CN104523641B - Lansoprazole intestine preparation and preparation method thereof - Google Patents
Lansoprazole intestine preparation and preparation method thereof Download PDFInfo
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- CN104523641B CN104523641B CN201410834496.2A CN201410834496A CN104523641B CN 104523641 B CN104523641 B CN 104523641B CN 201410834496 A CN201410834496 A CN 201410834496A CN 104523641 B CN104523641 B CN 104523641B
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Abstract
The invention belongs to field of medicaments, and in particular to a kind of proton pump inhibitor Lansoprazole intestine preparation and preparation method thereof.The property of Lansoprazole is highly unstable; it is improper to prepare or store; it can degrade rapidly, change colour; the curative effect and drug safety of drug are directly affected, to solve the above-mentioned problems, enteric coated preparations of the present invention are using Lansoprazole as main ingredient; it is prepared using three layers of coating; three layers of coatings are respectively as follows: alkaline protective layer, separation layer, enteric layer from the inside to the outside；Wherein: alkaline protective layer includes film forming agent, lubricant, opacifier, alkaline stabiliser, solvent, and the pH value of coating solution is 8.0~13.0；Separation layer includes film forming agent, lubricant, plasticizer, opacifier, solvent, and the pH value of coating solution is 7.0~8.0；Enteric layer includes film forming agent, plasticizer, lubricant, opacifier, stabilizer, solvent, and the pH value of coating solution is 5.0~6.0.The present invention has life cycle of the product short, and small feature is influenced by environment, temperature and humidity, dust pollution.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of proton pump inhibitor Lansoprazole intestine preparation and its preparation side
Method.
Background technique
The chemical structural formula of Lansoprazole are as follows:
Chemical name: 5- methoxyl group -2- { [(- 2 pyridyl group of 4- methoxyl group -3,5- dimethyl)-methyl] sulfinyl } -1H-
Benzimidazole.
It is monoalkoxy pyridine compounds for clinical benzimidazole class PPI that Lansoprazole, which is first, after the 2h that takes medicine
Plasma concentration reaches peak, half-life period about 1h.The bioavilability of single dose is 35%, and multi-dose bioavilability increases to 60%.
The potent inhibitor of film inner proton pump is secreted for parietal cell tip, Lansoprazole is suitable for gastric ulcer, duodenal ulcer, erosive
Stomach-esophageal reflux disease, helicobacter pylori syndrome.Present clinical application is most widely Lansoprazole enteric-coated tablet.Due to
Its strength Acidinhibitor makes some cankers for being previously required to operative treatment that healing can be obtained by this drug therapy.
Lansoprazole is unstable under acidic condition, into stomach, can be destroyed by gastric acid；Acid, wet, hot and illumination
Under the conditions of, it can all degrade rapidly.The Lansoprazole enteric-coated tablet of preparation, if storage requirement is improper, product can be during storage
It degrades.The existing technology for preparing Lansoprazole enteric-coated tablet, in process of production or in product storage process, is produced from centre
Perhaps the character of finished product label changes and becomes yellowish or grey product.Contaminant overstandard, there are security-hidden troubles.
The present invention is intended to provide a kind of completely new Lansoprazole intestine preparation and preparation method thereof, to improve the steady of Lansoprazole
It is qualitative, reduce storage process mesometamorphism the phenomenon that.
Summary of the invention
The property of Lansoprazole is highly unstable, and it is improper to prepare or store, and can degrade rapidly, change colour, directly affect drug
Curative effect and drug safety, present inventor has carried out the technical study of many years thus, provides a kind of completely new blue rope
Draw azoles enteric coated preparations and preparation method thereof.
Lansoprazole intestine preparation of the present invention, it is characterised in that: it is to be made using Lansoprazole as main ingredient using three layers of coating
Standby to form, three layers of coatings are respectively as follows: alkaline protective layer, separation layer, enteric layer from the inside to the outside；Wherein:
Alkaline protective layer includes film forming agent, lubricant, opacifier, alkaline stabiliser, solvent, and the pH value of coating solution is 8.0
~13.0 (preferably 10.0~12.0)；
Separation layer includes film forming agent, lubricant, plasticizer, opacifier, solvent, and the pH value of coating solution is 7.0~8.0；
Enteric layer includes film forming agent, plasticizer, lubricant, opacifier, stabilizer, solvent, and the pH value of coating solution is 5.0~
6.0。
Wherein, the alkaline protective layer each component weight proportion are as follows: film forming agent 4~10%, lubricant 1~5%, opacifier
0.5~3%, alkaline stabiliser 0.5~3%, solvent 80~95%；The pH value of coating solution be 8.0~13.0 (preferably 10.0~
12.0)；
It is preferred that alkaline protective layer each component weight proportion are as follows: film forming agent 5~7%, lubricant 2~2.5%, opacifier 0.8
~1.5%, alkaline stabiliser 0.5~0.8%, solvent 80~90%；The pH value of coating solution be 8.0~13.0 (preferably 10.0~
12.0)；
Most preferably, alkaline protective layer each component weight proportion are as follows: film forming agent 5.94%, lubricant 2.28%, opacifier
1.19%, alkaline stabiliser 0.59%, solvent 90%；The pH value of coating solution is 8.0~13.0 (preferably 10.0~12.0)；
Wherein, the separation layer each component weight proportion are as follows: film forming agent 4~10%, lubricant 1~5%, opacifier 0.5
~3%, solvent 80~95%, the pH value of coating solution is 7.0~8.0；
It is preferred that separation layer each component weight proportion are as follows: film forming agent 5~7%, lubricant 2~4%, opacifier 0.8~
1.5%, solvent 80~90%；The pH value of coating solution is 7.0~8.0；
Most preferably, separation layer each component weight proportion are as follows: film forming agent 5.88%, lubricant 2.94%, opacifier 1.18%,
Solvent 90%；The pH value of coating solution is 7.0~8.0；
Wherein, the enteric layer each component weight proportion are as follows: film forming agent 3~8%, plasticizer 1~3%, lubricant 1~
5%, opacifier 0.5~3%, stabilizer 0.5~3%, solvent 80~95%；The pH value of coating solution is 5.0~6.0；
It is preferred that enteric layer each component weight proportion are as follows: film forming agent 3~5%, plasticizer 1~2%, lubricant 1~3% hide
Photo etching 1.5~2.5%, stabilizer 0.5~1%, solvent 80~90%；The pH value of coating solution is 5.0~6.0；
Most preferably, enteric layer each component weight proportion are as follows: film forming agent 4.23%, plasticizer 1.76%, lubricant 2.12%,
Opacifier 2.30%, stabilizer 0.71%, solvent 88.88%；The pH value of coating solution is 5.0~6.0.
Wherein, lubricant can also be used as antiplastering aid use.
Key point of the invention is to use alkaline protective layer-three layers of separation layer-enteric layer coated systems, establish
Good coating procedure, formulates suitable technological parameter, and product appearance obtained is smooth, rounding, has gloss, while having three
The protection of layer coating, can influence to avoid moisture, air, light to label, the quality of product is more stable.Pass through this function
Energy property coating, not only protects label, also achieves drug positioning release, reduces destruction of the gastric acid to main component, improve
The clinical efficacy of product.
In coated systems of the present invention, film forming agent described in alkaline protective layer is hydroxypropyl methylcellulose, ethyl cellulose, poly- dimension
At least one of ketone, methylcellulose, hydroxypropylcellulose；It is preferred that hydroxypropyl methylcellulose；
Lubricant described in alkaline protective layer is at least one of talcum powder, silica, polyethylene glycol, magnesium stearate；
Preferably talc powder；
Opacifier described in alkaline protective layer is titanium dioxide, in iron oxide (iron oxide can also be used as colorant use)
It is at least one；It is preferred that titanium dioxide；
Alkaline stabiliser described in alkaline protective layer is calcium carbonate, sodium carbonate, sodium bicarbonate, calcium oxide, calcium hydroxide, smart ammonia
At least one of acid, meglumine, magnesia, magnesium hydroxide, disodium hydrogen phosphate, sodium phosphate, sodium hydroxide；It is preferred that magnesia；
Solvent described in alkaline protective layer is water, 50-90%v/v ethanol solution；It is preferred that 60~80%v/v ethanol solution；
Film forming agent described in separation layer is hydroxypropyl methylcellulose, ethyl cellulose, povidone, methylcellulose, hydroxypropyl fiber
At least one of element；It is preferred that hydroxypropyl methylcellulose；
Lubricant described in separation layer is at least one of talcum powder, silica, polyethylene glycol, magnesium stearate；It is preferred that
Talcum powder or polyethylene glycol；
Separation layer the plasticizer is at least one of polyethylene glycol, phthalate；It is preferred that polyethylene glycol；
Opacifier described in separation layer is titanium dioxide, (iron oxide can also be used as colorant use) at least in iron oxide
It is a kind of；It is preferred that titanium dioxide；
Solvent described in separation layer is water, 50-90%v/v ethanol solution；It is preferred that 60~80%v/v ethanol solution；
Film forming agent described in enteric layer is at least one of polyacrylic resin, hypromellose phthalate；It is preferred that poly-
Acrylic resin；
Enteric layer the plasticizer is at least one of castor oil, polyethylene glycol, diethyl phthalate；It is preferred that castor
Sesame oil；
Lubricant described in enteric layer is at least one of talcum powder, silica, magnesium stearate；Preferably talc powder；
Opacifier described in enteric layer is at least one of titanium dioxide, iron oxide；It is preferred that titanium dioxide；
Stabilizer described in enteric layer is at least one of polysorbate, poloxamer；It is preferred that polysorbate；
Solvent described in enteric layer is water, 50-90%v/v ethanol solution；It is preferred that 60~80%v/v ethanol solution.
In order to which application is convenient, beautiful, enteric layer further includes colorant；Colorant described in enteric layer be iron oxide, in pigment extremely
Few one kind；It is preferred that iron oxide.
Lansoprazole intestine preparation of the present invention is prepared using following methods:
A, using Lansoprazole as main ingredient, using filler, stabilizer, disintegrating agent, adhesive, lubricant as auxiliary material；
B, particle is prepared according to a conventional method, then tabletting, label is made；
C, three layers of coatings are successively wrapped, are drying to obtain；
Preferably: steps are as follows for method one:
A, by Lansoprazole, filler, stabilizer, adhesive, particle is made in the disintegrating agent of 1/2-2/3 amount, dry,
B, after mixing particle with lubricant, remaining disintegrating agent, label is made in tabletting according to a conventional method；
C, three layers of coatings are successively wrapped, are drying to obtain；
Preferably: steps are as follows for method two:
A, auxiliary material filler, stabilizer, the disintegrating agent of 1/2-2/3 amount, adhesive is taken to prepare particle, it is dry；
B, Lansoprazole, lubricant, remaining disintegrating agent are taken, is mixed with particle, according to a conventional method tabletting, label is made；
C, three layers of coatings are successively wrapped, are drying to obtain.
Wherein, in method one and method two, when step A, preparing tablet in B, the weight of main ingredient Lansoprazole and each auxiliary material
Percentage are as follows:
It is preferred that the weight percent of main ingredient Lansoprazole and each auxiliary material are as follows:
Or, it is preferable that the weight percent of main ingredient Lansoprazole and each auxiliary material are as follows:
Wherein, dry described in step C is control label or pellet moisture less than 1%.
Wherein, in preferred method one and method two, dry described in step A is that particle is dry at 50 DEG C or less.
Lansoprazole intestine preparation coatings weight gain of the present invention: alkaline protective layer weight gain 2~3%；Separation layer weight gain 2~
3%；Enteric layer weight gain 12~15%.
Lansoprazole intestine preparation of the present invention is by preparing point of sample and long-term reserved sample observing and accelerated test result
Analysis, inventor have screened excellent filler (also referred to as diluent), stabilizer.Institute in the step A of method one and method two
Stating auxiliary material filler is mannitol, lactose, microcrystalline cellulose, pregelatinized starch, preferably mannitol and/or lactose；The stabilization
Agent is calcium carbonate, sodium carbonate, sodium bicarbonate, calcium oxide, calcium hydroxide, arginine, meglumine, magnesia, magnesium hydroxide, phosphoric acid
Disodium hydrogen, sodium phosphate, sodium hydroxide, preferably magnesia.The disintegrating agent is calcium carboxymethylcellulose, carboxyrnethyl starch sodium, crosslinking
Povidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, preferably crospovidone；Described adhesive is hydroxypropyl first
Cellulose, povidone, methylcellulose, starch slurry, preferably hydroxypropyl methylcellulose；It is living using surface can also be added when adhesive
With addition of using, polyoxyethylene sorbitan monoleate, poloxamer, lauryl sodium sulfate is can be used in the surface-active for property agent；It is preferred that pool Lip river is husky
Nurse；That is the preferred hydroxypropyl methylcellulose of adhesive and poloxamer is with addition of using.Lubricant is that magnesium stearate talc stearoyl is rich
Horse acid sodium, preferably magnesium stearate.The mouldability and Lansoprazole that filler has had have good compatibility, to Lansoprazole
The stability of material composition in enteric coatel tablets does not have adverse effect.Stabilizer can be protected in Lansoprazole enteric-coated tablet well
Material composition Lansoprazole prevents Lansoprazole degradation, discoloration.Equally, inventor has screened adhesive, disintegrating agent, lubrication
Agent, these ingredients are conducive to formed product, are also beneficial to main release in tablet, while meeting appearance and inherent quality
It is required that.
The moisture of Lansoprazole intestine preparation, the especially moisture in label and particle are reduced to effectively controlling related substance
It generates, prevents mass change from having a significant impact, inventor has found that control moisture is down to 1% or less and can realize quality control very well
Purpose.
Method one is typical wet granulation technology；Method two is the preparation work of tabletting after blank granules are mixed with raw material
Skill: after blank granules processed, then mixing with main ingredient, lubricant, disintegrating agent, avoids Lansoprazole raw material in granulation link by damp and hot
Influence prevent impurity from generating conducive to the stabilization of preparation.
By a series of technology exploration, process modification, have life cycle of the product short, it is dirty by environment, temperature and humidity, dust
The small feature of the influence of dye, fully ensure that stable product quality.Lansoprazole intestine preparation provided by the invention at 40 DEG C,
Under conditions of relative humidity 75%, accelerated test 6 months, label was non-discolouring, and single impurity is no more than 0.3%, and total impurities do not surpass
Cross 0.6%.The regulation that other indices are met the quality standard；Room temperature keeps sample 3 years, and label is non-discolouring, other indices
The regulation met the quality standard.Especially, within defined storage period, product quality keeps stablizing, and complies fully with quality and wants
It asks.
Specific embodiment
There are two types of different technical solutions when the present invention prepares particle
(1) preparation method one
1, the composition of label:
| Main ingredient ingredient | Filler | Stabilizer | Disintegrating agent | Adhesive | Lubricant |
| Lansoprazole | Mannitol and/or lactose | Magnesia | Crospovidone | Hydroxypropyl methylcellulose is with addition of poloxamer | Magnesium stearate |
Filler of the present invention includes: mannitol, lactose, microcrystalline cellulose, pregelatinized starch etc., by technique system
Standby and stability test, preferably mannitol and/or lactose.
Stabilizer of the present invention include: calcium carbonate, sodium carbonate, sodium bicarbonate, calcium oxide, calcium hydroxide, arginine,
Meglumine, magnesia, magnesium hydroxide, disodium hydrogen phosphate, sodium phosphate, sodium hydroxide etc., by technique preparation and stability test,
It is preferred that magnesia.
Disintegrating agent of the present invention includes: calcium carboxymethylcellulose, carboxyrnethyl starch sodium, crospovidone, crosslinking carboxylic first
Base sodium cellulosate, (low substitution) hydroxypropylcellulose etc., by technique preparation and stability test, preferably crospovidone.
Adhesive of the present invention includes: hydroxypropyl methylcellulose, povidone, methylcellulose, starch slurry etc., by work
Skill preparation and study on the stability, preferably hydroxypropyl methylcellulose.Using surfactant can also be added when adhesive with addition of using,
Polyoxyethylene sorbitan monoleate, poloxamer, lauryl sodium sulfate can be used in the surface-active；It is preferred that poloxamer；I.e. adhesive is excellent
Select hydroxypropyl methylcellulose and poloxamer with addition of using.
Lubricant of the present invention includes: magnesium stearate talc sodium stearyl fumarate, by technique preparation and surely
Qualitative test, preferably magnesium stearate.
2, preparation method
Lansoprazole is uniformly mixed with filler, stabilizer, partial disintegration agent, is placed in granulator, adhesive is added,
It is mixed, softwood is made, then by 20 mesh screens, particle is made, in 50 DEG C or less dry particles, remaining disintegrating agent is added
And lubricant, tabletting, then be coated.
3, three layers of coating: according to coating material characteristic, preferably different coating compositions.
First layer: alkaline protective layer
It is coated composition:
The characteristics of alkaline protective layer coating solution be pH value between 8.0~13.0, preferably 10.0~12.0.
The second layer: separation layer
It is coated composition:
The characteristics of spacer layer coating liquid, is pH value between 7.0~8.0.
Third layer: enteric layer (function coatings)
It is coated composition:
The characteristics of enteric layer coating solution, is pH value between 5.0~6.0.
Coating process: coating material is dissolved or is distributed in defined solvent, is stirred evenly, is sieved, then according to packet
Clothing operation requires to be coated respectively.Three layers of coating are completed altogether.
The drying of coating tablet: dry to label moisture 1% hereinafter, entering packaging link.
(2) preparation method two
The characteristics of program is that Lansoprazole raw material is not involved in pelletization, can be to avoid the damp and hot influence to raw material.
1, the composition of label: identical as technical solution one, detailed content is formed referring to the label in technical solution one.
2, filler, stabilizer, partial disintegration agent are uniformly mixed by preparation method, are placed in efficient mixer-granulator, are added
Enter adhesive, be mixed, be made softwood, then by 24 mesh screens, particle is made, in 50 DEG C or less dry particles, then with orchid
Rope draws azoles, remaining disintegrating agent, mix lubricant uniform, tabletting, then is coated.
3, three layers of coating: according to coating material characteristic, preferably different coating compositions.
First layer: alkaline protective layer
It is coated composition:
The characteristics of alkaline protective layer coating solution be pH value between 8.0~13.0, preferably 10.0~12.0.
The second layer: separation layer
It is coated composition:
The characteristics of spacer layer coating liquid, is pH value between 7.0~8.0.
Third layer: enteric layer (function coatings)
It is coated composition:
The characteristics of enteric layer coating solution, is pH value between 5.0~6.0.
Coating process: coating material is dissolved or is distributed in defined solvent, is stirred evenly, is sieved, then according to packet
Clothing operation requires to be coated respectively.Three layers of coating are completed altogether.
The drying of coating tablet: dry to label moisture 1% hereinafter, entering packaging link.
The following are the stability tests for investigating enteric coated preparations beneficial effect of the present invention.
Be respectively adopted after preparation plain piece three layers, two layers and single coats prescription simultaneously amplified using different preparation methods
Amount is verified.
PH value measurement is carried out to the coating solution of all coatings, the pH value for verifying different coatings is limiting in range.
6 months study on the stability of accelerated test are carried out to the sample of all embodiments, to the character, content, release of sample
Degree, acid-resistant strength, related substance are detected, and obtain data, and the sample quality of different embodiments is compared.
(1) three layer of coating embodiment
Embodiment 1-5
Preparation method (method one):
1) micronization processes Lansoprazole；
2) Lansoprazole, magnesia, crospovidone are mixed, No. 5 sieves is then crossed, makes color uniformity；Add cream
Sugar, mannitol mixing, sieve after No. 5, make color uniformity；
3) be added adhesive softwood, 20 mesh screen oscillating granulations, 50 DEG C drying 1 hour.Moisture 1.5-2.5% is controlled,
20 mesh screen whole grains；
4) magnesium stearate is added, sieving is uniformly mixed；
5) suitable hardness and friability tabletting: are controlled.Hardness 4-6kg, friability are no more than 0.3%；
6) it is coated: according to the coating prescription in table, preparing coating solution, implement coating；
7) after the completion of being coated, dry coationg piece to moisture is less than 1%, packaging.
Embodiment 6-10
Preparation method (method two):
1) Lansoprazole is taken, No. 5 pharmacopeia sieves (80 mesh) are crossed；
2) poloxamer F68 is mixed, No. five pharmacopeia sieves are crossed；
3) said mixture is mixed with unclassified stores, is sieved 1-2 times after No. 3 pharmacopeia, makes mixed-powder color uniform one
It causes；
4) suitable hardness and friability tabletting: are controlled.Hardness 4-6kg, friability are no more than 0.3%；
5) it is coated: according to the coating prescription in table, preparing coating solution, implement coating；
6) after the completion of being coated, dry coationg piece to moisture is less than 1%, packaging.
(2) two-layered coating embodiment
Embodiment 11-12
Preparation method (method one):
1) micronization processes Lansoprazole；
2) Lansoprazole, magnesia, crospovidone are mixed, No. 5 sieves is then crossed, makes color uniformity；Add cream
Sugar, mannitol mixing, sieve after No. 5, make color uniformity；
3) be added adhesive softwood, 20 mesh screen oscillating granulations, 50 DEG C drying 1 hour.Moisture 1.5-2.5% is controlled,
20 mesh screen whole grains；
4) magnesium stearate is added, sieving is uniformly mixed；
5) suitable hardness and friability tabletting: are controlled.Hardness 4-6kg, friability are no more than 0.3%；
6) it is coated: according to the coating prescription in table, preparing coating solution, implement coating；
7) after the completion of being coated, dry coationg piece to moisture is less than 1%, packaging.
Embodiment 13-14
Preparation method (method two):
1) Lansoprazole is taken, No. 5 pharmacopeia sieves (80 mesh) are crossed；
2) poloxamer F68 is mixed, No. five pharmacopeia sieves are crossed；
3) said mixture is mixed with unclassified stores, is sieved 1-2 times after No. 3 pharmacopeia, makes mixed-powder color uniform one
It causes；
4) suitable hardness and friability tabletting: are controlled.Hardness 4-6kg, friability are no more than 0.3%；
5) it is coated: according to the coating prescription in table, preparing coating solution, implement coating；
6) after the completion of being coated, dry coationg piece to moisture is less than 1%, packaging.
(3) single coats embodiment
Embodiment 15-16
Preparation method (method one):
1) micronization processes Lansoprazole；
2) Lansoprazole, magnesia, crospovidone are mixed, No. 5 sieves is then crossed, makes color uniformity；Add cream
Sugar, mannitol mixing, sieve after No. 5, make color uniformity；
3) be added adhesive softwood, 20 mesh screen oscillating granulations, 50 DEG C drying 1 hour.Moisture 1.5-2.5% is controlled,
20 mesh screen whole grains；
4) magnesium stearate is added, sieving is uniformly mixed；
5) suitable hardness and friability tabletting: are controlled.Hardness 4-6kg, friability are no more than 0.3%；
6) it is coated: according to the coating prescription in table, preparing coating solution, implement coating；
7) after the completion of being coated, dry coationg piece to moisture is less than 1%, packaging.
Embodiment 17-18
Preparation method (method two):
1) Lansoprazole is taken, No. 5 pharmacopeia sieves (80 mesh) are crossed；
2) poloxamer F68 is mixed, No. five pharmacopeia sieves are crossed；
3) said mixture is mixed with unclassified stores, is sieved 1-2 times after No. 3 pharmacopeia, makes mixed-powder color uniform one
It causes；
4) suitable hardness and friability tabletting: are controlled.Hardness 4-6kg, friability are no more than 0.3%；
5) it is coated: according to the coating prescription in table, preparing coating solution, implement coating；
6) after the completion of being coated, dry coationg piece to moisture is less than 1%, packaging.
Hydroxypropylcellulose in embodiment 1-18 is (low substitution) hydroxypropylcellulose.
(4) detection data after 0 month detection data of the test specimen of each embodiment and study on the stability:
1, three layers of coating 0 month detection data of test specimen:
| Serial number | Piece disposition shape | Content | Release | Acid-resistant strength | Single impurity | Total impurities |
| 1 | White | 98.3% | 96.2% | 98.3% | 0.079% | 0.42% |
| 2 | White | 101.2% | 97.1% | 99.2% | 0.061% | 0.39% |
| 3 | White | 100.4% | 98.3% | 99.6% | 0.064% | 0.35% |
| 4 | White | 99.1% | 97.2% | 97.3% | 0.087% | 0.51% |
| 5 | White | 99.4% | 97.9% | 99.2% | 0.063% | 0.34% |
| 6 | White | 100.3% | 97.3% | 99.6% | 0.094% | 0.49% |
| 7 | White | 99.3% | 96.2% | 98.3% | 0.082% | 0.33% |
| 8 | White | 100.2% | 97.1% | 99.2% | 0.083% | 0.37% |
| 9 | White | 100.2% | 98.3% | 99.6% | 0.094% | 0.53% |
| 10 | White | 99.3% | 96.2% | 95.3% | 0.078% | 0.51% |
10 batches of three layers of sample coatings: every Testing index meets regulation, and single impurity average level 0.0785% is total miscellaneous
Matter average level 0.424%.
2,0 month detection data of two-layered coating test specimen
| Serial number | Piece disposition shape | Content | Release | Acid-resistant strength | Single impurity | Total impurities |
| 11 | White | 101.8% | 97.5% | 98.4% | 0.083% | 0.57% |
| 12 | White | 99.3% | 96.5% | 98.4% | 0.091% | 0.46% |
| 13 | White | 99.6% | 94.5% | 98.4% | 0.093% | 0.52% |
| 14 | White | 100.5% | 95.5% | 96.4% | 0.094% | 0.48% |
4 batches of sample two-layered coatings: every Testing index meets regulation, single average level 0.0903%, and total impurities are put down
Equal level 0.51%.
3,0 month detection data of single coats test specimen
| Serial number | Piece disposition shape | Content | Release | Acid-resistant strength | Single impurity | Total impurities |
| 15 | The piece central layer contacted with coatings has light grey spot | 100.3% | 96.4% | 97.6% | 0.144% | 0.67% |
| 16 | The piece central layer contacted with coatings has light grey spot | 97.2% | 95.4% | 96.3% | 0.127% | 0.66% |
| 17 | The piece central layer contacted with coatings has light grey spot | 98.2% | 94.2% | 95.3% | 0.162% | 0.82% |
| 18 | The piece central layer contacted with coatings has light grey spot | 101.2% | 97.5% | 98.4% | 0.125% | 0.78% |
4 batches of sample single coats: piece disposition shape is undesirable, other every Testing index meet regulation, single flat
Equal level 0.14%, total impurities average level 0.73%.
(5) 6 months detection datas (40 DEG C, relative humidity 75%) of the test specimen accelerated test of each embodiment:
1, three layers of coating 6 months accelerated test detection data of test specimen:
| Serial number | Piece disposition shape | Content | Release | Acid-resistant strength | Single impurity | Total impurities |
| 1 | White | 99.4% | 96.2% | 98.1% | 0.079% | 0.54% |
| 2 | White | 101.2% | 97.1% | 99.2% | 0.068% | 0.46% |
| 3 | White | 99.3% | 98.3% | 94.6% | 0.074% | 0.37% |
| 4 | White | 99.1% | 97.2% | 97.3% | 0.097% | 0.51% |
| 5 | White | 98.3% | 97.9% | 94.2% | 0.073% | 0.39% |
| 6 | White | 102.3% | 97.3% | 99.6% | 0.094% | 0.47% |
| 7 | White | 99.3% | 96.2% | 97.3% | 0.082% | 0.43% |
| 8 | White | 98.9% | 97.1% | 95.2% | 0.082% | 0.37% |
| 9 | White | 100.2% | 98.3% | 99.6% | 0.104% | 0.48% |
| 10 | White | 100.4% | 96.2% | 95.3% | 0.088% | 0.61% |
10 batches of three layers of sample coatings: after accelerating 6 months, every Testing index meets regulation.Single impurity average level
0.0841%, total impurities average level 0.463%.
2,6 months accelerated test detection datas of two-layered coating test specimen
| Serial number | Piece disposition shape | Content | Release | Acid-resistant strength | Single impurity | Total impurities |
| 11 | White (part is yellowish) | 99.8% | 95.5% | 93.5% | 0.15% | 0.67% |
| 12 | White (part is yellowish) | 99.3% | 94.5% | 93.4% | 0.14% | 0.56% |
| 13 | White (part is light yellow) | 99.0% | 97.5% | 94.4% | 0.21% | 0.73% |
| 14 | White (part is yellowish) | 101.5% | 97.1% | 95.2% | 0.14% | 0.58% |
4 batches of sample two-layered coatings, after accelerating 6 months, the piece heart has changed colour, single impurity average level 0.162%, total impurities
Level 0.635%.
3,6 months accelerated test detection datas of single coats test specimen
| Serial number | Piece disposition shape | Content | Release | Acid-resistant strength | Single impurity | Total impurities |
| 15 | Piece heart gray | 100.3% | 96.4% | 97.6% | 0.274% | 1.47% |
| 16 | Piece heart gray | 97.2% | 95.4% | 96.3% | 0.317% | 2.06% |
| 17 | Piece heart gray | 98.2% | 94.2% | 95.3% | 0.362% | 1.72% |
| 18 | The piece heart is in canescence | 101.2% | 97.5% | 98.4% | 0.245% | 0.98% |
4 batches of sample single coats: the piece heart has changed colour, single average level 0.299%, total impurities average level 1.56%.
From testing result it can be seen that
1, three layers of product quality being coated and stability are better than two-layered coating, hence it is evident that are better than single coats.
2, the two-layered coating related levels of substance of sample and three layers of coating difference at 0 month are little, but at accelerated test 6
Month after, can see with the piece central layer that coatings directly contact it is light yellow or yellowish, and the piece central layer of single coats present ash
White or grey, and related levels of substance is apparently higher than the sample of two-layered coating and three layers of coating.
3, two-layered coating and single coats sample, after accelerated test 6 months, related levels of substance is apparently higher than three layers of packet
Clothing.
The Lansoprazole intestine prepared using Lansoprazole enteric-coated tablet prepared by technology of the invention with other techniques
Piece is compared, and has following advantages；
1, moisture is low, and moisture is usually no more than 1%.
2, preparation stabilization accelerates 6 months, and piece heart color is no more than 0.1% without significant change, single impurity, and total impurities are not
More than 0.5%.
3, it stores 3 years, label character is still white or off-white color, no metachromatism.Impurity, related substance, release
Degree, the items quality index such as acid-resistant strength meet the requirements.
Claims (16)
1. Lansoprazole intestine preparation, it is characterised in that: it is using Lansoprazole as main ingredient, and routinely particle is made in process
Afterwards, then tabletting or encapsulated is prepared using three layers of coating, three layers of coatings are respectively as follows: alkaline protective layer from the inside to the outside,
Separation layer, enteric layer；Wherein:
The alkalinity protective layer includes film forming agent, lubricant, opacifier, alkaline stabiliser and solvent, each component weight proportion are as follows:
Film forming agent 4~10%, lubricant 1~5%, opacifier 0.5~3%, alkaline stabiliser 0.5~3%, solvent 80~95%；Packet
The pH value of clothing liquid is 8.0~13.0；
The separation layer includes film forming agent, lubricant, opacifier and solvent, each component weight proportion are as follows: film forming agent 4~10%,
Lubricant 1~5%, opacifier 0.5~3%, solvent 80~95%, the pH value of coating solution are 7.0~8.0；
The enteric layer includes film forming agent, plasticizer, lubricant, opacifier, stabilizer and solvent, each component weight proportion are as follows:
Film forming agent 3~8%, plasticizer 1~3%, lubricant 1~5%, opacifier 0.5~3%, stabilizer 0.5~3%, solvent 80~
95%；The pH value of coating solution is 5.0~6.0；
The enteric coated preparations are prepared using following methods:
A, using Lansoprazole as main ingredient, using filler, stabilizer, disintegrating agent, adhesive, lubricant as auxiliary material；
B, particle is prepared according to a conventional method, then tabletting or encapsulated, label or capsule is made；
C, three layers of coatings are successively wrapped, are drying to obtain；
Wherein, it includes two methods that conventional method, which prepares particle:
Steps are as follows for method one:
A, by Lansoprazole, filler, stabilizer, adhesive, particle is made in the disintegrating agent of 1/2-2/3 amount, dry,
B, after mixing particle with lubricant, remaining disintegrating agent, label or glue is made in tabletting or encapsulated according to a conventional method
Capsule；
C, three layers of coatings are successively wrapped, are drying to obtain；
Steps are as follows for method two:
A, auxiliary material filler, stabilizer, the disintegrating agent of 1/2-2/3 amount, adhesive is taken to prepare particle, it is dry；
B, Lansoprazole, lubricant, remaining disintegrating agent are taken, is mixed with particle, tabletting or encapsulated, is made piece according to a conventional method
Core or capsule；
C, three layers of coatings are successively wrapped, are drying to obtain；
In the step A and step B of method one and method two: the auxiliary material filler is mannitol and/or lactose；The stabilizer
For magnesia；The disintegrating agent is crospovidone；Described adhesive is hydroxypropyl methylcellulose；Surface is added in described adhesive
For activating agent with addition of using, the surface-active uses poloxamer；Lubricant is magnesium stearate；It is dry for control described in step C
Label or capsule endoparticle moisture are less than 1%.
2. Lansoprazole intestine preparation according to claim 1, it is characterised in that:
The alkalinity protective layer each component weight proportion are as follows: film forming agent 5~7%, lubricant 2~2.5%, opacifier 0.8~
1.5%, alkaline stabiliser 0.5~0.8%, solvent 80~90%；The pH value of coating solution is 8.0~13.0；
The separation layer each component weight proportion are as follows: film forming agent 5~7%, lubricant 2~4%, opacifier 0.8~1.5% are molten
Agent 80~90%；The pH value of coating solution is 7.0~8.0；
The enteric layer each component weight proportion are as follows: film forming agent 3~5%, plasticizer 1~2%, lubricant 1~3%, opacifier
1.5~2.5%, stabilizer 0.5~1%, solvent 80~90%；The pH value of coating solution is 5.0~6.0.
3. Lansoprazole intestine preparation according to claim 1, it is characterised in that:
The alkalinity protective layer each component weight proportion are as follows: film forming agent 5.94%, lubricant 2.28%, opacifier 1.19%, alkali
Property stabilizer 0.59%, solvent 90%；The pH value of coating solution is 8.0~13.0；
The separation layer each component weight proportion are as follows: film forming agent 5.88%, lubricant 2.94%, opacifier 1.18%, solvent
90%；The pH value of coating solution is 7.0~8.0；
The enteric layer each component weight proportion are as follows: film forming agent 4.23%, plasticizer 1.76%, lubricant 2.12%, opacifier
2.30%, stabilizer 0.71%, solvent 88.88%；The pH value of coating solution is 5.0~6.0.
4. Lansoprazole intestine preparation according to claim 1-3, it is characterised in that: the alkalinity protective layer
The pH value of coating solution preferably 10.0~12.0.
5. Lansoprazole intestine preparation according to claim 1-3, it is characterised in that:
Wherein, film forming agent described in alkaline protective layer is hydroxypropyl methylcellulose, ethyl cellulose, povidone, methylcellulose, hydroxypropyl
At least one of cellulose；
Lubricant described in alkaline protective layer is at least one of talcum powder, silica, polyethylene glycol, magnesium stearate；
Opacifier described in alkaline protective layer is at least one of titanium dioxide, iron oxide；
Alkaline stabiliser described in alkaline protective layer be calcium carbonate, sodium carbonate, sodium bicarbonate, calcium oxide, calcium hydroxide, arginine,
At least one of meglumine, magnesia, magnesium hydroxide, disodium hydrogen phosphate, sodium phosphate, sodium hydroxide；
Solvent described in alkaline protective layer is water, 50-90%v/v ethanol solution；
Wherein, film forming agent described in separation layer is hydroxypropyl methylcellulose, ethyl cellulose, povidone, methylcellulose, hydroxypropyl fiber
At least one of element；
Lubricant described in separation layer is at least one of talcum powder, silica, polyethylene glycol, magnesium stearate；
Opacifier described in separation layer is at least one of titanium dioxide, iron oxide；
Solvent described in separation layer is water, 50-90%v/v ethanol solution；
Wherein, film forming agent described in enteric layer is at least one of polyacrylic resin, hypromellose phthalate；Enteric layer
The plasticizer is at least one of castor oil, polyethylene glycol, diethyl phthalate；Lubricant described in enteric layer is to slide
At least one of mountain flour, silica, magnesium stearate；
Opacifier described in enteric layer is at least one of titanium dioxide, iron oxide；
Stabilizer described in enteric layer is at least one of polysorbate, poloxamer；
Solvent described in enteric layer is water, 50-90%v/v ethanol solution.
6. Lansoprazole intestine preparation according to claim 1-3, it is characterised in that:
Wherein, film forming agent described in alkaline protective layer is hydroxypropyl methylcellulose；
Lubricant described in alkaline protective layer is talcum powder；
Opacifier described in alkaline protective layer is titanium dioxide；
Alkaline stabiliser described in alkaline protective layer is magnesia；
Solvent described in alkaline protective layer is 60~80%v/v ethanol solution；
Wherein, film forming agent described in separation layer is hydroxypropyl methylcellulose；
Lubricant described in separation layer is talcum powder or polyethylene glycol；
Opacifier described in separation layer is titanium dioxide；
Solvent described in separation layer is 60~80%v/v ethanol solution；
Wherein, film forming agent described in enteric layer is polyacrylic resin；
Enteric layer the plasticizer is castor oil；
Lubricant described in enteric layer is talcum powder；
Opacifier described in enteric layer is titanium dioxide；
Stabilizer described in enteric layer is polysorbate；
Solvent described in enteric layer is 60~80%v/v ethanol solution.
7. Lansoprazole intestine preparation according to claim 1, it is characterised in that: enteric layer further includes colorant.
8. Lansoprazole intestine preparation according to claim 7, it is characterised in that: colorant described in enteric layer is iron oxide.
9. Lansoprazole intestine preparation according to claim 1, it is characterised in that: coatings weight gain: alkaline protective layer increases
Weigh 2~3%；Separation layer weight gain 2~3%；Enteric layer weight gain 12~15%.
10. the preparation method of -9 described in any item Lansoprazole intestine preparations according to claim 1, it is characterised in that: described
Enteric coated preparations are prepared using following methods:
A, using Lansoprazole as main ingredient, using filler, stabilizer, disintegrating agent, adhesive, lubricant as auxiliary material；
B, particle is prepared according to a conventional method, then tabletting or encapsulated, label or capsule is made；
C, three layers of coatings are successively wrapped, are drying to obtain；
Wherein, it includes two methods that conventional method, which prepares particle:
Steps are as follows for method one:
A, by Lansoprazole, filler, stabilizer, adhesive, particle is made in the disintegrating agent of 1/2-2/3 amount, dry,
B, after mixing particle with lubricant, remaining disintegrating agent, label or glue is made in tabletting or encapsulated according to a conventional method
Capsule；
C, three layers of coatings are successively wrapped, are drying to obtain；
Steps are as follows for method two:
A, auxiliary material filler, stabilizer, the disintegrating agent of 1/2-2/3 amount, adhesive is taken to prepare particle, it is dry；
B, Lansoprazole, lubricant, remaining disintegrating agent are taken, is mixed with particle, tabletting or encapsulated, is made piece according to a conventional method
Core or capsule；
C, three layers of coatings are successively wrapped, are drying to obtain.
11. the preparation method of Lansoprazole intestine preparation according to claim 10, it is characterised in that: method one and method
In two, when step A, preparing tablets and capsules in B, the weight percent of main ingredient Lansoprazole and each auxiliary material are as follows:
12. the preparation method of Lansoprazole intestine preparation according to claim 11, it is characterised in that: method one and method
In two, when step A, preparing tablets and capsules in B, the weight percent of main ingredient Lansoprazole and each auxiliary material are as follows:
13. the preparation method of Lansoprazole intestine preparation according to claim 11, it is characterised in that: method one and method
In two, when step A, preparing tablets and capsules in B, the weight percent of main ingredient Lansoprazole and each auxiliary material are as follows:
14. the preparation method of the described in any item Lansoprazole intestine preparations of 0-13 according to claim 1, it is characterised in that: side
In the step A and step B of method one and method two:
The auxiliary material filler is mannitol and/or lactose；
The stabilizer is magnesia；
The disintegrating agent is crospovidone；
Described adhesive is hydroxypropyl methylcellulose；
Surfactant is added in described adhesive with addition of using, the surface-active uses poloxamer；
Lubricant is magnesium stearate.
15. the preparation method of Lansoprazole intestine preparation according to claim 10, it is characterised in that: method one and method
In two, dry described in step A is that particle is dry at 50 DEG C or less.
16. the preparation method of Lansoprazole intestine preparation according to claim 10, it is characterised in that: done described in step C
Dry is control label or capsule endoparticle moisture less than 1%.
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| CN201410836966.9A Pending CN104586772A (en) | 2013-12-30 | 2014-12-29 | Proton pump inhibitor enteric-coated preparation and coating system and preparation method thereof |
| CN201410837154.6A Active CN104490840B (en) | 2013-12-30 | 2014-12-29 | Pantoprazole sodium enteric-coated preparation and preparation method thereof |
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| CN201410837154.6A Active CN104490840B (en) | 2013-12-30 | 2014-12-29 | Pantoprazole sodium enteric-coated preparation and preparation method thereof |
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| CN104825414B (en) * | 2015-05-07 | 2018-11-16 | 山东新时代药业有限公司 | A kind of stable S-pantoprazole sodium enteric tablet |
| CN104887674B (en) * | 2015-05-12 | 2019-07-23 | 上海信谊万象药业股份有限公司 | A kind of solid pharmaceutical preparation and preparation method thereof containing Omeprazole |
| CN105534979A (en) * | 2016-03-04 | 2016-05-04 | 中国药科大学 | Esomeprazole magnesium enteric-coated tablets and preparation method thereof |
| CN105833281B (en) * | 2016-05-18 | 2018-02-02 | 连云港万泰医药辅料技术有限公司 | A kind of aqueous enteric film coating pre-mix dose and preparation method thereof |
| CN106138000A (en) * | 2016-07-19 | 2016-11-23 | 南京正宽医药科技有限公司 | A kind of Omeprazole Enteric-coated Tablets and preparation method thereof |
| CN107137372A (en) * | 2017-05-07 | 2017-09-08 | 济南同路医药科技发展有限公司 | Omeprazole Enteric-coated Tablets and preparation method thereof |
| CN109125282B (en) * | 2018-09-05 | 2020-07-14 | 珠海润都制药股份有限公司 | Omeprazole enteric capsule and preparation method thereof |
| CN110507628B (en) * | 2019-09-30 | 2020-07-28 | 双鹤药业(海南)有限责任公司 | Rabeprazole sodium tablet, rabeprazole sodium enteric-coated tablet and preparation method thereof |
| CN114569579B (en) * | 2020-12-02 | 2023-10-31 | 丽珠医药集团股份有限公司 | Enteric coated pellets, process for their preparation and formulations containing them |
| CN114617852B (en) * | 2020-12-10 | 2023-06-27 | 昆药集团股份有限公司 | Omeprazole enteric preparation and preparation method thereof |
| CN114191411B (en) * | 2021-11-29 | 2023-02-28 | 苏州中化药品工业有限公司 | Proton pump inhibitor capsule and preparation method thereof |
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- 2014-12-29 CN CN201410834496.2A patent/CN104523641B/en active Active
- 2014-12-29 CN CN201410836476.9A patent/CN104546786A/en active Pending
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| Publication number | Publication date |
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| CN104523641A (en) | 2015-04-22 |
| CN104490840A (en) | 2015-04-08 |
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| CN104490840B (en) | 2018-09-28 |
| CN104586772A (en) | 2015-05-06 |
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Application publication date: 20150422 Assignee: YAAN XUNKANG MEDICINE Co.,Ltd. Assignor: Chengdu Di Kang medicine companies LLC Contract record no.: X2021510000036 Denomination of invention: Lansoprazole enteric coated preparation and its preparation method Granted publication date: 20191119 License type: Common License Record date: 20210915 |