOSEC ".
Currently, the main dosage form that Omeprazole lists at home is enteric coatel tablets and enteric capsule.Listing specification have 10mg,
20mg,40mg.There are 15 enterprises to list Omeprazole Enteric-coated Tablets at home, more than 50 enterprises list Omeprazole intestines at home
Colloidal sol capsule, the approval number of the drug up to 114.
Omeprazole enteric-coated capsules (specification: 10mg, 20mg) granted listing of AstraZeneca pharmaceutical Co. Ltd, authentication code point
Not are as follows: H20030413, H20030412 have omeprazole enteric-coated capsules (specification: 20mg) original to grind real estate launch.
The omeprazole enteric-coated capsules Σ κ λ η ρ γ α σ τ ρ ο α ν θ ε that 30 days April nineteen ninety of AstraZeneca list in Greece
κ τ ι κ κ α ψ κ ι α ο μ ε π ρ α ζ λ η (trade name: LOSEC 20mg omeprazole), and the medicine lists in Europe
It for many years, is the drug with complete and sufficient safety, efficacy data；Meet the third of CFDA reference preparation selection principle
Item, that is, drafting reference preparation and meeting " if original grinds drug and internationally recognized same drug does not list at home, may be selected in Europe
Alliance, the U.S., Japan list and are listed in the drug of reference preparation ".
On July 19th, 2017, state food pharmaceuticals administration general bureau is about publication imitation medicine reference preparation catalogue the (the 7th
Batch and the 8th batch) notice (2017 the 115th and No. 116), wherein the Aomei of accredited quotient AstraZeneca UK Limited
Azoles capsulae enterosolubilis 10MG, 20MG and 40MG is drawn to be listed in reference preparation.
Omeprazole is that proton pump inhibitor belongs to fat-soluble weakly basic drugs, is easily concentrated in acidic environment, thus it is oral after can
It is specifically distributed in the secretory tubyle of stomach lining parietal cell, and is converted into the active shape of sulfenamide under this high acid environment
Then formula secretes the H+ in film by disulfide bond and parietal cell, the sulfydryl of K+-ATP enzyme (also known as proton pump) is in irreversibility
In conjunction with, the compound away from sulfonamide and proton pump, which is generated, to inhibit the enzymatic activity blocks the final step of gastric acid secretion, because
This this product has strong and lasting inhibiting effect to gastric acid secretion caused by a variety of causes.
Omeprazole enteric-coated capsules by oral administration after, through small intestinal absorption, work in 1 hour, 0.5~3.5 hour blood concentration
Reach to peak value effect lasts 24 hours or more, can be distributed to the tissue such as liver, kidney, Stomach duodenum, thyroid gland, and easily penetrate tire
Disk.Usual single dose bioavailability about 35%, multi-dose bioavilability increase to about 60%, and plasma protein binding rate is 95%~
96%, plasma half-life is 0.5~1 hour, and patients with chronic liver is 3 hours.Omeprazole enteric-coated capsules are micro- through liver in vivo
The metabolism of mitochondrial cytochrome P450 oxidase system, metabolin about 80% is through homaluria, remaining after bile secretion from excrement by arranging
It lets out.
The reason of difference is generated after subject takes orally omeprazole enteric-coated capsules, between individual has following two: first is that Aomei
Difference in drawing azoles capsulae enterosolubilis batch and between criticizing, the i.e. difference of different batches and/or batch interior different omeprazole enteric-coated capsules quality
It is different, especially had differences in terms of In Vitro Dissolution characteristic；Second is that since omeprazole enteric-coated capsules are in vivo through liver microsomes
The difference of Cytochrome P450 oxidase system metabolism.It is known that the speed of its internal enzyme metabolism of different ethnic groups have it is larger
Difference, the half-life period of Omeprazole only has 0.5~1 hour in addition, and therefore, different subjects take orally omeprazole enteric-coated capsules
There are biggish difference, AUC also to vary with each individual by Tmax, Cmax afterwards, that is, makes a variation between individual.In general, this enzyme generation
Inter-individual difference caused by the speed and ability thanked, it is difficult to realize by prescription and this mode of technique adjustment.
We are during the bioequivalence trial test of omeprazole enteric-coated capsules, it has unexpectedly been found that, product, which are ground, in original carries
On the basis of pill, Tween 80 and low-substituted hydroxypropyl cellulose are increased, the omeprazole enteric-coated capsules of preparation either exist
On an empty stomach or during postprandial Bioequivalence Test, Tmax, Cmax and AUC between different subjects are very close.And
The omeprazole enteric-coated capsules of Tween 80 and low-substituted hydroxypropyl cellulose are not added, it is no matter on an empty stomach or postprandial, it is different tested
Tmax, Cmax and AUC difference between person is very big, and Tmax, Cmax difference especially under the conditions of empty stomach are bigger.
For this purpose, the present invention starts with from the formula and technique of omeprazole enteric-coated capsules, on the basis of original grinds product and carries pill,
Increase Tween 80 and low-substituted hydroxypropyl cellulose, the omeprazole enteric-coated capsules thus prepared, batch between and/or batch in product
Quality difference it is smaller, different subjects take orally omeprazole enteric-coated capsules after, peak reaching time of blood concentration (Tmax), highest blood
Concentration (Cmax) and bioavilability (AUC) are almost the same.Omeprazole enteric-coated capsules prepared by the present invention, are not only released in vitro
Degree of putting is high, and stability is good, it is often more important that the quality that omeprazole enteric-coated capsules greatly improved reduces the difference between individual
It is different, there is good commercial promise.
Summary of the invention
The object of the present invention is to provide a kind of omeprazole enteric-coated micro-pills.
It is a further object of the present invention to provide a kind of omeprazole enteric-coated capsules.
It is a further object of the present invention to provide a kind of preparation methods of omeprazole enteric-coated capsules.
Omeprazole enteric-coated capsules prepared by the present invention not only without the stability and reproducibility of change product, also improve
The dissolution in vitro of drug in particular improves homogeneity between individual, and different health volunteer's peak reaching time of blood concentration is more
It reaches unanimity, there is good application value in terms of clinical application.
To achieve the goals above, the invention provides the following technical scheme:
A kind of omeprazole enteric-coated micro-pill, the omeprazole enteric-coated micro-pill be followed successively by from inside to outside Omeprazole carry pill core,
Separation layer and enteric layer, it includes Tween 80 and low-substituted hydroxypropyl cellulose that the Omeprazole, which carries pill core,.
The present invention provides a kind of omeprazole enteric-coated micro-pills, and further, the Omeprazole carries pill core and further includes
Omeprazole, Lactis Anhydrous, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, high substitution hydroxypropylcellulose and dodecyl sulphate
Sodium.
The present invention provides a kind of omeprazole enteric-coated micro-pills, further, tween in the omeprazole enteric-coated micro-pill
80 and the weight percent of low-substituted hydroxypropyl cellulose be 1:3 ~ 5, preferably 1:3.5, low-substituted hydroxypropyl cellulose and Aomei are drawn
The weight percent of azoles is 1:30 ~ 70, preferably 1:57.
The present invention provides a kind of omeprazole enteric-coated micro-pills, and further, the separation layer includes hydroxypropyl methylcellulose
And water, hydroxypropyl methylcellulose packet is carried to the surface of pill core by fluidized-bed coating machine in Omeprazole.
The present invention provides a kind of omeprazole enteric-coated micro-pills, and further, the enteric layer includes Utech L30D-55
Aqueous dispersion, Macrogol 6000 and lauryl sodium sulfate and water are existed hydroxypropyl methylcellulose packet by fluidized-bed coating machine
The surface of separation layer.
The present invention provides a kind of omeprazole enteric-coated micro-pills, and further, the crystal form of the Omeprazole is Type B, grain
Degree distribution D90 < 10um, D50 < 3um.
The present invention provides a kind of omeprazole enteric-coated micro-pills, and further, the Omeprazole carries pill core using crowded
Round as a ball technique preparation out.
It is described the present invention also provides a kind of omeprazole enteric-coated capsules prepared using above-mentioned omeprazole enteric-coated micro-pill
Omeprazole enteric-coated capsules include the omeprazole enteric-coated micro-pill and gelatine capsule shell, in every omeprazole enteric-coated capsules
Tween and low-substituted hydroxypropyl cellulose are no more than 1mg and 3.5mg respectively.
The present invention also provides a kind of preparation methods of above-mentioned omeprazole enteric-coated capsules, include the following steps:
(1) preparation for carrying pill core, successively includes: stock-preparation granulation liquid-mixing-granulation-pill-drying-discharging-sieving；
(2) spacer layer coating successively includes: that after preparing spacer layer coating liquid, drug containing vegetable pill is put into multifunctional granulation coating machine
It is interior, set device parameter: blower frequency: 10~25Hz, inlet air temperature :≤70 DEG C, spacer ring height: 20~50mm, atomizing pressure:
1.2~3.5bar, fluid supply rotate speed: 10~200rpm；It controls temperature of charge: 35 ± 3 DEG C, carrying out spacer layer coating operation, isolation
Stop-spraying after layer coating solution has sprayed；It is dry later to discharge and be sieved；
(3) enteric layer is coated, and successively includes: to prepare enteric layer coating solution, and coating operations are sieved after dry discharging later；
(4) filling, plastic-aluminum, outsourcing.
The present invention also provides a kind of preparation methods of omeprazole enteric-coated capsules, specifically comprise the following steps:
(1) preparation of pill core is carried
Stock: material is got from warehouse by regulation.Mannitol is crushed, the screen mesh size of Highefficientpulverizer is
1.0mm.Operator checks the name of an article, specification, the lot number, quantity of supplementary material, and after confirmation is errorless, each material is by batch production ordering rule
Fixed recipe quantity carries out weighing stock.
It prepares granulation liquid: under stirring, the disodium hydrogen phosphate of recipe quantity being added into the purified water of recipe quantity.It fills
Point stir to clarify it is transparent after, the lauryl sodium sulfate and Tween 80 of recipe quantity is added.Be stirred until homogeneous, without agglomeration after, add
Enter the Omeprazole of recipe quantity, it is stirring no less than 15 minutes, spare.
Mixing: after equipment trial operation is normal, mannitol is taken, lactose, microcrystalline cellulose, high replace hydroxypropylcellulose and low takes
It each 1 part for hydroxypropylcellulose, successively puts into wet mixing pelletizer, sets technological parameter as " agitating paddle frequency 5-20Hz, system
Grain knife frequency 1-10Hz ", mixes about 600s, wait pelletize.
Granulation: weighing granulation liquid, sets technological parameter as " agitating paddle frequency 5-20Hz, granulating cutter frequency 1-10Hz " system
Grain.After granulation, wet granular is transferred between pill.
Pill: after trial operation is normal, wet granular being put into extrusion spheronization machine, " is squeezed out by " feed 10~40rpm of motor "
The parameter of 40~80rpm " of motor " round as a ball 150~800rpm of motor " carries out pill operation.After completing pill operation, by wet ball
It is transferred to dry post.
It is dry: after trial operation is normal, the wet ball of collection being put into multifunctional granulation coating machine, set device parameter: blower
Frequency: it 10~25Hz, inlet air temperature :≤70 DEG C, sets temperature of charge: 40 DEG C, being dried.
Discharging: when dry materials are to moisture < 2.5%, dehumidifying is closed, closes heating, blower open state is kept, works as temperature of charge
35 DEG C of <, shut down discharging.
Sieving: crossing 14 mesh and 20 meshes for the drug containing vegetable pill dried respectively, collects 14 mesh to the drug containing element between 20 mesh
Ball, weighing, are put into desiccant (specification: 120g) between PE bags in two layers by then PE bags of housing black.
(2) spacer layer coating
Spacer layer coating liquid is prepared: under stirring, will be converted the hydroxypropyl methylcellulose of material quantity, is slowly added to purified water
In, it is stirred well to clear, fills in material weighing label, it is spare.
After trial operation is normal, drug containing vegetable pill is put into multifunctional granulation coating machine, set device parameter: blower frequency:
10~25Hz, inlet air temperature :≤70 DEG C, spacer ring height: 20~50mm, atomizing pressure: 1.2~3.5bar, fluid supply rotate speed: 10~
200rpm；It controls temperature of charge: 35 ± 3 DEG C, carrying out spacer layer coating operation, stop-spraying after spacer layer coating liquid has sprayed.
It is dry: after coating, to set temperature of charge as 40 DEG C, be dried.
Discharging: when the moisture < 2.5% of layer pellet to be isolated, dehumidifying is closed, closes heating, keeps blower open state.Work as material
35 DEG C of temperature <, shut down discharging.
Sieving: crossing 14 mesh and 20 meshes for the separation layer pellet dry respectively, 14 mesh of collection to the pellet between 20 mesh,
Weighing, is put into desiccant (specification: 120g) between PE bags in two layers by then PE bags of housing black.
(3) enteric layer is coated
Enteric layer coating solution is prepared: 1. under stirring, will be converted the Macrogol 6000 of recipe quantity, is slowly added to purifying
In water, stir to clarify transparent.Then, it is slowly added to the lauryl sodium sulfate of conversion recipe quantity, is stirred to clarify transparent.②
Utech L30D-55 aqueous dispersion is weighed, puts into liquid dispensing tank, stirs at low speed.3. solution 1. is slowly poured into 2., keep
Stir at low speed to uniformly, without agglomeration, cross 60 meshes.
Coating: after trial operation is normal, by isolation ball investment multifunctional granulation coating machine, set device parameter: blower is frequently
Rate: 10~25Hz, inlet air temperature :≤70 DEG C, spacer ring height: 20~50mm, atomizing pressure: 1.2~3.5bar, fluid supply rotate speed:
10~200rpm；It controls temperature of charge: 33 ± 3 DEG C, carrying out enteric layer coating operations, stop-spraying after enteric layer coating solution has sprayed.
It is dry: after coating, to set temperature of charge as 40 DEG C, be dried.
Discharging: when the moisture < 2.5% of enteric layer pellet, dehumidifying is closed, closes heating, keeps blower open state.Work as material
35 DEG C of temperature <, discharging is shut down, is encapsulated with double-deck PE bags.
Stiffened fatty acid magnesium: magnesium stearate dosage is calculated according to " magnesium stearate dosage=enteric layered pills weight × 1% ", after weighing
It is added in enteric layered pills, operator catches sack both ends, hand shaken sack mixing 10min respectively.
Sieving: crossing 14 mesh and 20 meshes for the enteric layer pellet dried respectively, collects 14 mesh to the pellet between 20 mesh
And inspection is sampled, it weighs, PE bags of housing black, is put into desiccant (specification: 120g) between PE bags in two layers.
(4) filling, plastic-aluminum, outsourcing
Qualified intermediate products and gelatin hollow capsule are got, loading amount, filling are calculated according to intermediate products content.By production ordering
The good batch number of adjustment is installed, clear writing, marshalling are answered, carries out plastic-aluminum.Product to be packaged and outer packaging material are got, is carried out outer
Packaging operation, packing specification are every bag of 1 plate (composite film packaging inside puts 1 and is responsible for a task until it is completed drying prescription), 1 bag of every box.
The invention discloses a kind of omeprazole enteric-coated capsules and preparation method thereof, omeprazole enteric-coated micro-pill of the invention
Pill core, separation layer and enteric layer composition are carried by Omeprazole respectively from inside to outside, Omeprazole carries pill core using extrusion rolling
Round technique preparation, separation layer and enteric layer are prepared using the method for fluidized bed coating.Product are ground with omeprazole enteric-coated capsules original
(product batch number: YCLK；Specification: 20mg, trade name: LOSEC, manufacturer: AstraZeneca AB) unlike formula, it is difficult to understand
Beauty draws azoles to carry pill core in Omeprazole, Lactis Anhydrous, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, high substitution hydroxypropyl fiber
On the basis of element, lauryl sodium sulfate, Tween 80 and low-substituted hydroxypropyl cellulose are increased.It has been investigated that system of the present invention
Standby omeprazole enteric-coated capsules not only without the stability and reproducibility of change product, also improve the In Vitro Dissolution of drug
Degree, in particular improves homogeneity between individual, different health volunteer's peak reaching time of blood concentration more tends to unanimously, in clinic
Application aspect has good application value.
Specific embodiment
It is right combined with specific embodiments below in order to make those skilled in the art more fully understand technical solution of the present invention
The present invention is described in further detail.
The processing of 1 Omeprazole of embodiment micronization
The Omeprazole raw material 50Kg for weighing 80 meshes sets gas MQL03 airslide disintegrating mill (Weifang Ai Erpai powder technology equipment
Co., Ltd's manufacture) in micronization, and by the sieves of 325 mesh, the Omeprazole 46.8Kg being micronized, yield is
93.6%.Omeprazole sample after taking micronization, with 2000 Malvern laser particle size analyzer (Britain horse of Mastersizer
The manufacture of Er Wen instrument company) detection, D50 2.93um, D90 7.32um.
The preparation of 2 omeprazole enteric-coated capsules of embodiment
(1) preparation of Omeprazole drug-loaded layer
Smashed mannitol 1180g is weighed, it is spare.Under stirring, weighed 20g disodium hydrogen phosphate is added to 391g
Purified water in.After being stirred well to clear, the lauryl sodium sulfate (and Tween 80 of 1g) of 2g is added.It stirs to equal
It is even, without agglomeration after, be added the Omeprazole of 200g, it is stirring no less than 15 minutes, spare.By recipe quantity weigh mannitol, lactose,
Microcrystalline cellulose, high substitution hydroxypropylcellulose (and low-substituted hydroxypropyl cellulose), successively put into wet mixing pelletizer, setting
Reasonable technological parameter, wait pelletize.Granulation liquid is weighed, reasonable technological parameter is set, is pelletized.Wet granular is put into extrusion spheronization
In machine, by reasonable technological parameter, carries out pill, drying, shuts down discharging.The drug containing vegetable pill dried is crossed into 14 mesh and 20 respectively
Mesh, collects 14 mesh to the drug containing vegetable pill between 20 mesh, weighing, then PE bags of housing black, is put into desiccant between PE bags in two layers.
(2) preparation of separation layer
Under stirring, the hydroxypropyl methylcellulose of material quantity will be converted, be slowly added into purified water, be stirred well to clarification
It is transparent, it is spare.Drug containing vegetable pill is put into multifunctional granulation coating machine, temperature of charge is controlled: 35 ± 3 DEG C, carrying out separation layer packet
Clothing operation, stop-spraying after spacer layer coating liquid has sprayed.After coating, temperature of charge is set as 40 DEG C, is dried.Layer to be isolated
When the moisture < 2.5% of pellet, discharging is shut down.The separation layer pellet dried is crossed into 14 mesh and 20 meshes respectively, 14 mesh is collected and arrives
Pellet between 20 mesh, weighing, are put into desiccant between PE bags in two layers by then PE bags of housing black.
(3) preparation of enteric coating
Under stirring, the Macrogol 6000 of recipe quantity will be converted, be slowly added into purified water, stir to clarify
It is bright.Then, it is slowly added to the lauryl sodium sulfate of conversion recipe quantity, is stirred to clarify transparent.Weigh Utech L30D-55 water
Dispersion puts into liquid dispensing tank, stirs at low speed.Macrogol 6000 and the mixed solution of lauryl sodium sulfate are slowly poured into
In Utech L30D-55 aqueous dispersion, holding stir at low speed to uniformly, without agglomeration, cross 60 meshes.It is multi-functional that ball investment will be isolated
In granulator coater, controls temperature of charge: 33 ± 3 DEG C, carrying out enteric layer coating operations, stop-spraying after enteric layer coating solution has sprayed.
After coating, temperature of charge is set as 40 DEG C, is dried.When the moisture < 2.5% of enteric layer pellet, discharging is shut down, is used
The double-deck PE bags of encapsulation.Magnesium stearate is weighed by recipe quantity, is added in enteric layered pills, 10min is mixed.The enteric layer dried is micro-
Ball crosses 14 mesh and 20 meshes respectively, collects 14 mesh and to the pellet between 20 mesh and samples inspection, weighs, and PE bags of housing black, in
Desiccant is put between PE bags two layers.
(4) capsule is filled
Qualified intermediate products and gelatin hollow capsule are got, loading amount, filling, plastic-aluminum and outsourcing are calculated according to intermediate products content
(composite film packaging inside puts 1 and is responsible for a task until it is completed drying prescription), obtains self-control preparation prepared by the present invention.
3 omeprazole enteric-coated capsules prepared by preparation method of the present invention (T1, T2) of embodiment and omeprazole enteric-coated capsules
Original grinds the In Vitro Dissolution Character Comparison of product (R)
The acid-resistant strength and dissolution determination method of omeprazole enteric-coated capsules are respectively discussed with reference to " Chinese Pharmacopoeia " version two in 2015, it is resistance to
Sour power, water, pH6.8 phosphate buffer use high performance liquid chromatography, and chromatographic condition is surveyed according to contents of Omeprazole enteric-coated capsule
Determine under item；Since omeprazole enteric-coated capsules are to have generated degradation during dissolution in pH6.0 phosphate buffer, adopt
It is not applicable with high effective liquid chromatography for measuring, therefore use determined by ultraviolet spectrophotometry.
High performance liquid chromatography chromatographic condition: being filler with octyl silane group silica gel；With 0.01mol/L phosphoric acid hydrogen
Two sodium solutions (with phosphorus acid for adjusting pH value to 7.6)-acetonitrile (75:25) is mobile phase；Detection wavelength is 302nm.
By table 8,9 result of table it is found that T1, T2 and omeprazole enteric-coated capsules original grind product (R) 2 hours in the hydrochloric acid solution of pH1.2
It hardly discharges, still, it is almost the same that the dissolution curve in pH6.0 and pH6.8 dissolution medium grinds product with original.
7 omeprazole enteric-coated capsules prepared by preparation method of the present invention (T1, T2) of embodiment and omeprazole enteric-coated capsules
Original grinds the accelerated test stability study comparison of product (R)
It takes omeprazole enteric-coated capsules original to grind product R and self-control preparation T1, T2, aluminum-plastic blister+desiccant+composite membrane is carried out to it
After packaging, it is 40 ± 2 DEG C in temperature, is placed in the climatic chamber of humidity RH75% ± 5%, in 0 month, 1 month, 2 months, 3
A month, 6 the end of month it is separately sampled primary, check its character, content, dissolution rate and related substance.
Table 10 is as the result is shown: it in temperature is 40 ± 2 DEG C by omeprazole enteric-coated capsules T1, T2 produced by the present invention, humidity RH75%
It is placed 6 months in ± 5% climatic chamber, the related substance of this product, dissolution rate and assay are showed no significant changes, with Austria
It is almost the same that beauty draws azoles capsulae enterosolubilis original to grind product (R).
8 empty stomach oral administration of embodiment omeprazole enteric-coated capsules prepared by preparation method of the present invention (T1, T2) and Omeprazole
Capsulae enterosolubilis original grinds product (R) in Pharmacokinetics investigation and comparison
It evaluates health volunteer and takes orally omeprazole enteric-coated capsules under fasting state by test preparation T1(specification: 20mg, lot number:
20170701 Zhuhai Rundu Pharmaceutical Co., Ltd.), by test preparation T2(specification: 20mg, lot number: 20171105, Zhu Hairun
All Pharmacy stock Co., Ltd), reference preparation R(specification: 20mg, lot number: YCLK, AstraZeneca pharmaceutical Co. Ltd) after
Pharmacokinetic characteristics and bioequivalence.
The Bioequivalence that this test is single oral dose, opening, three periods, three formulation tests design at random is ground
Study carefully.Dosage 20mg, cleans 5 days phases, and 15 subjects complete test.Blood sampling time point be administration before and administration after 0.33h,
0.67h、1.00h、1.33h、1.67h、2.00h、2.33h、2.67h、3.00h、3.50h、4.00h、5.00h、6.00h、
8.00h, 10.00h, 12.00,16.00h, 24.00h(totally 19 blood sampling points).
15 health volunteers are selected, are randomly divided into 3 groups, every group of 5 people.Subject demographic and order of administration are shown in Table
1.Selected subject fasting (at least 10 h of fasting) after dinner in 1 day before the test, unified administration in second day, test same day acquisition
After blank blood sample, empty stomach oral administration is by test preparation or reference preparation 1.240mL warm water delivery service is forbidden drinking water after medication in 2h,
4 h that take medicine are interior to keep upper body upright state, unified into low fat meal after 4h, 10h after medication.Ulnar vein is taken at a set point in time
Blood 4.0mL is placed in and has posted in the heparin sodium anticoagulant tube of label in advance, and 3500r min-1 is centrifuged 10min, and separated plasma sets-
20 DEG C of refrigerators save, and -80 DEG C of refrigerators are transferred to after taking a blood sample to a cycle and are saved.Subject during test fasting cigarette,
Wine, tea and various beverages avoid bed or strenuous exercise for a long time.
This test measures Determination of omeprazole in blood plasma using the LC-MS/MS measuring method by simply verifying.Blood plasma
Internal standard (deuterated Omeprazole) is added after melting naturally in sample, then handles sample with precipitation of protein.Take supernatant sample introduction point
Analysis separates analyte and internal standard using RP chromatography, and with triple level four bars Mass Spectrometer Methods.Simple verifying shows measuring method
Selectivity is good, and range of linearity preci-sion and accuracy is good, and matrix effect does not influence to measure.
This experiment quantifies unknown sample using calibration curve method, the standard curve concentration level of Omeprazole: 2-
1000ng/mL；Quality Control concentration level 2,6,60 and 800ng/mL.
Same all blood samples of subject one analysis batch in measurement, continuous mode analysis personnel are set it is blind, i.e., analysis people
Member is unaware of the corresponding relationship of sample and drug.Trial test biological sample is divided to two analyses batch to be measured, first analysis batch
Measure the plasma sample of subject 1-3, the plasma sample of second analysis batch measurement subject 4-6, third analysis batch measurement
The plasma sample of subject 7-9, the 4th analysis batch measurement subject 10-12 plasma sample, the 5th analysis batch measurement by
The plasma sample of examination person 13-15, the 6th analysis batch measurement suspicious specimen.Every subject each period after the completion of sample measures
Cmax nearby a little criticize with respectively selection is eliminated mutually by composition ISR analysis.
According to the accuracy data of measurement analysis batch standard curve and Quality Control sample, receive analysis data.ISR qualification rate is
94.4%。
Plasma drug concentration data is taken off according to clinical administration sequence list it is blind, take off it is blind after 15 subjects to take orally Omeprazole tested
Preparation see the table below with Determination of Omeprazole In Plasma after reference preparation-time data.
It can be seen that empty stomach oral administration omeprazole enteric-coated capsules produced by the invention (T1, T2) in people's intracorporal medicine generation from table 17, table 18
It is almost the same that kinetic parameter and original grind product, carries in T1 and increases Tween 80 and low-substituted hydroxypropyl cellulose on pill prescription, is made
Product (T2), Cmax and AUC have different degrees of promotion, still, product is still ground with original with bioequivalence.
It can be seen that empty stomach oral administration omeprazole enteric-coated capsules produced by the invention (T1, T2) in human body from table 19, table 20
The coefficient of variation relatively, illustrates that T1, T2 exist between the individual of interior pharmacokinetic parameter Cmax, AUClast, AUCINF_obs
The difference of pharmacokinetic parameter Cmax, AUClast, AUCINF_obs between individual are little.
But we can be concerned about Tmax with regard to entirely different: in 15 health volunteers, empty stomach oral administration original grinds product
The Tmax of the health volunteer of R substantially reached peak at 1.33-3 hours, and only No. 1 subject reaches peak in 4.5 hours blood concentrations,
This illustrates that the former comparison in difference for grinding the peak time of product between individuals is small.It is similar that product R situation is ground with original, and there are also by test preparation
T2.In 15 health volunteers, the Tmax that empty stomach oral administration makes the health volunteer of preparation T2 by oneself is substantially small in 1.33-2.67
Shi Dafeng, only No. 1 and No. 10 subjects reach peak in 3.5 and 4 hours blood concentrations.But T1 is entirely different with T2, R, on an empty stomach
The Tmax fluctuation range of the health volunteer of oral self-control preparation T1 is very wide, from 1 hour to 6 hour.This explanation, on an empty stomach
Oral omeprazole enteric-coated capsules make preparation T1 by oneself, and peak reaching time of blood concentration variation is very big between individual, that is to say, that between individual
It is widely different, it works within 1 hour after some health volunteers take medicine, and some possibility just worked at 6 hours.
By the comparative study of T1 and T2, it has been found that increase Tween 80 and low-substituted hydroxypropyl in the load pill core of T1
Base cellulose helps to eliminate the difference of peak reaching time of blood concentration between different health volunteers' individuals, allow drug action when
Between be more likely to consistent, and the formula of T2 is easy to industrialization, can manufacture good omeprazole enteric-coated of homogeneity between individual
Capsule.It is found by comparative study, when Tween 80 is only added in the prescription in T1 omeprazole enteric-coated micro-pill or low take only is added
For hydroxypropyl cellulose, the result that the consistency of drug effect time is obviously inferior to T2 (is studied according to the Tamx of T1 and T2
The Tmax of Tween 80 is only added between -5 hours 1 hour in method；The Tmax of low-substituted hydroxypropyl cellulose is only added in 1-4
Between hour), and it is not easy to industrialization, homogeneity is poor compared with T2 between individual.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of omeprazole enteric-coated micro-pill, which is characterized in that the omeprazole enteric-coated micro-pill is followed successively by Aomei from inside to outside
Azoles is drawn to carry pill core, separation layer and enteric layer, it includes Tween 80 and low-substituted hydroxypropyl cellulose that the Omeprazole, which carries pill core,.
2. a kind of omeprazole enteric-coated micro-pill according to claim 1, which is characterized in that the Omeprazole carries pill core
It further include Omeprazole, Lactis Anhydrous, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, high substitution hydroxypropylcellulose and dodecane
Base sodium sulphate.
3. a kind of omeprazole enteric-coated micro-pill according to claim 2, which is characterized in that the omeprazole enteric-coated micro-pill
The weight percent of middle Tween 80 and low-substituted hydroxypropyl cellulose be 1:3 ~ 5, preferably 1:3.5, low-substituted hydroxypropyl cellulose and
The weight percent of Omeprazole is 1:30 ~ 70, preferably 1:57.
4. a kind of omeprazole enteric-coated micro-pill according to any one of claims 1 to 3, which is characterized in that the separation layer
Including hydroxypropyl methylcellulose and water, hydroxypropyl methylcellulose packet is carried to the table of pill core by fluidized-bed coating machine in Omeprazole
Face.
5. a kind of omeprazole enteric-coated micro-pill according to claim 4, which is characterized in that the enteric layer includes Utech
L30D-55 aqueous dispersion, Macrogol 6000 and lauryl sodium sulfate and water, by fluidized-bed coating machine by hypromellose
Element packet is on the surface of separation layer.
6. a kind of omeprazole enteric-coated micro-pill according to claim 5, which is characterized in that the crystal form of the Omeprazole is
Type B, size distribution D90 < 10um, D50 < 3um.
7. a kind of omeprazole enteric-coated micro-pill according to claim 6, which is characterized in that the Omeprazole carries pill core
It is prepared using the technique of extrusion spheronization.
8. a kind of omeprazole enteric-coated capsules of the preparation of omeprazole enteric-coated micro-pill described in -7 according to claim 1, feature
It is, the omeprazole enteric-coated capsules include the omeprazole enteric-coated micro-pill and gelatine capsule shell, every Omeprazole intestines
Tween and low-substituted hydroxypropyl cellulose in colloidal sol capsule are no more than 1mg and 3.5mg respectively.
9. a kind of preparation method of omeprazole enteric-coated capsules as claimed in claim 8, which is characterized in that including walking as follows
It is rapid:
(1) preparation for carrying pill core, successively includes: stock-preparation granulation liquid-mixing-granulation-pill-drying-discharging-sieving；
(2) spacer layer coating successively includes: that after preparing spacer layer coating liquid, drug containing vegetable pill is put into multifunctional granulation coating machine
It is interior, set device parameter: blower frequency: 10~25Hz, inlet air temperature :≤70 DEG C, spacer ring height: 20~50mm, atomizing pressure:
1.2~3.5bar, fluid supply rotate speed: 10~200rpm；It controls temperature of charge: 35 ± 3 DEG C, carrying out spacer layer coating operation, isolation
Stop-spraying after layer coating solution has sprayed；It is dry later to discharge and be sieved；
(3) enteric layer is coated, and successively includes: to prepare enteric layer coating solution, and coating operations are sieved after dry discharging later；
(4) filling, plastic-aluminum, outsourcing.
10. a kind of preparation method of omeprazole enteric-coated capsules as claimed in claim 9, which is characterized in that described
Carry pill core the preparation method is as follows:
Stock: material is got from warehouse by regulation, mannitol is crushed, the screen mesh size of Highefficientpulverizer is
1.0mm, operator checks the name of an article, specification, the lot number, quantity of supplementary material, and after confirmation is errorless, each material is by batch production ordering rule
Fixed recipe quantity carries out weighing stock；
Prepare the operation of granulation liquid are as follows: under stirring, the disodium hydrogen phosphate of recipe quantity is added to the purified water of recipe quantity
In, after being stirred well to clear, the lauryl sodium sulfate and Tween 80 of recipe quantity is added, is stirred until homogeneous, without agglomeration
Afterwards, the Omeprazole of recipe quantity is added, it is stirring no less than 15 minutes, spare；
Mixing: taking mannitol, lactose, microcrystalline cellulose, height to replace hydroxypropylcellulose and each 1 part of low-substituted hydroxypropyl cellulose, according to
In secondary investment wet mixing pelletizer, technological parameter is set as " agitating paddle frequency 5-20Hz, granulating cutter frequency 1-10Hz ", mixing
About 600s, wait pelletize；
Granulation: weighing granulation liquid, sets technological parameter as " agitating paddle frequency 5-20Hz, granulating cutter frequency 1-10Hz " granulation, system
After grain, wet granular is transferred between pill；
Pill: after trial operation is normal, wet granular being put into extrusion spheronization machine, by " feed 10~40rpm of motor " " extruder motor
The parameter of 40~80rpm " " round as a ball 150~800rpm of motor " carries out pill operation；After completing pill operation, wet ball is shifted
To dry post；
It is dry: after trial operation is normal, the wet ball of collection is put into multifunctional granulation coating machine, set device parameter: blower frequency:
10~25Hz, inlet air temperature: it≤70 DEG C, sets temperature of charge: 40 DEG C, being dried；
Discharging: when dry materials are to moisture < 2.5%, dehumidifying is closed, closes heating, blower open state is kept, as temperature of charge < 35
DEG C, shut down discharging；
Sieving: crossing 14 mesh and 20 meshes for the drug containing vegetable pill dried respectively, collects 14 mesh to the drug containing vegetable pill between 20 mesh, claims
Weight, is put into desiccant between PE bags in two layers by then PE bags of housing black.
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| CN110882227A (en) * | 2019-12-26 | 2020-03-17 | 沈阳达善医药科技有限公司 | High-efficiency enteric coating composition and preparation method thereof |
| CN111150719A (en) * | 2019-12-30 | 2020-05-15 | 寿光富康制药有限公司 | Preparation method of omeprazole enteric capsule |
| CN111481525A (en) * | 2020-04-21 | 2020-08-04 | 广东一力罗定制药有限公司 | Omeprazole enteric-coated pellet and production process thereof |
| CN112957340A (en) * | 2021-02-09 | 2021-06-15 | 桂林华信制药有限公司 | Omeprazole enteric capsule and preparation method thereof |
| CN112999188A (en) * | 2019-12-19 | 2021-06-22 | 康普药业股份有限公司 | Omeprazole enteric-coated pellet and preparation method thereof |
| CN113855647A (en) * | 2021-10-29 | 2021-12-31 | 海南海灵化学制药有限公司 | Omeprazole microsphere shell-core enteric capsule and preparation process thereof |
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