CN109833306A - A kind of roxatidine acetate pharmaceutical salts sustained release pellet and preparation method thereof and its application - Google Patents
A kind of roxatidine acetate pharmaceutical salts sustained release pellet and preparation method thereof and its application Download PDFInfo
- Publication number
- CN109833306A CN109833306A CN201810521589.8A CN201810521589A CN109833306A CN 109833306 A CN109833306 A CN 109833306A CN 201810521589 A CN201810521589 A CN 201810521589A CN 109833306 A CN109833306 A CN 109833306A
- Authority
- CN
- China
- Prior art keywords
- sustained release
- pellet
- pharmaceutical salts
- coating
- roxatidine acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
A kind of medicinal load medicine salt sustained release pellet of roxatidine acetate, the composition of slow release layer coating solution includes slow-release material, pore-foaming agent, plasticizer, coating solvent, coating solvent is the ethanol water that mass fraction is 70-100%, and the sustained release pellet has good dissolution characteristic and quality stability.
Description
Technical field
The invention belongs to field of medicine preparations, and in particular to a kind of roxatidine acetate pharmaceutical salts sustained release pellet and its system
Preparation Method and its application.
Background technique
Hydrochloric acid roxatidine acetate (Roxatidine aidcetate hydrochlore, ROX) be after ranitidine,
Another H developed after famotidine etc.2The selective antagonistic of receptor, it can block stomach lining parietal cell histamine H2-receptor
And show lasting gastric acid secretion inhibiting effect, also there is Mucosa for Protective Effect, simultaneously for clinical treatment peptic gastric ulcer disease
Ideal medicament with appropriate acid suppression effect.For proton pump inhibitor (PPI), hydrochloric acid roxatidine acetate has
Many clinical advantages: 1. acting in histamine activated pathway, moderate inhibition gastric acid secretion, to the pre- of inpatient stress ulcer
Prevent curative for effect, effectively prevent stress ulcer, and its control efficiency is suitable with Lansoprazole, and it treats duodenal ulcer
Effect it is suitable with ranitidine；2. the flexible carbochain in hydrochloric acid roxatidine acetate structure can stimulate Gastric Mucosal Cells point
Secrete mucin and mucus, unique gastric mucosal protection function, and the effect of its gastric acid secretion inhibiting is 6 times of Cimetidine, thunder Buddhist nun replaces
2 times of fourth；3. the acetylamino group in hydrochloric acid roxatidine acetate structure is instead of guanidine/amidine group, formation effect is strong, biological
The H2RA of availability height, long half time；4. the acetic acid ester structure in hydrochloric acid roxatidine acetate structure carries out ester water in vivo
Solution reaction, is metabolized, no drug drug interaction without liver enzyme；5. without the antiandrogen sample side effect of other H2RAs；6. avoiding
Adverse reaction caused by PPI medication, including PPI medication is avoided to cause patient's Nosocomial Pneumonia risk, clostridium difficile infection
Diarrhea (CDI) risk, such as be combined with clopidogrel and increase cardiovascular event occurrence risk.
The Yuan Yan company of hydrochloric acid roxatidine acetate spansule is Japan's あ The か (ASKA) pharmacy strain formula meeting, existing
Without the concrete composition dosage and preparation method of open あ The か (ASKA) pharmacy strain formula meeting spansule in technology.
Liao Peng etc. disclose a kind of hydrochloric acid roxatidine acetate pulsatile release pellets (" China Dispensary ", 2010, the 21st
Volume, the 17th phase), controlled release micro pill is prepared using duplicature time control-disintegration method, the supplementary product kind that said preparation uses is more, system
Standby complex process.
Sustained release preparation can overcome the peak valley phenomenon of blood concentration, so that blood concentration is maintained at comparison steady lasting effective
In range, Drug safety is improved.Sustained release preparation can also reduce medicining times, improve the compliance of patient, user
Just.
Summary of the invention
The purpose of the present invention is to provide a kind of roxatidine acetate pharmaceutical salts sustained release pellet with good stability.
It is relatively low another object of the present invention is to solve the drug-loaded layer of roxatidine acetate pharmaceutical salts sustained release pellet coating drugloading rate
Problem.It is another object of the present invention to the load medicine coating of pellets for solving roxatidine acetate pharmaceutical salts sustained release pellet is hardened
The problem of.Another technical problem of the invention is to improve the dissolution rate and quality of roxatidine acetate pharmaceutical salts sustained release pellet
Stability.
One of the objects of the present invention is to provide a kind of load medicine pellets of roxatidine acetate pharmaceutical salts, including blank pill
Core and drug-loaded layer, drug-loaded layer contain the roxatidine acetate pharmaceutical salts of micronization, wherein the micronization Roxatidine vinegar
Acid esters pharmaceutical salts partial size D90 numerical value is less than or equal to 50 μm of (≤), and preferably D90 is less than or equal to 40 μm of (≤), 30 μm, 25 μm, 22.2 μ
M, 20 μm, 16 μm or 9 μm any.
Roxatidine acetate pharmaceutical salts of the invention carry medicine pellet, including blank capsule core and drug-loaded layer, and drug-loaded layer uses
The ethanol water solvent or dehydrated alcohol that parts by weight are 95% or more are as drug-loaded layer coating solvent, preferably drug-loaded layer coating solvent
The parts by weight of middle ethyl alcohol are more than or equal to any of (>=) 96%, 97%, 98%, 99%, 99.2%, 99.5% or 99.7%
Kind.
In precedence technique scheme of the invention, roxatidine acetate pharmaceutical salts and coating in the drug-loaded layer Coating Solution
The weight ratio of solvent is 75:750-250, preferably 75:750-281.25,75:700-350,75:700-400,75:656.25-
406.25 it is any.
In precedence technique scheme of the invention, adhesive is added in the drug-loaded layer, preferably described adhesive is alcohol-soluble
Any of or a combination of adhesive, more preferably hydroxypropyl cellulose, polyvinylpyrrolidone.
In precedence technique scheme of the invention, the viscosity number of the hydroxypropyl cellulose is 2.0-10.0mPas (measurement
20 DEG C of HPC concentration 2% of condition), preferably one of 2.0-2.9,3.0-5.9,6.0-10.0mPas or several specifically may be used
With any or combinations thereof selected from HPC-L, HPC-SL, HPC-SSL.
In precedence technique scheme of the invention, the polyvinylpyrrolidone be selected from PVP-K12, PVP-K25, PVP-K30,
PVP-K60, PVP-K90's is any or combinations thereof.
In precedence technique scheme of the invention, roxatidine acetate pharmaceutical salts in the drug-loaded layer Coating Solution: bonding
The mass ratio of agent is 75:1-25, and preferably 75:3.75-20,75:3.75-15's is any.
In precedence technique scheme of the invention, water-insoluble plasticizer is added in the drug-loaded layer, it is preferably described non-aqueous
Any of property plasticizer in triethyl citrate, PEG6000, castor oil, diethyl phthalate, propylene glycol, silicone oil
Kind or combinations thereof.
In precedence technique scheme of the invention, in the drug-loaded layer dosage of plasticizer be 0-4%, preferably 1%, 2%,
3%, 3.5% or 3.75%.
In precedence technique scheme of the invention, the blank capsule core material is selected from microcrystalline cellulose, sucrose, starch, lactose
Or any of or a combination of silica.
In precedence technique scheme of the invention, the load pack clothing gain in weight for carrying medicine pellet is selected from 120%-150%, excellent
Be selected as 125%, 130%, 135%, 140%, 145% it is any, most preferably 141%, 142%, 143%, 144%,
145%, 146%, 147%, 148%, 149% it is any.
In precedence technique scheme of the invention, the antiplastering aid in drug-loaded layer is selected from talcum powder, superfine silica gel powder, dioxide/silica gel
Any of or a combination of body, sodium stearyl fumarate, magnesium stearate, polyethylene glycol, potassium chloride.
Roxatidine acetate pharmaceutical salts of the present invention be selected from its hydrochloride, oxalates, acetate any or its
Combination.
Dehydrated alcohol of the present invention typically refers to the ethyl alcohol of 99% (W/W%) or more, may be selected to meet and meets pharmacopeia
The dehydrated alcohol that standard (such as United States Pharmacopeia, British Pharmacopoeia, European Pharmacopoeia and Japanese Pharmacopoeia) requires, the preferably grade of dehydrated alcohol
Not Xuan Zi pharmaceutical grade, chemistry is pure, analysis is pure and its above standard it is any, parts by weight of ethyl alcohol in the dehydrated alcohol >=
99.2%, 99.5% or 99.7%.
Roxatidine acetate pharmaceutical salts of the present invention carry medicine pellet and are used to prepare oral preparation, and ability can be used
The preparation technique of domain routine is to be prepared.
Roxatidine acetate pharmaceutical salts of the present invention carry medicine pellet and are used to prepare ordinary preparation, sustained release preparation or control
It is applied in release formulation, preferably the preparation is selected from any of tablet, capsule or enteric coated preparations.
Another object of the present invention is to provide the preparation method that a kind of roxatidine acetate pharmaceutical salts carry medicine pellet, packets
It includes following steps: roxatidine acetate pharmaceutical salts being subjected to mechanical crushing or micronization processes, weigh each component by recipe quantity,
After mixing, it is spare to be prepared into load medicine coating solution, then is sprayed onto medicine coating solution is carried in blank capsule core, it is dry, it is sieved, system
Medicine pellet must be carried.
In the preferred technical solution of the present invention, the micronization processes method is selected from ball mill grinding, vibrating membrane crushing or gas
Any of or a combination of stream crushing.
In the preferred technical solution of the present invention, the drug-loaded layer coating method is in fluidized bed coating, coating pan rolling
It is any or combinations thereof.
In the preferred technical solution of the present invention, the fluidized bed coating condition are as follows: intake 120-160m3/ h, air inlet
Temperature is 30-50 DEG C, atomizing pressure 1.6-2.2kg/cm2, until stopping coating, dry 20-40min after theoretical weight gain.
Another object of the present invention is to provide a kind of roxatidine acetate pharmaceutical salts sustained release pellets, which is characterized in that
It is coated using sustained release coating liquid to medicine pellet is carried, the slow release layer coating solution includes Sustained release coating materials, pore-foaming agent, plasticising
Agent, coating solvent.
In the preferred technical solution of the present invention, the Sustained release coating materials selection is selected from ethyl cellulose, acrylic acid tree
Any of or a combination of rouge, cellulose acetate.
In the preferred technical solution of the present invention, the sustained release coating solvent is ethanol water, the preferably described ethanol water
Ethyl alcohol mass fraction in solution is 70-100%, preferably 80%, 85%, 90%, 95%, 100% it is any.
In the preferred technical solution of the present invention, the pore-foaming agent in the sustained release coating solution is selected from PEG6000, hydroxypropyl
Any of or a combination of cellulose, hydroxypropyl methylcellulose, sorbierite, sodium chloride, surfactant.
In the preferred technical solution of the present invention, in the sustained release coating solution plasticizer be selected from triethyl citrate,
Any of or a combination of PEG6000, castor oil, diethyl phthalate, propylene glycol, silicone oil.
In the preferred technical solution of the present invention, ethyl cellulose in the sustained release coating solution: the weight ratio of pore-foaming agent
For 10-7:0.9-3, preferably 9.99-7.37:0.94-2.5.
In the preferred technical solution of the present invention, ethyl cellulose in the sustained release coating solution: pore-foaming agent: plasticizer
Weight ratio is 10-7:0.9-3:0.9-2, preferably 9.99-7.37:0.94-2.5:0.94-1.72.
In the preferred technical solution of the present invention, ethyl cellulose in the sustained release coating solution: pore-foaming agent: plasticizer:
The weight ratio of coating solvent is 10-7:0.9-3:0.9-2:90-140, preferably 9.99-7.37:0.94-2.5:0.94-1.72:
94.97-137.11。
In the preferred technical solution of the present invention, the sustained-release coating layer weight gain for carrying medicine pellet is 6.0%-10.0%, excellent
Be selected as 6.5%, 7.5%, 8%, 8.5%, 9% it is any.
The carry out separation layer packet of the sustained release pellet of roxatidine acetate pharmaceutical salts of the invention, drug-loaded layer and slow release layer
Clothing does not add spacer layer coating.
Another object of the present invention is to provide a kind of preparation method of roxatidine acetate pharmaceutical salts sustained release pellet, packets
Include following steps: 1. preparations carry medicine pellet；2. preparing sustained release coating liquid: weighing sustained release coating liquid component by recipe quantity, stirring
Under the conditions of, coating solvent and other auxiliary materials are uniformly mixed；3. packet slow release layer: after slow release layer coating reaches gain in weight, stopping packet
Clothing, it is dry to get sustained release pellet.
In the preferred technical solution of the present invention, the slow release layer coating method is selected from fluidized bed coating, coating pan rolling
It is any or combinations thereof.
In the preferred technical solution of the present invention, the fluidized bed coating condition are as follows: intake 120-160m3/ h, air inlet
Temperature is 30-50 DEG C, atomizing pressure 1.6-2.2kg/cm2, until stopping coating, dry 20-40min after theoretical weight gain.
In the preferred technical solution of the present invention, the load medicine pellet is subjected to sustained release coating, Roxatidine acetic acid is made
Ester pharmaceutical salts sustained release pellet.The sustained release pellet can be further prepared into capsule.It include that load medicine is micro- in the capsule preparations
Ball and/or sustained release pellet.
In the preferred technical solution of the present invention, the roxatidine acetate pharmaceutical salts carry medicine pellet, sustained release pellet system
It further include any of or a combination of acid inhibitor, gastric mucosa protectant, pyloric spirobacterium inhibitor in standby composition.
In the preferred technical solution of the present invention, the roxatidine acetate pharmaceutical salts carry medicine pellet or sustained release pellet with
Any of or a combination of acid inhibitor, gastric mucosa protectant, pyloric spirobacterium inhibitor are administered in combination, preferably described
Be administered in combination selected from order of administration, be administered simultaneously, consecutive administration it is any or combinations thereof.
Another object of the present invention is to provide roxatidine acetate pharmaceutical salts carry medicine pellet or its sustained release pellet and its
The composition further prepared is for treating or preventing gastric ulcer, duodenal ulcer, anastomotic part ulcer, zes, inverse
Fluidity esophagitis, the application in acute gastritis, chronic gastritis, upper gastrointestinal bleeding or the drug of the anti-error suction of preoperative anesthesia.
In the preferred technical solution of the present invention, the gastric ulcer is selected from times of peptic ulcer or acute stress ulcer
One kind or combinations thereof.
In the preferred technical solution of the present invention, the patient is the low danger patient of upper gastrointestinal bleeding.
Load medicine pellet in the present invention is made of blank capsule core and drug-loaded layer.Sustained release pellet in the present invention is by blank pill
Core, drug-loaded layer and slow release layer are constituted.
Unless otherwise indicated, the present invention relates to when the percentage between liquid and liquid, the percentage is volume/body
Product percentage；The present invention relates to when percentage between liquid and solid, the percentage is volume/weight percentage；This hair
When the bright percentage being related between solid and liquid, the percentage is weight/volume percent；Remaining is w/w hundred
Divide ratio.
Compared with prior art, the present invention have it is following the utility model has the advantages that
1, it is relatively low to solve drug-loaded layer coating drugloading rate for roxatidine acetate pharmaceutical salts sustained release pellet produced by the present invention
The technical issues of.By micronization technology, the drugloading rate of active constituent is increased to 98% or more by 95% or so in drug-loaded layer.
2, by adjusting the weight percent of ethyl alcohol in drug-loaded layer coating solvent, roxatidine acetate produced by the present invention
It is hardened that pharmaceutical salts sustained release pellet solves the problems, such as that load medicine microbedding is coated.
3, roxatidine acetate pharmaceutical salts sustained release pellet produced by the present invention has good stability.Sustained release coating solvent
Middle concentration of alcohol, which improves, to slow down the dissolution rate of preparation, improves slow release effect.Under the conditions of Acceleration study, the present invention is made
The related content of material conspicuousness of the medicinal salt sustained release capsules of roxatidine acetate be lower than commercially available product.In addition, in Acceleration study item
Under part, dissolution rate variation of the medicinal salt sustained release capsules of roxatidine acetate produced by the present invention in preceding 60min is better than city
Sell product.
4, roxatidine acetate pharmaceutical salts sustained release pellet produced by the present invention is more conducive to play hydrochloric acid Roxatidine acetic acid
Ester has many clinical advantages: 1. acting in histamine activated pathway, moderate inhibition gastric acid secretion, bursts to inpatient irritability
The prevention of ulcer is curative for effect, effectively prevents stress ulcer, and its control efficiency is suitable with Lansoprazole, and its treatment 12 refers to
The effect of enterelcosis is suitable with ranitidine；2. the flexible carbochain in hydrochloric acid roxatidine acetate structure can stimulate stomach lining
Cell secrete mucin and mucus, unique gastric mucosal protection function, and the effect of its gastric acid secretion inhibiting be 6 times of Cimetidine,
2 times of ranitidine；3. the acetylamino group in hydrochloric acid roxatidine acetate structure is instead of guanidine/amidine group, formation effect
By force, the H2RA of bioavilability height, long half time；4. acetic acid ester structure in hydrochloric acid roxatidine acetate structure in vivo into
Row ester hydrolysis reaction, is metabolized without liver enzyme, no drug drug interaction；5. without the antiandrogen sample side effect of other H2RAs；
6. avoiding adverse reaction caused by PPI medication, including PPI medication is avoided to cause patient's Nosocomial Pneumonia risk, clostridium difficile
Infectious diarrhea (CDI) risk, such as be combined with clopidogrel and increase cardiovascular event occurrence risk.
Detailed description of the invention
The dissolution curve of Fig. 1 commercially available product and embodiment 13-16
The dissolution curve of Fig. 2 commercially available product and embodiment 20-22
The dissolution curve of Fig. 3 commercially available product and embodiment 23
Specific embodiment
The present invention is illustrated below with reference to embodiment, the embodiment of the present invention is merely to illustrate technical side of the invention
Case, and non-limiting essence of the invention.
Embodiment 1The preparation of hydrochloric acid roxatidine acetate load medicine pellet
Cane sugar core 65mg
Hydrochloric acid roxatidine acetate 75mg
Hydroxypropyl cellulose-SL 3.75mg
Talcum powder 15mg
95% ethyl alcohol 656.25mg
Raw material is mechanically pulverized, 95% ethyl alcohol of recipe quantity is weighed, hydroxypropyl cellulose-SL and master is added under stirring
Medicine is stirring evenly and then adding into talcum powder, and stirring is sieved for subsequent use.Blank is sprayed by medicine coating solution is carried with fluidized bed granulation seed-coating machine
In capsule core, fluidized bed coating condition are as follows: intake volume: 120-160m3/ h, inlet air temperature: 30-50 DEG C, atomizing pressure 1.6-
2.2kg/cm2.Yoke plate knot is glued in coating process between coating micro-pill, is unable to complete and is coated and reaches theoretical weight gain.
Embodiment 2The preparation of hydrochloric acid roxatidine acetate load medicine pellet
Cane sugar core 65mg
Hydrochloric acid roxatidine acetate 75mg
Hydroxypropyl cellulose-SL 3.75mg
Talcum powder 15mg
Dehydrated alcohol 656.25mg
Raw material mechanical crushing is handled, the dehydrated alcohol of recipe quantity is weighed, hydroxypropyl cellulose-is added under stirring
SL, stirring are added main ingredient, stir evenly, talcum powder is added afterwards, stir evenly, sieve for subsequent use to dissolving.Use fluidized bed granulation
Seed-coating machine is sprayed onto medicine coating solution is carried in blank capsule core, and drying and screening is made and carries medicine pellet.Coating conditions are anhydrous with embodiment 1
Ethyl alcohol is pure or more for chemistry, and ethyl alcohol alcohol parts by weight therein are greater than 99.5%.
Embodiment 3Hydrochloric acid roxatidine acetate carries medicine pellet
Cane sugar core 65mg
Hydrochloric acid roxatidine acetate 75mg
Hydroxypropyl cellulose-L 3.75mg
Talcum powder 15mg
Dehydrated alcohol 656.25mg
Raw material mechanical crushing is handled, the dehydrated alcohol of recipe quantity is weighed, hydroxypropyl cellulose-L is added under stirring,
Stirring is added main ingredient, stirs evenly, talcum powder is added afterwards, stir evenly, sieve for subsequent use to dissolving.It is coated with fluidized bed granulation
Machine, is sprayed onto blank capsule core using with the identical condition of embodiment 2 by medicine coating solution is carried, and drying and screening is made and carries medicine pellet.
Embodiment 4Hydrochloric acid roxatidine acetate carries medicine pellet
Cane sugar core 65mg
Hydrochloric acid roxatidine acetate 75mg
Hydroxypropyl cellulose-SL 3.75mg
Dehydrated alcohol 671.25mg
Raw material mechanical crushing is handled, the dehydrated alcohol of recipe quantity is weighed, hydroxypropyl cellulose-L is added under stirring,
Stirring is added main ingredient, stirs evenly, sieve for subsequent use to dissolving.With fluidized bed granulation seed-coating machine, using identical with embodiment 2
Condition is sprayed onto medicine coating solution is carried in blank capsule core, and drying and screening is made and carries medicine pellet.
Embodiment 5Hydrochloric acid roxatidine acetate carries medicine pellet
Cane sugar core 65mg
Hydrochloric acid roxatidine acetate 75mg
PVP K30 3.75mg
Talcum powder 15mg
95% ethyl alcohol 656.25mg
Raw material mechanical crushing is handled, 95% ethyl alcohol of recipe quantity is weighed, PVP K30 is added under stirring, stirring is extremely
Dissolution is added main ingredient, is stirring evenly and then adding into talcum powder, stirring is sieved for subsequent use.With fluidized bed granulation seed-coating machine, use and reality
It applies the identical condition of example 1 and is sprayed onto medicine coating solution is carried in blank capsule core, glue yoke plate knot in coating process between coating micro-pill, it can not
It completes to be coated and reaches theoretical weight gain.
Embodiment 6Hydrochloric acid roxatidine acetate carries medicine pellet
Cane sugar core 65mg
Hydrochloric acid roxatidine acetate 75mg
PVP K30 3.75mg
Talcum powder 15mg
Dehydrated alcohol 656.25mg
Raw material mechanical crushing is handled, the dehydrated alcohol of recipe quantity is weighed, PVP K30 is added under stirring, stirring is extremely
Dissolution is added main ingredient, stirs evenly, talcum powder is added afterwards, stir evenly, sieve for subsequent use.With fluidized bed granulation seed-coating machine, adopt
It is sprayed onto blank capsule core with the identical condition of embodiment 2 by medicine coating solution is carried, drying and screening is made and carries medicine pellet.
Embodiment 7The influence that drug-loaded layer group is coated in pairs
The appearance of pellet after the process and drug-loaded layer for recording the coating of drug-loaded layer described in embodiment 1-6 respectively are coated.Knot
Fruit shows that 95% ethyl alcohol is used to occur the hardened situation of pellet in coating process as drug-loaded layer coating solvent, is unable to complete
Coating, addition antiplastering aid talcum powder, which is unable to improve, carries the hardened problem of medicine pellet.Bulk pharmaceutical chemicals are configured to mix using dehydrated alcohol
Suspension coating significantly improves drug-loaded layer coating hardened phenomenon relative to 95% ethyl alcohol.
The pairs of coating process of 1 drug-loaded layer group of table and appearance effects
By solution in placing under room temperature for 24 hours, 0h and for 24 hours related substance of solution are detected respectively, investigates and carries pack clothing
The stability of solution.The result shows that using dehydrated alcohol that can improve as coating solvent relative to ethanol water and carrying medicine pellet
The stability of middle active constituent.
Influence of the different coating solvents of table 2 to drug-loaded layer in relation to substance
| Title | 1 solution of embodiment | 2 solution of embodiment |
| 0h is total miscellaneous (%) | 0.161 | 0.161 |
| Total miscellaneous (%) for 24 hours | 0.269 | 0.190 |
Embodiment 8-12Influence of the bulk pharmaceutical chemicals partial size to drugloading rate in medicine pellet is carried
Hydrochloric acid roxatidine acetate is prepared into D by mechanical dispersion90For the particle of 50um, bulk pharmaceutical chemicals are passed through into gas
Stream crushes and prepares D90For 22.2 μm, 16 μm and 9 μm of particle.The dehydrated alcohol of recipe quantity is weighed, is added under stirring
Triethyl citrate (TEC) and hydroxypropyl cellulose (HPC) stirring are added the main ingredient of crushing, stir evenly, be sieved to dissolving,
It is spare.It being sprayed onto blank capsule core with fluidized bed granulation seed-coating machine by medicine coating solution is carried, coating conditions are with embodiment 1, drying and screening,
It is made and carries medicine pellet, it is round and smooth that hardened phenomenon appearance does not occur for the load medicine pellet of preparation.The hydrochloric acid Luo Sha that measurement carries in medicine pellet is replaced
D ritalinic acid ester is relative to theoretical value content.Active constituent is relative to theoretical value content=practical measurement content/theory in load pill
Content * 100%.
Influence of the 3 bulk pharmaceutical chemicals partial size of table to drugloading rate in medicine pellet is carried
| Ingredient | Embodiment 8 | Embodiment 9 | Embodiment 10 | Embodiment 11 | Embodiment 12 |
| Blank capsule core | 65 | 65 | 65 | 65 | 65 |
| Bulk pharmaceutical chemicals D9050μm | 75 | 75 | |||
| Bulk pharmaceutical chemicals D9022.2μm | 75 | ||||
| Bulk pharmaceutical chemicals D9016μm | 75 | ||||
| Bulk pharmaceutical chemicals D909μm | 75 | ||||
| HPC | 15 | 15 | 15 | 15 | 15 |
| TEC | 3.75 | 3.75 | 3.75 | 3.75 | 3.75 |
| Dehydrated alcohol | 656.25 | 281.25 | 406.25 | 406.25 | 406.25 |
| Relative to theoretical value content | 94.95% | 95.85% | 98.81% | 99.74% | 100.8% |
Drug-loaded layer prepares coating solution using dehydrated alcohol (parts by weight are greater than 99.5%), and main ingredient can not be completely dissolved, and wraps
Clothing liquid is suspension, and undissolved part main ingredient is not easy to be adhered to pellet surface in coating process, the phenomenon that spray drying,
The non-equal proportion of coating solution is caused to be adhered to pellet surface, so that content is relatively low.Raw material is mechanically pulverized to D90For 50um, carry
Hydrochloric acid roxatidine acetate content is the 94.95% of theoretical value in pill；By flow of feed gas pulverization process to D90For 22. μm,
16 μm or 9 μm, hydrochloric acid roxatidine acetate is higher than D relative to theoretical value content90For the embodiment 8-9 of 50um.Therefore, by salt
Sour roxatidine acetate bulk pharmaceutical chemicals micronization is conducive to improve the active constituent actual content carried in medicine pellet, solves drug-loaded layer
It is coated the relatively low technical problem of practical drugloading rate, improves the stable content of finished product.
Embodiment 13-18Hydrochloric acid roxatidine acetate sustained release pellet
Load medicine pellet prepared by selection example 11 weighs 95% ethyl alcohol and purified water of recipe quantity, adds under stirring
Enter other auxiliary materials, to dissolving, sieving carries out slow release layer packet, coating conditions are as follows: intake volume: 120-160m for stirring3/ h, air inlet
Temperature: 30-50 DEG C, atomizing pressure 1.6-2.2kg/cm2, stopping is coated after coating weight gain reaches 6.5%, continues dry 20-
40min carries out total mix encapsulating capsule after coating, spansule described in embodiment 12-18 is made.
The composition of 4 embodiment 13-18 sustained release preparation of table
19 dissolution rate of embodiment is investigated
According to paddle method+sedimentation basket, 50rpm measures commercially available product in 900ml purified water and embodiment 13-16 prepares capsule
Dissolution data.Commercially available product (producer: Japanese ASKA, lot number: K623A).Dissolving-out method: taking this product, and paddle method adds sedimentation basket, and photograph is molten
Out-degree and drug release determination method (four general rules of Chinese Pharmacopoeia version in 2015,0,931 second method) turn using water 900ml as dissolution medium
Speed is 50 turns per minute, is operated according to methods.
The dissolution rate of 5 commercially available product of table and embodiment 12-17 are investigated
14 use of embodiment has both plasticizer and pore-foaming agent effect PEG6000, and dissolution rate is slower than commercially available product.Identical
Under the conditions of weight gain, the dissolution without using the pellet of pore-foaming agent is slower than commercially available product.The adjustment pair of the ratio of plasticizer and sustained release agent dosage
The dissolution of spansule influences not significant.
Embodiment 20-23Hydrochloric acid roxatidine acetate sustained release pellet
Load medicine pellet prepared by selection example 11, weighs the solvent of recipe quantity, other auxiliary materials is added under stirring, stir
It mixes to dissolution, sieving, carries out slow release layer packet, clothing coating weight gain 8.5% carries out total mix encapsulating capsule after coating, be made and implement
It is packed after spansule described in example 20-22.The spansule of embodiment 23 according to embodiment 21 prescription and method system
It is standby, by coating weight gain adjust to 8.0% to get.
The composition of 6 embodiment 20-22 sustained release preparation of table
Embodiment 24Dissolution rate is investigated
Dissolution experiment is carried out according to the method for embodiment 18, the dissolution situation of embodiment 20-22 is investigated, is shown in Table 7.
The dissolution rate of 7 commercially available product of table and embodiment 20-22 are investigated
| Time (min) | Commercially available product | Embodiment 20 | Embodiment 21 | Embodiment 22 |
| 0 | 0.00 | 0.00 | 0.00 | 0.00 |
| 15 | 3.20 | 6.65 | 4.01 | 1.92 |
| 30 | 12.20 | 20.41 | 13.31 | 9.10 |
| 45 | 25.90 | 31.87 | 23.11 | 21.27 |
| 60 | 38.11 | 40.22 | 31.40 | 30.80 |
| 90 | 51.82 | 53.30 | 44.72 | 43.73 |
| 120 | 59.66 | 62.19 | 53.78 | 52.64 |
| 180 | 68.93 | 72.09 | 64.32 | 63.58 |
| 240 | 74.62 | 79.74 | 72.44 | 71.23 |
| 300 | 78.30 | 83.43 | 77.26 | 76.26 |
| 360 | 81.70 | 86.83 | 80.13 | 80.15 |
| 480 | 87.78 | 91.34 | 85.31 | 85.12 |
| 600 | 91.17 | 93.74 | 89.70 | 88.06 |
It selects 70%-100% ethyl alcohol coated granule rounding not occur hardened, can be used as sustained release coating solvent.Experiment knot
Fruit shows that the concentration of ethyl alcohol in sustained release coating solvent will affect the release characteristic of sustained release pellet, and ethyl alcohol is dense in sustained release coating solvent
Degree, which improves, will slow down preparation dissolution rate, improve slow release effect.
Embodiment 256 months Acceleration study study on the stability
Commercially available product and embodiment sample are placed 6 under conditions of 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%
Month, detect dissolution curve and/or related substance.
8 commercially available product of table and 23 Acceleration study dissolution rate of embodiment are investigated
The variation of the dissolution rate of 0 day group of commercially available product and 6 months acceleration groups is more significant in preceding 60min difference.Embodiment 23 is made
The dissolution variation of 0 day and 6 months Acceleration study of standby sustained release preparation is smaller, is better than commercially available product.Under the conditions of Acceleration study, this hair
The sustained release preparation of bright preparation has preferably dissolution stability, is shown in Table 8 and Fig. 3.
9 commercially available product of table and the related substance of 23 Acceleration study of embodiment are investigated
| Title | Commercially available product | Embodiment 23 |
| 0 day (%) | 0.189 | 0.165 |
| Accelerate June (%) | 10.633 | 0.301 |
In accelerated test, the related content of material conspicuousness of 23 sustained release preparation of embodiment is dropped in commercially available product.Embodiment 20-22
The same conspicuousness of related content of material of sustained release preparation is lower than commercially available product.Therefore sustained release preparation prepared by the present invention is relative to commercially available
Product have better quality stability.
Claims (10)
1. a kind of sustained release pellet of roxatidine acetate pharmaceutical salts, feature is being carried out using sustained release coating liquid to medicine pellet is carried
Coating, the slow release layer coating solution include slow-release material, pore-foaming agent, plasticizer, coating solvent, and the coating solvent is ethyl alcohol
Aqueous solution, wherein the mass fraction of ethyl alcohol be coating solvent 70-100%, preferably 80%, 85%, 90%, 95%, 100%.
2. the sustained release pellet of roxatidine acetate pharmaceutical salts described in claim 1, feature is using in sustained release coating liquid
Slow-release material include one or more of ethyl cellulose, acrylic resin, cellulose acetate.
3. the sustained release pellet of roxatidine acetate pharmaceutical salts claimed in claims 1-2, it is characterised in that the pore-foaming agent choosing
From one or more of PEG6000, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sorbierite, sodium chloride, surfactant.
4. the sustained release pellet of roxatidine acetate pharmaceutical salts described in claim 1-3 any one, plasticizer choosing therein
From one or more of triethyl citrate, PEG6000, castor oil, diethyl phthalate, propylene glycol, silicone oil.
5. the sustained release pellet of roxatidine acetate pharmaceutical salts described in claim 1-4 any one, ethyl in Coating Solution
Cellulose, pore-foaming agent weight ratio be 10-7:0.9-3, preferably 9.99-7.37:0.94-2.5.
6. the sustained release pellet of roxatidine acetate pharmaceutical salts described in claim 1-5 any one, wherein carrying medicine pellet
Sustained-release coating layer weight gain is 6.0%-10.0%, preferably 6.5%, 7.5%, 8%, 8.5%, 9%.
7. the sustained release pellet of roxatidine acetate pharmaceutical salts as claimed in any one of claims 1 to 6, load medicine pellet therein
Including blank capsule core and drug-loaded layer, drug-loaded layer contains the roxatidine acetate pharmaceutical salts of micronization, Roxatidine after micronization
The partial size D of acetate pharmaceutical salts90Numerical value is less than or equal to 50 μm, 40 μm, 30 μm, 25 μm, 22.2 μm, 20 μm, 16 μm or 9 μm.
8. the sustained release pellet of roxatidine acetate pharmaceutical salts described in claim 1-7 any one, load medicine pellet therein
Including blank capsule core and drug-loaded layer, the ethanol water solvent of 95% or more parts by weight or dehydrated alcohol is used to be coated as drug-loaded layer
Solvent, in drug-loaded layer coating solvent the parts by weight of ethyl alcohol be preferably greater than or equal to 96%, 97%, 98%, 99%, 99.2%, 99.5% or
99.7%。
9. the sustained release pellet of roxatidine acetate pharmaceutical salts described in claim 1-8 any one, it is characterised in that it is special
Sign is that capsule and or tablet can be further prepared into.
It include the slow of roxatidine acetate pharmaceutical salts described in claim 1-9 10. a kind of pharmaceutical composition, in the combination
Pellet is released, and further comprises one or more of acid inhibitor, gastric mucosa protectant, pyloric spirobacterium inhibitor, sieve
Sand for d ritalinic acid ester pharmaceutical salts with other active components simultaneously, successively or sequence is given.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810521589.8A CN109833306B (en) | 2018-05-25 | 2018-05-25 | Roxatidine acetate medicinal salt sustained-release pellet as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810521589.8A CN109833306B (en) | 2018-05-25 | 2018-05-25 | Roxatidine acetate medicinal salt sustained-release pellet as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109833306A true CN109833306A (en) | 2019-06-04 |
| CN109833306B CN109833306B (en) | 2022-02-18 |
Family
ID=66882972
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810521589.8A Active CN109833306B (en) | 2018-05-25 | 2018-05-25 | Roxatidine acetate medicinal salt sustained-release pellet as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109833306B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110859829A (en) * | 2019-12-17 | 2020-03-06 | 山东康美乐医药科技有限公司 | Roxatidine acetate hydrochloride pellet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20060016382A (en) * | 2004-08-17 | 2006-02-22 | 바이오네스트 주식회사 | Drug delivery system using multi-coating methods contained roxantidine acetate hydrochloride |
| CN1795858A (en) * | 2004-12-30 | 2006-07-05 | 北京德众万全医药科技有限公司 | Oral taking tablets of Roxatidine Acetate Hydrochloride |
| CN102018677A (en) * | 2010-12-28 | 2011-04-20 | 哈药集团三精制药股份有限公司 | Roxatidine acetate hydrochloride used for injection and preparation method thereof |
-
2018
- 2018-05-25 CN CN201810521589.8A patent/CN109833306B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20060016382A (en) * | 2004-08-17 | 2006-02-22 | 바이오네스트 주식회사 | Drug delivery system using multi-coating methods contained roxantidine acetate hydrochloride |
| CN1795858A (en) * | 2004-12-30 | 2006-07-05 | 北京德众万全医药科技有限公司 | Oral taking tablets of Roxatidine Acetate Hydrochloride |
| CN102018677A (en) * | 2010-12-28 | 2011-04-20 | 哈药集团三精制药股份有限公司 | Roxatidine acetate hydrochloride used for injection and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| 廖鹏: "盐酸罗沙替丁醋酸酯脉冲控释微丸的研制", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 张兆旺主编: "《中药药剂学》", 31 January 2003, 中国中医药出版社 * |
| 潘卫三主编: "《工业药剂学》", 31 August 2015, 中国医药科技出版社 * |
| 王沛主编: "《制药原理与设备》", 31 March 2014, 上海科学技术出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110859829A (en) * | 2019-12-17 | 2020-03-06 | 山东康美乐医药科技有限公司 | Roxatidine acetate hydrochloride pellet and preparation method thereof |
| CN110859829B (en) * | 2019-12-17 | 2021-07-23 | 山东康美乐医药科技有限公司 | Roxatidine acetate hydrochloride pellet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109833306B (en) | 2022-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20130171199A1 (en) | Controlled release pharmaceutical composition | |
| BG65398B1 (en) | Enteric coated pharmaceutical composition and method of manufacturing it | |
| HU186538B (en) | Process for producing retarde pharmaceutical compositions containing bromohexine | |
| CA2494017A1 (en) | Delayed release anti-viral product, use and formulation thereof | |
| CN103356489B (en) | Proton pump inhibitor enteric coated pellet and preparation and preparation method thereof | |
| CN111150714A (en) | Dabigatran etexilate mesylate solid pharmaceutical preparation and preparation method thereof | |
| CN103520169B (en) | Mirtazapine tablet and preparation method thereof | |
| CN105106168B (en) | A kind of esomeprazole magnesium intestines capsule and preparation method thereof | |
| CN102552218A (en) | Memantine hydrochloride capsule sustained-release preparation and preparation method for same | |
| CN109833306A (en) | A kind of roxatidine acetate pharmaceutical salts sustained release pellet and preparation method thereof and its application | |
| CN102631327B (en) | Enteric coated omeprazole pellet and preparation method thereof | |
| CN109833299A (en) | A kind of micronization roxatidine acetate pharmaceutical salts pellet and preparation method thereof and its application | |
| CN114302712B (en) | Acipimox multi-unit sustained-release pellet tablet and preparation method thereof | |
| CN105769773B (en) | Loxoprofen sodium sustained-release pellet | |
| CN105055350B (en) | A kind of preparation method of the tablet containing proton pump inhibitor | |
| CN103191065A (en) | Celecoxib new formulation and preparation method thereof | |
| CN109833308A (en) | A kind of load medicine pellet of roxatidine acetate pharmaceutical salts and its preparation method and application | |
| CN104224728B (en) | A kind of Esomeprazole enteric pellet and preparation method thereof | |
| CN103432149B (en) | A kind of compound capsule containing ilaprazole composition of sodium and preparation method thereof | |
| CN101653423A (en) | Lacidipine tablets and preparation method thereof | |
| CN102068418B (en) | Sofalcone sustained-release pellet capsule preparation and preparation method thereof | |
| CN104027320A (en) | Esomeprazole magnesium suspension tablet and preparation method thereof | |
| CN115531350B (en) | Azilsartan capsule and preparation method thereof | |
| CN107613978B (en) | Pharmaceutical composition of mek inhibitor and preparation method thereof | |
| CN104337783B (en) | A kind of capecitabine tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20191120 Address after: Room 101113, Room 301, 3 Building East, Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing (in Beijing Sihuan Pharmaceutical Co., Ltd.) Applicant after: Beijing Aohe Pharmaceutical Research Institute Co., Ltd. Applicant after: Beijing Sihuan Pharmaceutical Co., Ltd. Applicant after: Beijing Tianxinyuan Pharmaceutical Science and Technology Development Co., Ltd. Applicant after: Jilin Huikang Pharmaceutical Co., Ltd. Address before: Room 301, building 3, East qishanzhuang village, Zhangjiawan Town Applicant before: Beijing Aohe Pharmaceutical Research Institute Co., Ltd. Applicant before: Beijing Sihuan Pharmaceutical Co., Ltd. Applicant before: Jilin Huikang Pharmaceutical Co., Ltd. |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20220110 Address after: 101114 Beijing city Tongzhou District Zhangjiawan Town Qi Shanzhuang East Village Applicant after: BEIJING SIHUAN PHARMACEUTICAL Co.,Ltd. Address before: 101113 Room 301, building 3, East qishanzhuang village, Zhangjiawan Town, Tongzhou District, Beijing (in the hospital of Beijing Sihuan Pharmaceutical Co., Ltd.) Applicant before: Beijing Aohe Pharmaceutical Research Institute Co.,Ltd. Applicant before: BEIJING SIHUAN PHARMACEUTICAL Co.,Ltd. Applicant before: Beijing Tianxinyuan Pharmaceutical Science and Technology Development Co.,Ltd. Applicant before: JILIN HUIKANG PHARMACEUTICAL Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220322 Address after: 101113 101, floor 3, building 8, courtyard 13, Guangyuan West Street, Tongzhou District, Beijing Patentee after: Beijing Xuansheng Pharmaceutical Co.,Ltd. Address before: 101114 Beijing city Tongzhou District Zhangjiawan Town Qi Shanzhuang East Village Patentee before: BEIJING SIHUAN PHARMACEUTICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right |