CN106727381A - A kind of oral disintegrating tablet of R-lansoprazole sodium and preparation method thereof - Google Patents
A kind of oral disintegrating tablet of R-lansoprazole sodium and preparation method thereof Download PDFInfo
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- 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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- 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
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Abstract
The present invention relates to a kind of R-lansoprazole sodium oral disintegrating tablet and preparation method thereof, the R-lansoprazole sodium oral disintegrating tablet be by R-lansoprazole sodium-novel crystal forms A, sodium acid carbonate, enteric-coated quick releasing micropill A, enteric sustained-release pellet B, premixing auxiliary material compound, and other pharmaceutically acceptable auxiliary material compressing tablets be obtained, wherein R-lansoprazole sodium-novel crystal forms A the θ of the angle of diffraction 2 be 5.9,7.6,12.2,12.7,16.6,18.4,20.5,25.8, there is characteristic diffraction peak at 26.8,31.4 degree；Enteric-coated quick releasing micropill A and enteric sustained-release pellet B be all with R-lansoprazole sodium-novel crystal forms A as bulk drug by hot-melt extrusion process be obtained, and the enteric coating degraded under condition of different pH is coated with, premixing auxiliary material compound is also to be obtained through hot-melt extrusion process by the suitable auxiliary material of oral disintegrating tablet.Oral disintegrating tablet of the present invention discharges medicine on a small quantity under one's belt, reduces unstable shortcoming to gastrointestinal stimulation and in hydrochloric acid in gastric juice.Follow-up micropill is main to be dissolved and discharges in enteron aisle, extends drug effect.Oral disintegrating tablet of the invention has a good mouthfeel, and disintegration is rapid, and dissolution is fast, convenient to take, and the advantages of improve patient's compliance, and preparation technology is advanced, safety non-pollution simple to operate, it is adaptable to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of oral disintegrating tablet of R-lansoprazole sodium and its preparation side
Method.
Background technology
R-lansoprazole（Dexlansoprazole, R- (+)-Lansoprazole）, chemical name is (R)-(+) -2-
([3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- bases] methylsulfinyl) -1H- benzimidazoles, its structural formula is such as
Shown in lower,
。
R-lansoprazole is the esophagitis treatment new drug of Japanese Takeda Pharmaceutical Company Limited research and development, January 30 in 2009 the Nikkei U.S.
FDA approval listings.The medicine is single enantiomer of proton pump inhibitor Lansoprazole, for treatment and Non-erosive gastroesophageal reflux
Sick related heartburn and different degrees of erosive esophagitis, than Lansoprazole there is bioavilability higher to make with less secondary
With.
R-lansoprazole belongs to drawing azole PPIs anti-ulcer agents, there is sulfinyl benzo miaow in R-lansoprazole structure
The chemical constitution of azoles, physicochemical property is extremely unstable, easily by light, heavy metal ion, oxidisability and reproducibility composition etc. it is various because
The influence of element, especially in acid condition, the chemical constitution of R-lansoprazole can occur destructive change, discoloration occur and be polymerized
Phenomenon, thus R-lansoprazole is unstable in the diluent of slant acidity, after being made oral formulations, drug absorption need to be by medicine
Disintegration release process, and due in stomach hydrochloric acid in gastric juice cause R-lansoprazole destroy decompose, and reduce drug effect speed and biology profit
How expenditure, make main not being destroyed in hydrochloric acid in gastric juice of R-lansoprazole capsule even can play drug effect.Additionally, how to ensure
Rate controlling release under intestinal environment is one of key technology point.
The preparation technique that active component discharges in hydrochloric acid in gastric juice is avoided at present mostly using in one layer of side of enteric coating of outer layer bag
Formula, the R-lansoprazole spansule of military field pharmacy（Trade name DEXILANT）, two kinds of different enteric bags are contained in every capsule
The micropill 1 and micropill 2 of clothing.To avoid active component from being discharged in hydrochloric acid in gastric juice and controlling the release twice in enteron aisle, DEXILANT is adopted
With three kinds of different enteric-coating materials, Utech L30D-55, Utech L100, Utech S100 undoubtedly increased cost.This
Ethanol has also been used as coating solution solvent outward, production security has additionally been reduced, and workshop and equipment must possess explosion-proof dress
Put, do not meet Modern Green environmental requirement, also easily produce the quality problems such as alcohol solvent is exceeded.
R-lansoprazole increased some stability after being although made sodium salt, but be insoluble in water, degradable in hydrochloric acid in gastric juice,
It is made tablet or capsule absorbs relatively slow, bioavilability is relatively low, and stability is not high, main dose of current Lansoprazole product
Type has lansoprazole tablet and capsulae enterosolubilis, but the patient that these formulations are not suitable for children, old man and dysphagia uses, so
It is important to develop a kind of Lansoprazole sodium novel form that has for using of these patients that is adapted to, and also possesses very strong practicality.
Torching mark（HME）Refer to, using mono-/bis-screw extruder, to pass through material also known as melt extrusion technology
Solid Conveying and Melting, melting, the stage of melt conveying three are gone through, under the strong shear effect of kneading device and screw element, height is obtained mixed
Close scattered shaped article.Hot-melt extruded process can realize the unit operation such as mixing, granulation and moulded products in an equipment,
Few with operation, energy consumption is low, and low cost, yield is high, serialization, can closed production the features such as.The technology is improving slightly solubility
Drug dissolution, preparing sustained release preparation and local administration preparation aspect has breakthrough sexual clorminance, it has also become preparation technique medicine
A new focus in transmission system, especially valuable is that preparation technology is easily achieved industrial amplification production.In the prior art
Not yet report R-lansoprazole sodium is used for the report of hot-melt extrusion process, does not more filter out suitable for hot-melt extrusion process
The novel crystal forms of R-lansoprazole sodium.
The content of the invention
In view of the shortcomings of the prior art, it is poor for existing R-lansoprazole stability, it is sensitive to temperature humidity, it is applied to system
Operation difficulty is big in agent technique, and production cost is high, its formulation products stability defect not high, and heat is not suitable for more particularly
The defect of molten expressing technique, drug degradation is obvious such as in reflow process, the invention provides a kind of R-lansoprazole sodium diformazan
More preferably, fusing point is suitable, stability for the physicochemical property of novel crystal forms A of yl acetamide solvate and preparation method thereof, novel crystal forms A
By force, it is very convenient to be made various kinds of drug formulation, it is also convenient for being applicable hot-melt extrusion process processing.
Novel crystal forms A it is another object of the present invention to provide the R-lansoprazole sodium is preparing treatment gastric ulcer, ten
Application in two Duodenalulcers and reflux esophagitis and eliminating pylorus medicine.
Meanwhile, for the novel crystal forms A of R-lansoprazole sodium, it is good that the present inventor is also directed to a kind of compliance, quality
Stabilization, can play drug effect in stomach and enteron aisle position in good time, and the dry mouth of bioavilability R-lansoprazole sodium higher collapses
Piece, so as to children, old man and dysphagia patients are used.
In order to realize the technical goal of above-mentioned oral disintegrating tablet, the present invention is adopted the following technical scheme that.
The invention provides a kind of oral disintegrating tablet of R-lansoprazole sodium, novel crystal forms of the oral disintegrating tablet comprising R-lansoprazole sodium
A, sodium acid carbonate, enteric-coated quick releasing micropill A, enteric sustained-release pellet B, premixing auxiliary material compound, and other are pharmaceutically acceptable
Auxiliary material compressing tablet；Wherein, the chemical constitution of the novel crystal forms A of R-lansoprazole sodium is the dimethylacetamide solvent of R-lansoprazole sodium
Compound, structural formula is as follows,
；
Enteric-coated quick releasing micropill A be the novel crystal forms A with R-lansoprazole sodium as bulk drug, quick-release ball is prepared using hot-melt extrusion process
Core A, then coat enteric coating A and obtain final product, enteric coating A is decomposed under conditions of pH value is more than or equal to 5.5；
Enteric sustained-release pellet B be the novel crystal forms A with R-lansoprazole sodium as bulk drug, using hot-melt extrusion process prepare sustained release ball
Core B, then coat enteric coating B and obtain final product, enteric coating B is decomposed under conditions of pH value is more than or equal to 6.8；
Filler is included in the premixing auxiliary material compound, adhesive, disintegrant, lubricant, flavouring heats adjuvant,
Preferably, the x-ray diffractogram of powder spectrum of the R-lansoprazole sodium novel crystal form A is 5.9,7.6 in the θ of the angle of diffraction 2,
Have characteristic diffraction peak at 12.2,12.7,16.6,18.4,20.5,25.8,26.8,31.4 degree, wherein 2 θ values error ranges for ±
0.2, the collection of illustrative plates is as shown in Figure of description 1；Also, its DSC collection of illustrative plates has endothermic characteristics peak at 132.4 ± 1 DEG C, 204.6 ± 1
DEG C there is exothermic characteristic peak, the collection of illustrative plates is as shown in Figure of description 2.
Preferably, the Fourier transform infrared spectroscopy of the R-lansoprazole sodium novel crystal form A is 3383 ± 2 in wave number,
3134 ± 2,3072 ± 2,2975 ± 2,1646 ± 2,1583 ± 2,1475 ± 2,1441 ± 2,1316 ± 2,1265 ± 2,
1198 ± 2,1168 ± 2,1111 ± 2,1036 ± 2,972 ± 2,915 ± 2,857 ± 2,745 ± 2,662 ± 2 cm-1Place
There is characteristic absorption peak, the collection of illustrative plates is as shown in Figure of description 3；Also, the thermogravimetric analysis of the novel crystal forms A of above-mentioned R-lansoprazole sodium
TG collection of illustrative plates is as shown in Figure of description 4.
Oral disintegrating tablet of the present invention, it is characterised in that the mass parts of each component are as follows,
R-lansoprazole sodium novel crystal form A：1 part；
Sodium acid carbonate：4~6 parts；
Enteric-coated quick releasing micropill A：35~40 parts；
Enteric sustained-release pellet B：85~100 parts；
Premixing auxiliary material compound：200~250 parts；
Also, above-mentioned free R-lansoprazole sodium：R-lansoprazole sodium in enteric-coated quick releasing micropill A：In enteric sustained-release pellet B
R-lansoprazole sodium weight ratio be 1：3.8~4.2：9.8~10.2, preferably 1：4：10；The premixing auxiliary material compound
In, filler is selected from glucose, lactose, xylitol, sucrose, mannitol, sorbierite, pregelatinized starch, microcrystalline cellulose, sugarcane
Sugar, one or more in starch；Adhesive is selected from PVP, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose water, hydroxypropyl
One or more in base cellulose；Disintegrant is selected from low-substituted hydroxypropyl cellulose, PVPP, cross-linked carboxymethyl fiber
Plain sodium, sodium carboxymethyl starch, sodium carboxymethylcellulose, one or more in calcium carboxymethylcellulose；Lubricant is selected from tristearin
Sour magnesium, calcium stearate, talcum powder, one or more in superfine silica gel powder；Flavouring is selected from Mint Essence, glycyrrhizin, malt
Sugar alcohol, flavoring banana essence, flavoring pineapple essence, orange taste essence, lemon extract, blueberry flavor, aspartame, stevioside, in acesulfame potassium
One or more；Hot melt adjuvant is selected from Compritol 888 ATO, one or more in polyethylene glycol.
Component of the premixing auxiliary material compound of the present invention comprising following weight fraction：
The content of filler is 75~85%, preferably microcrystalline cellulose：Xylitol：The weight ratio of lactose is 1：1：1 mixing
Thing；
The content of adhesive is 2~9%, preferably PVP K30；
The content of disintegrant is 3~6%, preferably Ac-Di-Sol；
The content of lubricant is 1~3%, preferably magnesium stearate；
The content of flavouring is 2~4%, preferably Mint Essence：The weight ratio of aspartame is 1：1 mixture；
The content for heating adjuvant is 5~10%, preferably PEG6000；
Each component percentage by weight summation is 100%.
The preparation method of premixing auxiliary material compound of the present invention is as follows：By filler, adhesive, disintegrant, lubricant,
Flavouring, hot melt adjuvant is well mixed, and is added in hot-melt extruded machine, sets melting extrusion temperature as 180~280 degree, makes
Particle is obtained, is ground, cross 80~100 mesh pharmacopeia sieve, obtain final product premixing auxiliary material compound, it is standby.
The prescription and mass parts of quick-release capsule core A of the present invention are as follows,
R-lansoprazole sodium crystal A：10~20 parts；
Magnesium carbonate：10~20 parts；
Water-solubility carrier：40~80 parts, the water-solubility carrier includes PVP class, polyacrylic resin class, cellulose family, choosing
From Plasdone K29, Plasdone K32, Kollidon VA64, Plasdone S630, Eudragit E100,
Eudragit EPO, Klucel EF, Klucel ELF, PLURONICS F87, PEG4000, one or more in PEG6000；
Plasticizer：2~10 parts, selected from sorbierite, mannitol, xylitol, glycerin monostearate, in Compritol 888 ATO one
Plant or several；
Stabilizer：10~20 parts, selected from polyoxyethylene sorbitan monoleate, Soluplus, Gelucire 44/14 Gelucire 44/
14, one or more in polyoxyl 40 hydrogenated castor oil KolliphorRH40；
Age resister：2~5 parts, selected from tromethamine, glycerine, one or more in propylgallate；
Disintegrant：0.2~1 part, selected from Ac-Di-Sol, PVPP, low-substituted hydroxypropyl cellulose, carboxymethyl
One or more in sodium starch.
The prescription and mass parts of sustained release capsule core B of the present invention are as follows,
R-lansoprazole sodium crystal A：10~20 parts；
Magnesium carbonate：10~20 parts；
Enteric solubility carrier：40~80 parts, selected from CAP, cellulose acetate succinate, phthalic acid
Hydroxypropyl methyl cellulose HPMCP, acetic acid butanedioic acid hydroxypropyl methyl cellulose HPMCAS, acetic acid maleic acid hydroxypropyl methyl are fine
Dimension element, carboxymethylethylcellulose, Eudragit L100-55, Utech S100, Utech RL100, in Utech RS100 one
Plant or several,；
Plasticizer：2~10 parts, selected from sorbierite, mannitol, xylitol, glycerin monostearate, in Compritol 888 ATO one
Plant or several；
Stabilizer：10~20 parts, selected from polyoxyethylene sorbitan monoleate, Soluplus, Gelucire 44/14 Gelucire 44/
14, one or more in polyoxyl 40 hydrogenated castor oil KolliphorRH40；
Age resister：2~5 parts, selected from tromethamine, glycerine, one or more in propylgallate；
Release regulator：0~1 part, selected from lauryl sodium sulfate, Bile Salts, xanthans, the one kind or several in Carbomer
Kind.
Preferably, the coating prescription and mass parts of enteric-coated quick releasing micropill A are as follows,
The suitable 93F19255 of Ya Ke：20 parts；
Arginine：11~12 parts；
Talcum powder：5 parts；
Triethyl citrate：3 parts；
Water：In right amount；
Coating weight gain 10~20%；
The coating prescription and mass parts of enteric sustained-release pellet B are as follows,
The suitable 93F19255 of Ya Ke：20 parts；
Arginine：3~4 parts；
Talcum powder：5 parts；
Macrogol 4000：4 parts；
Water：In right amount；
Coating weight gain 10~20%.
Present invention also offers a kind of method for preparing the dry suspensoid agent as described in claim 1-8, comprise the following steps：
1）The preparation of enteric-coated quick releasing micropill A：R-lansoprazole novel crystal forms A, water-solubility carrier, plasticizer, stabilizer is anti-aging
Agent, is added in the loading hopper of double screw extruder after disintegrant is well mixed, sets charging rate as 2kg/h, and rotating speed is
200rpm, sets melting extrusion temperature as 80~120 DEG C, and collection material is started after 10min to be extruded, is cut by the cutting knife of end
The piller for being cut into a diameter of 0.3~0.8mm is standby；Each component in enteric coating liquid A is well mixed, using fluidized bed coating
Machine is coated under the following conditions, 45 DEG C of inlet temperature, Coating Solution spray rate 3.8g/ minutes, atomisation pressure 1.0kg/ ㎝2,
It is dried to obtain enteric-coated quick releasing micropill A；
2）The preparation of enteric sustained-release pellet B：R-lansoprazole sodium novel crystal form A, enteric solubility carrier, plasticizer, stabilizer is anti-aging
Agent, release regulator is added in the loading hopper of double screw extruder after being well mixed, and sets charging rate as 2kg/h, rotating speed
It is 200rpm, sets melting extrusion temperature as 80~120 DEG C, starts collection material after 10min to be extruded, by the cutting knife of end
The piller for cutting into a diameter of 0.3~0.8mm is standby；Each component in enteric coating liquid B is well mixed, using fluid bed bag
Clothing machine is coated under the following conditions, 45 DEG C of inlet temperature, Coating Solution spray rate 3.8g/ minutes, atomisation pressure 1.0kg/
㎝2, it is dried to obtain enteric sustained-release pellet B；
3）R-lansoprazole sodium novel crystal form A, sodium acid carbonate, enteric-coated quick releasing micropill A, enteric sustained-release pellet B, premixing auxiliary material are combined
Thing is well mixed, and using direct powder compression, obtains final product R-lansoprazole sodium oral disintegrating tablet.
Through the further investigation of inventor, in oral disintegrating tablet of the invention, the right blue element for carrying out micronization processes draws azoles sodium newly brilliant
Type A maintains its crystalline structure feature all the time, and it is 5.9,7.6,12.2 to be composed in the θ of the angle of diffraction 2 in x-ray diffractogram of powder all the time,
There is characteristic diffraction peak at 12.7,16.6,18.4,20.5,25.8,26.8,31.4 degree, wherein 2 θ values error ranges are ± 0.2.Speed
Release the main ingredient composition that micropill A and sustained release pellet B wherein include to use right blue element to draw azoles sodium novel crystal form A is bulk drug preparation,
Can be crystallite state, or both mixture by after hot-melt extrusion process, end-state can be amorphous state,
May be relevant with melting extrusion temperature and other technologies index.
The present invention achieves following beneficial technique effect：
（1）It is not required to add bacteriostatic agent or preservative, improves drug safety；Physical and chemical stability is high, steady quality, storage fortune
All easily, preparation method is simple, easy to operate, is suitable to industrialized production and application for defeated and carrying.
（2）The oxidative impurity levels of the R-lansoprazole sodium novel crystal form A that the present invention is provided are significantly reduced, and with storage
Time lengthening, impurity is varied less, and with excellent mobility and the dissolution rate for significantly improving, is made using this novel crystal forms A
The oral disintegrating tablet good stability of R-lansoprazole sodium, impurity content is low.
（3）Because R-lansoprazole is easily degraded in hydrochloric acid in gastric juice, therefore the Lansoprazole preparation of domestic listing at present is mostly intestines
Solubility preparation, protects medicine not by gastric acid degradation by the way of enteric coated, but it has delayed the receipts of medicine and to the first of hydrochloric acid in gastric juice
Beginning inhibitory action.The present invention program is made oral disintegrating tablet, can discharge R-lansoprazole by preparation in hydrochloric acid in gastric juice, fast first with sodium acid carbonate
Speed neutralizes part hydrochloric acid in gastric juice so that stomach inner pH value is increased to optimum range and maintains a period of time to protect Omeprazole not by hydrochloric acid in gastric juice
Degraded, the effect for making it directly reach gastric acid secretion inhibiting rapidly.Sodium acid carbonate can improve the pH value of gastric environment and remain certain
Time so that the R-lansoprazole unstable to acid quick absorption before being destroyed by hydrochloric acid in gastric juice works, gastric acid secretion inhibiting, and in stomach
In it is dispersed, expand active area under one's belt, increase medicine and absorbed in stomach, improve bioavilability, stomach is alleviated rapidly
The symptom such as sour hypersecretion and stomach pain, improves the healing satisfaction of patient, to reach Preferred effects.
（4）Premixing auxiliary material compound is prepared using hot-melt extrusion process, and the premix specifically designed for oral disnitegration tablet is auxiliary
Material.The use of the premixing auxiliary material, can cause that direct pressed powder is more convenient and smooth, it is to avoid moisten in wet granulation technology
Degraded of the wet solvent to medicine.
（5）All contain magnesium carbonate in the prescription of fast release micropill A of the invention and sustained release pellet B, rather than sodium acid carbonate, be
Because the present inventor has found by repetition test, the use of magnesium carbonate maintains alkaline environment of the main ingredient in solid dispersions,
The stable in physicochemical property of main ingredient is kept, directly coat the enteric bag of different pH value releases on solid dispersions surface while may be such that
Clothing is possibly realized, it is to avoid used separation layer, simplifies operational sequence.The present invention discharges containing two distinct types of with positioning
The enteric-coated micro-pill of function and free R-lansoprazole sodium salt.When medicine enters stomach, free right blue element draws azoles sodium to coordinate
The therapeutic action of sodium acid carbonate, increased absorption of the medicine in stomach first, rapid to alleviate the symptom such as gastric acid secretion and stomachache.Intestines
Molten fast release micropill A starts to slough coatings in proximal small bowel, and medicine is gone out by water-soluble solid dispersion quick release, accepts
The therapeutic effect of upper stomach, continues rate controlling ground and provides drug effect.Enteric sustained-release pellet B starts to slough coatings in small intestine distal end, leads to
The slow Slow release of enteric solubility solid dispersions is crossed, steady lasting blood concentration is able to maintain that, it is ensured that therapeutic effect, while keeping away
Frequent drug administration is exempted from.
（6）The present invention contains two distinct types of enteric-coated micro-pill, and three kinds of intestines are used relative to commercialized product DEXILANT
Molten coating material, the enteric layer in the present invention uses the refined gram of suitable 93F19255 of Ka Lekang, by preferably water-soluble in refined gram of configuration
Different amounts of arginine is added during liquid, the carboxyl of different molal quantitys in polymer is neutralized, control enteric material is different
Dissolved under pH, it is achieved thereby that the dual controlled release effect of style twice, reduces production cost, simplify production technology.Due to
The present invention is coated using the aqueous solution, greatly improves the security of production, reduces the pollution to environment, effectively prevent ethanol
Residue problem.
（7）Oral disintegrating tablet of the invention is evenly distributed in intestines and stomach, is not likely to produce to dash forward and releases, and good stability facilitates fractionated dose,
Add water and take after mixing it with water, good absorbing is rapid-action, bioavilability is good, in good taste, improve the compliance of patient, preparation method is simple, is suitable to
Industrialized production and application.
（8）Two kinds of capsule cores of micropill are completed using torching mark in the present invention, and advanced technology, process is simple does not make
With organic solvent, safety non-pollution, without dead angle, dispersion effect is good, and drug loss is few for mixing, collects various units and operates in one,
Save space and reduces cost, are suitable for industrialized large-scaled production.
Brief description of the drawings
Fig. 1 is the powder x-ray diffraction PXRD figures of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate
Spectrum.
Fig. 2 is the DSC collection of illustrative plates of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate.
Fig. 3 is the infared spectrum of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate.
Fig. 4 is the TG collection of illustrative plates of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate.
Specific embodiment
Below will by the specific embodiment of embodiment form, it is further to the above of the invention specifically
It is bright, but this scope for being interpreted as aforementioned body of the present invention should not be limited only to following examples.It is all above-mentioned based on the present invention
The technology that content is realized belongs to the scope of the present invention.
The preparation of the novel crystal forms A of the R-lansoprazole sodium dimethylacetylamide of the invention of embodiment 1
A kind of novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate that the present invention is provided, the every mole new crystalline substance
Comprising 1 mole of dimethylacetamide solvent molecule in type A, structural formula is as follows：
。
The novel crystal forms A of R-lansoprazole sodium of the present invention, powder x-ray diffraction collection of illustrative plates is 5.9 in the θ of the angle of diffraction 2,
There is characteristic diffraction peak at 7.6,12.2,12.7,16.6,18.4,20.5,25.8,26.8,31.4 degree, wherein 2 θ value error ranges
It is ± 0.2, and the collection of illustrative plates is as shown in Figure of description 1.
The novel crystal forms A of R-lansoprazole sodium of the present invention, its DSC collection of illustrative plates has endothermic characteristics peak at 132.4 ± 1 DEG C,
204.6 ± 1 DEG C have exothermic characteristic peak；And the collection of illustrative plates is as shown in Figure of description 2.
The novel crystal forms A of R-lansoprazole sodium of the present invention, its Fourier transform infrared spectroscopy is 3383 ± 2 in wave number,
3134 ± 2,3072 ± 2,2975 ± 2,1646 ± 2,1583 ± 2,1475 ± 2,1441 ± 2,1316 ± 2,1265 ±
2,1198 ± 2,1168 ± 2,1111 ± 2,1036 ± 2,972 ± 2,915 ± 2,857 ± 2,745 ± 2,662 ± 2 cm-1
There is characteristic absorption peak at place, and the collection of illustrative plates is as shown in Figure of description 3；Also, the thermogravimetric of the novel crystal forms A of above-mentioned R-lansoprazole sodium
Analysis TG collection of illustrative plates is as shown in Figure of description 4.
Preparation method：The mixing of R-lansoprazole sodium 50g additions dimethylacetylamide 200mL and purified water 100mL is molten
In agent, 0.1g copolyvidone S630, and 0.1g propylgallates are added, the stirring and dissolving at 35~40 DEG C is applying super
Under conditions of sound wave effect, ul-trasonic irradiation frequency is 20~50KHz, and power is 50~100W, to slow in above-mentioned solution
Methyl tertiary butyl ether(MTBE) 900mL is added dropwise, under conditions of maintaining rate of temperature fall to be 0.3~1 DEG C/min, 0~5 DEG C is cooled to, continues to stir
1~3h is mixed, the suspension suction filtration that will be formed is pressed dry, is dried under conditions of 35~45 DEG C of temperature and 0~0.1Mpa of vacuum,
Obtain the novel crystal forms A about 57g of R-lansoprazole sodium Dimethylacetamide solvate, yield 93%.
The main granularity of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate of the present invention is 90 μm of left sides
It is right so that crystal size is moderate, good fluidity, is difficult to assemble and degrades, and facilitates the operation in production process.
Embodiment 2 contrasts the preparation of crystal formation 1
It is prepared with reference to the Example5 of page 15 of specification in PCT Patent WO2012095859A1.R-lansoprazole 25g is dissolved in
In absolute ethyl alcohol 250mL, 32.5g sodium iso-octoates are added, stirring reaction 30min, removal of solvent under reduced pressure is added in residue
250mL normal heptanes, are stirred at room temperature 3h, filtering, dry, and obtain contrast crystal formation 1 about 18.5g.
Embodiment 3 contrasts the preparation of crystal formation 2
It is prepared with reference to the Example8 of page 16 of specification in PCT Patent WO2012095859A1.
Right blue element draws azoles 10g to be dissolved in the mixed solvent of absolute ethyl alcohol 100mL and water 5mL, is cooled to -5 DEG C, adds 2.2g
NaOH, -5 DEG C of stirring 30min, to 80mL normal heptanes are added in reaction solution, continue to stir 30min, collect solid, do
It is dry, obtain contrast crystal formation 2 about 6g.
The estimation of stability of the novel crystal forms A of the R-lansoprazole sodium Dimethylacetamide solvate of embodiment 4
By obtained contrast crystal formation 1 and contrast crystal formation 2, carry out influence factor with R-lansoprazole sodium novel crystal form A of the invention and try
Test, accelerated stability test, test method instructs former referring to bulk drug in Chinese Pharmacopoeia annex and pharmaceutical preparation stability test
Then.
（One）, influence factor experiment：
1）Hot test：Take contrast crystal formation 1 and contrast crystal formation 2, and R-lansoprazole sodium novel crystal form A of the invention, in 60 DEG C of temperature
Degree is lower to be placed 10 days, is sampled in the 5th day and the 10th day, is determined indices and is compared with 0 day sample, and result of the test is as follows.
2）Wet test high：Former contrast crystal formation 1 and contrast crystal formation 2 are taken, and R-lansoprazole sodium novel crystal form A of the invention, in
Placed 10 days under RH75%, sampled in the 5th day and the 10th day, determined indices and be compared with 0 day sample, result of the test is such as
Under.
3）Strong illumination is tested：Take contrast crystal formation 1 and contrast crystal formation 2, and R-lansoprazole sodium novel crystal form A of the invention,
It is in illumination（4500±500）Placed 10 days under conditions of lx, sampled in the 5th day and the 10th day, determine indices and 0 day sample
Product are compared, and result of the test is as follows.
（Two）Accelerated stability test：
Crystal formation 1 and contrast crystal formation 2 will be contrasted, 6 will be carried out in climatic chamber with R-lansoprazole sodium novel crystal form A of the invention
The accelerated stability test of the moon.Experimental condition is：40 DEG C/75% relative humidity（RH）, sampled respectively at 0,1,2,3,6 months, enter
Row purity and foreign impurity matters test（High performance liquid chromatography）, as a result see the table below.
From the foregoing, it will be observed that the stability of R-lansoprazole sodium novel crystal form A is better than contrast crystal formation 1 and crystal formation 2 of the prior art.
Especially under high temperature, high humidity and illumination condition, the stability of R-lansoprazole sodium novel crystal form A has obvious raising.
The wettability test of embodiment 5
Crystal formation 1 and contrast crystal formation 2 will be contrasted, will be placed in dynamic vapor sorption instrument with R-lansoprazole sodium novel crystal form A of the invention,
Below 40 DEG C of temperature, weight when mass change is less than 0.01g in 3 hours is recorded.
The applicability that the different crystal forms of embodiment 6 are applied to hot-melt extrusion process is investigated
The present inventor such as weighs at the contrast crystal formation 1 of weight（Relevant material is 0.11%）, (relevant material is contrast crystal formation 2
0.12%), novel crystal forms A (relevant material is 0.10%), chooses water soluble carrier material PEG6000 and enteric solubility carrier material acetic acid
Butanedioic acid hydroxypropyl methyl cellulose HPMCAS is representative, with Compritol 888 ATO as plasticizer, according to following weight portion
Prescription carries out hot-melt extruded and prepares solid dispersion particles：1 part of bulk drug, 10 parts of carrier material, 2 parts of Compritol 888 ATO.Knot
Fruit is as follows.
The preparation of the fast release micropill A of embodiment 7
Prescription is as follows：
R-lansoprazole sodium novel crystal form A：8g；
Magnesium carbonate：10g；
Plasdone S630：24g；
Klucel EF：8g；
Compritol 888 ATO：4g；
Soluplus：8g；
Tromethamine：3g；
PVPP：0.8g；
The prescription of enteric coating liquid A is：
The suitable 93F19255 of Ya Ke：20 parts；
Arginine：11~12 parts；
Talcum powder：5 parts；
Triethyl citrate：3 parts；
Water：In right amount；
Coating weight gain 10%；
Micropill prepares as follows：
By R-lansoprazole novel crystal forms A, magnesium carbonate, Plasdone S630, Klucel EF, Compritol 888 ATO, Soluplus,
Tromethamine, PVPP is added in the loading hopper of double screw extruder after being well mixed, and sets charging rate as 2kg/
H, rotating speed is 200rpm, sets melting extrusion temperature as 80~90 DEG C, starts collection material after 10min to be extruded, by end
Cutting knife cut into a diameter of 0.5~0.7mm piller it is standby；Each component in enteric coating liquid A is well mixed, using stream
Change bed seed-coating machine to be coated under the following conditions, 45 DEG C of inlet temperature, Coating Solution spray rate 3.8g/ minutes, atomisation pressure
1.0kg/㎝2, it is dried to obtain enteric-coated quick releasing micropill A.
The preparation of the sustained release pellet B of embodiment 8
R-lansoprazole sodium novel crystal form A：20g；
Magnesium carbonate：25g；
HPMCAS：60g；
Utech RS100：20g；
Compritol 888 ATO：5g；
Gelucire 44/14 Gelucire 44/14：15g；
Propylgallate：5g；
Carbomer：1g；
The prescription of enteric coating B is as follows,
The suitable 93F19255 of Ya Ke：20 parts；
Arginine：3~4 parts；
Talcum powder：5 parts；
Macrogol 4000：4 parts；
Water：In right amount；
Coating weight gain 15%；
Micropill prepares as follows：
By R-lansoprazole sodium novel crystal form A, magnesium carbonate, HPMCAS, Utech RS100, Compritol 888 ATO, the poly- second two of laurate
Alcohol glyceride Gelucire 44/14, propylgallate is added to the charging of double screw extruder after Carbomer is well mixed
In bucket, charging rate as 2kg/h is set, rotating speed is 200rpm, set melting extrusion temperature as 85~95 DEG C, 10min to be extruded
After start collection material, the piller for cutting into a diameter of 0.5~0.7mm by the cutting knife of end is standby；By in enteric coating liquid B
Each component be well mixed, be coated under the following conditions using fluidized-bed coating machine, 45 DEG C of inlet temperature, Coating Solution spraying speed
Rate 3.8g/ minutes, atomisation pressure 1.0kg/ ㎝2, it is dried to obtain enteric sustained-release pellet B.
The preparation of the fast release micropill A of embodiment 9
Capsule core A prescriptions are as follows,
R-lansoprazole sodium novel crystal form A：8g；
Magnesium carbonate：11g；
Kollidon VA64：25g；
PEG6000：9g；
Compritol 888 ATO：5g；
Polyoxyethylene sorbitan monoleate：8g；
Tromethamine：3g；
Ac-Di-Sol：0.5g；
The prescription of enteric coating liquid A is：
The suitable 93F19255 of Ya Ke：20 parts；
Arginine：11~12 parts；
Talcum powder：5 parts；
Triethyl citrate：3 parts；
Water：In right amount；
Coating weight gain 10%；
Micropill prepares as follows：
By R-lansoprazole novel crystal forms A, magnesium carbonate, Kollidon VA64, Klucel EF, PEG6000, Compritol 888 ATO,
Tromethamine, Ac-Di-Sol is added in the loading hopper of double screw extruder after being well mixed, setting charging speed
It is 2kg/h to spend, and rotating speed is 200rpm, sets melting extrusion temperature as 80~90 DEG C, and collection material is started after 10min to be extruded,
The piller for cutting into a diameter of 0.5~0.7mm by the cutting knife of end is standby；Each component in enteric coating liquid A is mixed equal
It is even, it is coated under the following conditions using fluidized-bed coating machine, 45 DEG C of inlet temperature, Coating Solution spray rate 3.8g/ minutes, spray
Mist pressure 1.0kg/ ㎝2, it is dried to obtain enteric-coated quick releasing micropill A.
The preparation of the sustained release pellet B of embodiment 10
R-lansoprazole sodium novel crystal form A：20g；
Magnesium carbonate：30g；
HPMCP：65g；
Utech S100：25g；
Glycerin monostearate：5g；
Polyoxyl 40 hydrogenated castor oil KolliphorRH40：17g；
Glycerine：6g；
Natrium taurocholicum：1.5g；
The prescription of enteric coating B is as follows,
The suitable 93F19255 of Ya Ke：20 parts；
Arginine：3~4 parts；
Talcum powder：5 parts；
Macrogol 4000：4 parts；
Water：In right amount；
Coating weight gain 15%；
Micropill prepares as follows：
By R-lansoprazole sodium novel crystal form A, magnesium carbonate, HPMCP, Utech S100, glycerin monostearate, the hydrogen of polyoxyethylene 40
Change castor oil KolliphorRH40, glycerine is added to the loading hopper of double screw extruder after natrium taurocholicum is well mixed
In, charging rate as 2kg/h is set, rotating speed is 200rpm, melting extrusion temperature as 85~95 DEG C is set, after 10min to be extruded
Start collection material, the piller for cutting into a diameter of 0.5~0.7mm by the cutting knife of end is standby；By in enteric coating liquid B
Each component is well mixed, and is coated under the following conditions using fluidized-bed coating machine, 45 DEG C of inlet temperature, Coating Solution spray rate
3.8g/ minutes, atomisation pressure 1.0kg/ ㎝2, it is dried to obtain enteric sustained-release pellet B.
The preparation of the premixing auxiliary material compound of embodiment 11
It is 60g, Ac-Di-Sol by microcrystalline cellulose 560g, xylitol 560g, lactose 560g, PVP K30
80g, magnesium stearate 40g, Mint Essence 40g, aspartame 40g, PEG6000140g, are well mixed, and are added to hot-melt extruded machine
In, melting extrusion temperature as 180~240 DEG C is set, particle is obtained, grind, 80~100 mesh pharmacopeia sieve is crossed, obtain final product premix
Auxiliary material compound, it is standby.
The preparation of the oral disintegrating tablet of the present invention of embodiment 12, with 1000 calculating, specification 30mg
R-lansoprazole sodium novel crystal form A：2g；
Sodium acid carbonate：8g；
Enteric-coated quick releasing micropill A：70~75g, is prepared according to the prescription and technique of the gained of embodiment 7 fast release micropill A soluble in the stomach；
Enteric sustained-release pellet B：170~175g, is prepared according to the prescription and technique of the gained enteric sustained-release pellet B of embodiment 8；
Premixing auxiliary material compound：400g, is prepared according to the formulation and technology of the premixing auxiliary material compound of embodiment 11；
Preparation method is as follows：
Enteric-coated quick releasing micropill A is prepared according to embodiment 7, and enteric sustained-release pellet B is prepared according to embodiment 8, premixes auxiliary
Material compound is prepared according to embodiment 11, will not be repeated here.
By R-lansoprazole sodium novel crystal form A, sodium acid carbonate, enteric-coated quick releasing micropill A, enteric sustained-release pellet B, premixing auxiliary material is multiple
Compound is well mixed, and using direct powder compression, obtains final product R-lansoprazole sodium oral disintegrating tablet.
The preparation of the oral disintegrating tablet of the present invention of embodiment 13, with 1000 calculating, specification 30mg
R-lansoprazole sodium novel crystal form A：2g；
Sodium acid carbonate：10g；
Fast release micropill A soluble in the stomach：70~75g, is prepared according to the prescription and technique of the gained of embodiment 7 fast release micropill A soluble in the stomach；
Enteric sustained-release pellet B：170~175g, is prepared according to the prescription and technique of the gained enteric sustained-release pellet B of embodiment 8；
Premixing auxiliary material compound：400g, is prepared according to the formulation and technology of the premixing auxiliary material compound of embodiment 11
Preparation method is as follows：
Enteric-coated quick releasing micropill A is prepared according to embodiment 7, and enteric sustained-release pellet B is prepared according to embodiment 8, premixes auxiliary
Material compound is prepared according to embodiment 11, will not be repeated here.
By R-lansoprazole sodium novel crystal form A, sodium acid carbonate, enteric-coated quick releasing micropill A, enteric sustained-release pellet B, premixing auxiliary material is multiple
Compound is well mixed, and using direct powder compression, obtains final product R-lansoprazole sodium oral disintegrating tablet.
The preparation of the oral disintegrating tablet of the present invention of embodiment 14, with 1000 calculating, specification 30mg
R-lansoprazole sodium novel crystal form A：2g；
Sodium acid carbonate：8g；
Fast release micropill A soluble in the stomach：72~78g, is prepared according to the prescription and technique of the gained of embodiment 9 fast release micropill A soluble in the stomach；
Enteric sustained-release pellet B：192~198g, according to the prescription and technique system of the gained enteric sustained-release pellet B of embodiment 10
It is standby；
Premixing auxiliary material compound：400g, is prepared according to the formulation and technology of the premixing auxiliary material compound of embodiment 11；
Preparation method is as follows：
Enteric-coated quick releasing micropill A is prepared according to embodiment 9, and enteric sustained-release pellet B is prepared according to embodiment 10, premixes auxiliary
Material compound is prepared according to embodiment 11, will not be repeated here.
By R-lansoprazole sodium novel crystal form A, sodium acid carbonate, enteric-coated quick releasing micropill A, enteric sustained-release pellet B, premixing auxiliary material is multiple
Compound is well mixed, and using direct powder compression, obtains final product R-lansoprazole sodium oral disintegrating tablet.
Embodiment 15 compares the preparation of oral disintegrating tablet
Using R-lansoprazole sodium novel crystal form A of the invention, with reference to the method system of embodiment 1 in Chinese patent CN102805737A
Standby enteric-coated orally disintegrating tablets.Operation is as follows：Acrylic resin ethanol is made into capsule material solution, soybean oil is added, the main ingredient of nanosizing,
Stirring 0.5h, above-mentioned solution is slowly added into the aqueous solution of 5 times of volumes containing 0.1% poloxamer while stirring, stirs 1h,
Cross miillpore filter, stratification, drying precipitate is obtained enteric nanocapsule, by nanocapsule and the PVPP of recipe quantity, firmly
Fatty acid magnesium, citric acid mixed pressuring plate, obtains final product.
The stability data of the oral disintegrating tablet of the present invention of embodiment 16
From stability data, to embodiment 12-14 samples by accelerating 6 months relevant materials, isomers to be increased slightly,
, without significant change, each index change in long-term 12 months is not obvious, and accelerated 6 months relevant materials of reference examples increase for other each indexs
Plus it is more apparent, long-term 12 months relevant materials also increased.Illustrating the stability of the embodiment of the present invention must be improved and optimize
.
The dissolution test of micropill prepared by 17 3 kinds of different process of embodiment under the environment of pH6.8~7.0
1）It is prepared by micropill
The present inventor attempts weighing the R-lansoprazole sodium novel crystal form A and magnesium carbonate of same weight portion, and different works are respectively adopted
Skill is prepared for three kinds of micropills, and micropill size is controlled in 550~600um.One kind is according to quick-release capsule core A in the embodiment of the present invention 7
Preparation method, a kind of is that a kind of is according to the most frequently used in the prior art according to the preparation method that capsule core B is sustained in the embodiment of the present invention 8
Preparation method, will main ingredient, magnesium carbonate, sucrose, low-substituted hydroxypropyl cellulose is well mixed to obtain solid dusting, hydroxypropyl methyl fiber
Element is dispersed in water and obtains 3% binder solution, by blank microcrystalline cellulose capsule core（28~32 mesh）Insert centrifugal coating pelletizing
In machine, spray operation is carried out, gained micropill particle carries pill Opadry coating solution in 40 DEG C of oven drying 12h, then by gained
Carry out bag separation layer.Above-mentioned three kinds of micropills coat identical enteric clothing film again.Principle is the molten of the different preparation methods gained micropills of investigation
Go out speed, other factors are tried one's best and are consistent.
2）Dissolution determination
Dissolution method according to Chinese Pharmacopoeia is investigated, with pH6.8 phosphate buffers 900mL as dissolution medium, temperature
Be 37 DEG C, rotating speed is 75 rpms, medication amount in each testing sample is 30mg, using ultraviolet spectrophotometry respectively at
Each point in time sampling carries out the measure of dissolution rate, as a result see the table below.
Pharmacokinetics of the R-lansoprazole sodium capsulae enterosolubilis of embodiment 18 in rat body
Test method：SD rats 12 are taken, about 200 ± 10 grams of body weight, male is divided into two groups, oral disintegrating tablet is compareed respectively at random
Group（Embodiment 15）, by taking embodiment 12 as an example, specification is all 30mg to self-control oral disintegrating tablet group.R-lansoprazole dosage is 6mg
Per kilogram, administration detects, record data that calculating medicine generation is dynamic after 1h, 2h, 4h, 6h, 7h, 8h, 10h, 24h sampling through HPLC methods
Mechanics parameter.
Result of the test：After rat orally compares oral disintegrating tablet and self-control oral disintegrating tablet respectively, relevant pharmacokinetic parameter is as follows
Shown in table.
Under the conditions of same size, compared with control group, the peak time of oral disintegrating tablet of the present invention is close, the increase of AUC areas,
Peak concentration is improved, and supersession rate slows down, and this shows that the action time of oral disintegrating tablet group of the present invention is more long, and bioavilability is higher,
With obvious clinical advantage.
Claims (10)
1. a kind of oral disintegrating tablet of R-lansoprazole sodium, it is characterised in that novel crystal forms A of the oral disintegrating tablet comprising R-lansoprazole sodium,
Sodium acid carbonate, enteric-coated quick releasing micropill A, enteric sustained-release pellet B, premixing auxiliary material compound, and other are pharmaceutically acceptable auxiliary
Material compressing tablet；Wherein, the chemical constitution of the novel crystal forms A of R-lansoprazole sodium is the dimethylacetamide solvent conjunction of R-lansoprazole sodium
Thing, structural formula is as follows,
；
Enteric-coated quick releasing micropill A be the novel crystal forms A with R-lansoprazole sodium as bulk drug, quick-release ball is prepared using hot-melt extrusion process
Core A, then coat enteric coating A and obtain final product, enteric coating A is decomposed under conditions of pH value is more than or equal to 5.5；
Enteric sustained-release pellet B be the novel crystal forms A with R-lansoprazole sodium as bulk drug, using hot-melt extrusion process prepare sustained release ball
Core B, then coat enteric coating B and obtain final product, enteric coating B is decomposed under conditions of pH value is more than or equal to 6.8；
Filler is included in the premixing auxiliary material compound, adhesive, disintegrant, lubricant, flavouring heats adjuvant.
2. oral disintegrating tablet according to claim 1, it is characterised in that the X-ray powder of the R-lansoprazole sodium novel crystal form A
Diffracting spectrum is have feature at 5.9,7.6,12.2,12.7,16.6,18.4,20.5,25.8,26.8,31.4 degree in the θ of the angle of diffraction 2
Diffraction maximum, wherein 2 θ values error ranges are ± 0.2, the collection of illustrative plates is as shown in Figure of description 1；And its DSC collection of illustrative plates is 132.4 ± 1
DEG C there is endothermic characteristics peak, have exothermic characteristic peak at 204.6 ± 1 DEG C, the collection of illustrative plates is as shown in Figure of description 2.
3. oral disintegrating tablet according to claim 1, it is characterised in that the Fourier of the R-lansoprazole sodium novel crystal form A becomes
Change infrared spectrum wave number be 3383 ± 2,3134 ± 2,3072 ± 2,2975 ± 2,1646 ± 2,1583 ± 2,1475 ±
2,1441 ± 2,1316 ± 2,1265 ± 2,1198 ± 2,1168 ± 2,1111 ± 2,1036 ± 2,972 ± 2,915 ± 2,
857 ± 2,745 ± 2,662 ± 2 cm-1There is characteristic absorption peak at place, and the collection of illustrative plates is as shown in Figure of description 3；Also, above-mentioned right orchid
Rope draws the thermogravimetric analysis TG collection of illustrative plates of the novel crystal forms A of azoles sodium as shown in Figure of description 4.
4. oral disintegrating tablet according to claim 1, it is characterised in that the mass parts of each component are as follows,
R-lansoprazole sodium novel crystal form A：1 part；
Sodium acid carbonate：4~6 parts；
Enteric-coated quick releasing micropill A：35~40 parts；
Enteric sustained-release pellet B：85~100 parts；
Premixing auxiliary material compound：200~250 parts；
Also, above-mentioned free R-lansoprazole sodium：R-lansoprazole sodium in enteric-coated quick releasing micropill A：In enteric sustained-release pellet B
R-lansoprazole sodium weight ratio be 1：3.8~4.2：9.8~10.2, preferably 1：4：10；The premixing auxiliary material is combined
In thing, filler is selected from glucose, lactose, xylitol, sucrose, mannitol, sorbierite, pregelatinized starch, microcrystalline cellulose, sugarcane
Sugar, one or more in starch；Adhesive is selected from PVP, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose water, hydroxypropyl
One or more in base cellulose；Disintegrant is selected from low-substituted hydroxypropyl cellulose, PVPP, cross-linked carboxymethyl fiber
Plain sodium, sodium carboxymethyl starch, sodium carboxymethylcellulose, one or more in calcium carboxymethylcellulose；Lubricant is selected from tristearin
Sour magnesium, calcium stearate, talcum powder, one or more in superfine silica gel powder；Flavouring is selected from Mint Essence, glycyrrhizin, malt
Sugar alcohol, flavoring banana essence, flavoring pineapple essence, orange taste essence, lemon extract, blueberry flavor, aspartame, stevioside, in acesulfame potassium
One or more；Hot melt adjuvant is selected from Compritol 888 ATO, one or more in polyethylene glycol.
5. oral disintegrating tablet according to claim 1, it is characterised in that the premixing auxiliary material compound includes following weight fraction
Component：
The content of filler is 75~85%, preferably microcrystalline cellulose：Xylitol：The weight ratio of lactose is 1：1：1 mixing
Thing；
The content of adhesive is 2~9%, preferably PVP K30；
The content of disintegrant is 3~6%, preferably Ac-Di-Sol；
The content of lubricant is 1~3%, preferably magnesium stearate；
The content of flavouring is 2~4%, preferably Mint Essence：The weight ratio of aspartame is 1：1 mixture；
The content for heating adjuvant is 5~10%, preferably PEG6000；
Each component percentage by weight summation is 100%.
6. oral disintegrating tablet according to claim 1, it is characterised in that the preparation method of the premixing auxiliary material compound is as follows：
Filler, adhesive, disintegrant, lubricant, flavouring, hot melt adjuvant are well mixed, are added in hot-melt extruded machine, if
Melting extrusion temperature is determined for 180~280 DEG C, particle is obtained, ground, cross 80~100 mesh pharmacopeia sieve, obtain final product premixing auxiliary material and answer
Compound, it is standby.
7. oral disintegrating tablet according to claim 1, it is characterised in that the prescription and mass parts of quick-release capsule core A are as follows,
R-lansoprazole sodium crystal A：10~20 parts；
Magnesium carbonate：10~20 parts；
Water-solubility carrier：40~80 parts, the water-solubility carrier includes PVP class, polyacrylic resin class, cellulose family, choosing
From Plasdone K29, Plasdone K32, Kollidon VA64, Plasdone S630, Eudragit E100,
Eudragit EPO, Klucel EF, Klucel ELF, PLURONICS F87, PEG4000, one or more in PEG6000；
Plasticizer：2~10 parts, selected from sorbierite, mannitol, xylitol, glycerin monostearate, in Compritol 888 ATO one
Plant or several；
Stabilizer：10~20 parts, selected from polyoxyethylene sorbitan monoleate, Soluplus, Gelucire 44/14 Gelucire 44/
14, one or more in polyoxyl 40 hydrogenated castor oil KolliphorRH40；
Age resister：2~5 parts, selected from tromethamine, glycerine, one or more in propylgallate；
Disintegrant：0.2~1 part, selected from Ac-Di-Sol, PVPP, low-substituted hydroxypropyl cellulose, carboxymethyl
One or more in sodium starch.
8. oral disintegrating tablet according to claim 1, it is characterised in that the prescription and mass parts of sustained release capsule core B be：
R-lansoprazole sodium crystal A：10~20 parts；
Magnesium carbonate：10~20 parts；
Enteric solubility carrier：40~80 parts, selected from CAP, cellulose acetate succinate, phthalic acid
Hydroxypropyl methyl cellulose HPMCP, acetic acid butanedioic acid hydroxypropyl methyl cellulose HPMCAS, acetic acid maleic acid hydroxypropyl methyl are fine
Dimension element, carboxymethylethylcellulose, Eudragit L100-55, Utech S100, Utech RL100, in Utech RS100 one
Plant or several,；
Plasticizer：2~10 parts, selected from sorbierite, mannitol, xylitol, glycerin monostearate, in Compritol 888 ATO one
Plant or several；
Stabilizer：10~20 parts, selected from polyoxyethylene sorbitan monoleate, Soluplus, Gelucire 44/14 Gelucire 44/
14, one or more in polyoxyl 40 hydrogenated castor oil KolliphorRH40；
Age resister：2~5 parts, selected from tromethamine, glycerine, one or more in propylgallate；
Release regulator：0~1 part, selected from lauryl sodium sulfate, Bile Salts, xanthans, the one kind or several in Carbomer
Kind.
9. oral disintegrating tablet according to claim 1, it is characterised in that the coating prescription and mass parts of enteric-coated quick releasing micropill A are such as
Under,
The suitable 93F19255 of Ya Ke：20 parts；
Arginine：11~12 parts；
Talcum powder：5 parts；
Triethyl citrate：3 parts；
Water：In right amount；
Coating weight gain 10~20%；
The coating prescription and mass parts of enteric sustained-release pellet B are as follows,
The suitable 93F19255 of Ya Ke：20 parts；
Arginine：3~4 parts；
Talcum powder：5 parts；
Macrogol 4000：4 parts；
Water：In right amount；
Coating weight gain 10~20%.
10. it is a kind of to prepare such as the method for claim 1~8 oral disintegrating tablet of any one, it is characterised in that to comprise the following steps：
1）The preparation of enteric-coated quick releasing micropill A：R-lansoprazole novel crystal forms A, water-solubility carrier, plasticizer, stabilizer is anti-aging
Agent, disintegrant is added in the loading hopper of double screw extruder after being well mixed, and sets charging rate as 2kg/h, and rotating speed is
200rpm, sets melting extrusion temperature as 80~120 DEG C, and collection material is started after 10min to be extruded, is cut by the cutting knife of end
The piller for being cut into a diameter of 0.3~0.8mm is standby；Each component in enteric coating liquid A is well mixed, using fluidized bed coating
Machine is coated under the following conditions, 45 DEG C of inlet temperature, Coating Solution spray rate 3.8g/ minutes, atomisation pressure 1.0kg/ ㎝2,
It is dried to obtain enteric-coated quick releasing micropill A；
2）The preparation of enteric sustained-release pellet B：R-lansoprazole sodium novel crystal form A, enteric solubility carrier, plasticizer, stabilizer is anti-aging
Agent, release regulator is added in the loading hopper of double screw extruder after being well mixed, and sets charging rate as 2kg/h, rotating speed
It is 200rpm, sets melting extrusion temperature as 80~120 DEG C, starts collection material after 10min to be extruded, by the cutting knife of end
The piller for cutting into a diameter of 0.3~0.8mm is standby；Each component in enteric coating liquid B is well mixed, using fluid bed bag
Clothing machine is coated under the following conditions, 45 DEG C of inlet temperature, Coating Solution spray rate 3.8g/ minutes, atomisation pressure 1.0kg/
㎝2, it is dried to obtain enteric sustained-release pellet B；
3）R-lansoprazole sodium novel crystal form A, sodium acid carbonate, enteric-coated quick releasing micropill A, enteric sustained-release pellet B, premixing auxiliary material are combined
Thing is well mixed, and using direct powder compression, obtains final product R-lansoprazole sodium oral disintegrating tablet.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112294772A (en) * | 2020-10-30 | 2021-02-02 | 扬州中宝药业股份有限公司 | Shuxinding sulfate double-release orally disintegrating tablet and preparation method thereof |
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| CN112294772A (en) * | 2020-10-30 | 2021-02-02 | 扬州中宝药业股份有限公司 | Shuxinding sulfate double-release orally disintegrating tablet and preparation method thereof |
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| CN106727381B (en) | 2020-07-07 |
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Address after: 210061 122, Hua Kang Road, hi tech Development Zone, Nanjing, Jiangsu. Applicant after: NANJING HAIRONG PHARMACEUTICAL CO., LTD. Applicant after: Chengdu Dikang pharmaceutical Limited by Share Ltd Address before: 210061 122, Hua Kang Road, hi tech Development Zone, Nanjing, Jiangsu. Applicant before: NANJING HAIRONG PHARMACEUTICAL CO., LTD. Applicant before: Chengdu Dikang Pharmaceutical Co., Ltd. |
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Application publication date: 20170531 Assignee: Chongqing Dikang Changjiang Pharmaceutical Co.,Ltd. Assignor: NANJING HAIRONG PHARMACEUTICAL Co.,Ltd.|Chengdu Di Kang medicine companies LLC Contract record no.: X2021510000035 Denomination of invention: The invention relates to an orally disintegrating tablet of right lansoprazole sodium and a preparation method thereof Granted publication date: 20200707 License type: Common License Record date: 20210916 |
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