CN107213131A - Packaging technique for treating angiocardiopathy solid pharmaceutical preparation - Google Patents
Packaging technique for treating angiocardiopathy solid pharmaceutical preparation Download PDFInfo
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- CN107213131A CN107213131A CN201710132953.7A CN201710132953A CN107213131A CN 107213131 A CN107213131 A CN 107213131A CN 201710132953 A CN201710132953 A CN 201710132953A CN 107213131 A CN107213131 A CN 107213131A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Packaging technique for treating angiocardiopathy solid pharmaceutical preparation, the invention provides a kind of while suitable for bisulfate clopidogrel or the coating prescription and art for coating of A Lishatan esters, the prescription has has more preferable isolation effect compared with prior art, so that preparation can also keep stable in extreme circumstances, and then cause preparation to realize the preservation of longer time under customary storage conditions, be conducive to extending keeping life.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, specifically, the present invention relates to for treating angiocardiopathy solid pharmaceutical preparation
Packaging technique, including it is coated prescription and art for coating.
Background technology
With the raising of China's national life level, Chinese cardiovascular disease is in lasting ascent stage ill rate this year, according to
There are cardiovascular patient about 2.9 hundred million, wherein hypertension 2.7 hundred million in cardiovascular disease report in 2014, the current whole nation, and cerebral apoplexy is at least
7000000, myocardial infarction 2,500,000, heart failure 4,500,000, pulmonary heart disease 5,000,000, rheumatic heart disease 2,500,000, congenital heart disease 2,000,000, every 5 into
Nian Renzhong is to have 1 people to suffer from angiocardiopathy.By data above it can be seen that hypertension, cerebral apoplexy and myocardial infarction patient are in the heart
Accounting is maximum in vascular disease.
Clopidogrel (is also known as dextrorotation clopidogrel, CAS：113665-84-2), molecular formula：C16H16ClNO2S, is clinical mouth
Anticoagulation medication is taken, the platelet aggregation inhibitory action with inductivity reduces obstruction of artery by suppressing platelet aggregation
Chance, reach pre- anti-stroke and heart attack curative effect, and can effectively treat and prevention of arterial atherosis.Chlorine pyrrole lattice
Thunder clinic is administered with sulphate form, and the formulation products of clopidogrel mainly have Plavix (Plavix) and Shenzhen in the market
The Tai Jia of Xin Litai medicine companies limited company.
A Lishatan esters (CAS：947331-05-7), chemical name：The chloro- 1- of 2- butyl -4- [2 '-(1H-TETRAZOLE -5- bases) -
1,1 '-diphenyl-methyl]-imidazole-5-carboxylic acid, 1- [(isopropoxy)-carbonyloxy group]-methyl esters, is clinical antihypertensive, tool
There is angiotensin-ii receptor antagonism, A Lishatan esters are 1.1 listed by SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD
Kind new medicine, trade name：Letter is vertical smooth, compared with same type other antihypertensive products (such as Losartan), A Lishatan esters have small toxicity,
The excellent feature of antihypertensive effect.
Bisulfate clopidogrel and A Lishatan the esters form to be administered based on oral administration, its common formulation are being gone
Except be after coating white or off-white color.
The stability of medicine is one of major issue that formulation art needs solution, during storage, due to preparation matter
Amount is changed, and the change of color may be presented as in terms of formulation aesthetics and then clinical application is influenceed.Specifically, for sulfuric acid
Clopidogrel hydrogen and A Lishatan esters, its preparation, which is exposed to, has the different degrees of quality of the pharmaceutical preparations change when under hot and humid environment
Change and/or metachromatism.In field of pharmaceutical preparations, the technological means for solving above technical problem is various, such as adjustment preparation prescription,
Exterior and interior packing, coating formulation and technology etc., wherein it is a kind of effective solution to improve coating formulation and technology.Existing skill
It is coated more than art using single hydroxypropyl methylcellulose or commercially available coating material, such as Opadry (Opadry), its composition is more
For：Single hydroxypropyl methylcellulose, titanium dioxide, lactose etc., and commercially available coating material formula fixes, it is difficult to accomplish root
It is adjusted according to products characteristics.
Therefore, find a kind of simultaneously suitable for bisulfate clopidogrel and A Lishatan esters coating prescription and corresponding coating
Technique so that (such as hot and humid environment) is still protected in extreme circumstances for gained bisulfate clopidogrel and A Lishatan ester formulations
It is fixed to keep steady, and is the unsolved technical problem of prior art.
The content of the invention
First purpose of the present invention is to provide while suitable for the coating of bisulfate clopidogrel or A Lishatan esters
Prescription, the prescription has has more preferable isolation effect compared with prior art so that preparation (such as hot and humid ring in extreme circumstances
Border) it can also keep stable, and then cause preparation to realize the preservation of longer time under customary storage conditions, be conducive to extension
Keeping life.
The above-mentioned beneficial effect of the present invention is achieved through the following technical solutions：
It is a kind of to be used for the coating prescription of bisulfate clopidogrel or A Lishatan ester solid pharmaceutical preparations, include hydroxypropyl methylcellulose
I and hydroxypropyl methylcellulose II, it is characterised in that the hydroxypropyl methylcellulose I and hydroxypropyl methylcellulose II mass ratio is 1:1~
5。
The hydroxypropyl methylcellulose I is the hydroxypropyl methylcellulose that viscosity is 30~60mPa.s, the hydroxypropyl methylcellulose II
The hydroxypropyl methylcellulose for being 2.2~10mPa.s for viscosity.
For bisulfate clopidogrel and A Lishatan ester products, its coating membrane needs preferable isolation effect and protection against the tide
Property, certain adhesiveness and toughness is also met, commercially available coating material is generally fixed prescription, such as Opadry (Opadry), its
Prescription generally comprises filmogen (such as hydroxypropyl methylcellulose, acrylic resin, polyvinyl alcohol), plasticizer (such as polyethylene glycol
6000, triethyl citrate etc.), antiplastering aid (such as talcum powder), opacifier (such as titanium dioxide), commercially available preparation coating material
Because at least one in the properties such as adhesiveness, toughness, isolation effect is undesirable so that it can not meet hydrogen sulfate chlorine pyrrole
Gray and A Lishatan ester product higher quality storage requirements.Specifically, due to bisulfate clopidogrel and A Lishatan esters
Contain more disintegrant in preparation Core formulation so that tablet has stronger moisture absorption performance, when using at traditional films coating
When side is coated, due to the limitation of clothing film isolation effect, products obtained therefrom is easily influenceed and gone bad by extreme storage conditions, shows as tablet
After placing a period of time under the conditions of high humidity (RH92.5%) after except unlap, coating membrane would generally be cracking；And in height
(RH75%, 40 DEG C) was placed after a period of time under warm super-humid conditions, and coating membrane, which is opened, often splits rear piece wicking surface flavescence, even with
Increase coating thickness can not solve the technical problem using multiple coatings technique.
Research finds that being coated prescription using the hydroxypropyl methylcellulose mixture of different viscosities can solve by coating means
The further technical problem of extension bisulfate clopidogrel and A Lishatan ester formulations storage-stable in extreme circumstances.Specifically
, described to be used for the coating prescription of bisulfate clopidogrel or A Lishatan ester solid pharmaceutical preparations, the prescription includes highly viscous hydroxyl
Third methylcellulose I and low viscosity hydroxypropyl methylcellulose II, it is characterised in that the hydroxypropyl methylcellulose I and hydroxypropyl methylcellulose
II mass ratio is 1:1~5, wherein, hydroxypropyl methylcellulose I is the hydroxypropyl methylcellulose that viscosity is 30~60mPa.s, the hydroxyl
Third methylcellulose II is the hydroxypropyl methylcellulose that viscosity is 2.2~10mPa.s.Specifically, high viscosity hydroxypropyl first under the same terms
The compactness and clothing film intensity that cellulose forms coating membrane are superior to low viscosity hydroxypropyl methylcellulose, but high viscosity hydroxypropyl first is fine
The plain coating membrane of dimension can make the reduction of preparation dissolution rate, and its coating efficiency is not also good；And low viscosity hydroxypropyl methylcellulose can then be made into compared with
Highly concentrated solution, and then coating efficiency is improved, but the usual clothing film intensity of low viscosity hydroxypropyl methylcellulose is not good, in extreme storage bar
Preferable isolation effect can not be realized under part；Research is found, when the highly viscous hydroxyl using particular viscosity scope and special ratios
Mixing coating material obtained by the third methylcellulose I and hydroxypropyl methylcellulose II of low viscosity mixing, can take into account high viscosity hydroxypropyl
The advantage of methylcellulose and the hydroxypropyl methylcellulose of low viscosity, is coated prescription and is applied to bisulfate clopidogrel and A Lishatan esters
The coating of formulation products.The hydroxypropyl methylcellulose I is in 30~60mPa.s hydroxypropyl methylcellulose using commercially available viscosity
Can, such as HPMC 60RT50, HPMC E50, the hydroxypropyl methylcellulose II is using commercially available viscosity 2.2~10mPa.s's
Hydroxypropyl methylcellulose, such as HPMC 606, HPMC E5, HPMC E6, HPMC VLV, unless otherwise instructed, institute of the present invention
State viscosity and refer to and determinand is prepared into aqueous assay obtained, the detection of the viscosity is to use rotary viscosimeter, is adopted
Obtain that (specific method is recorded in the pass of Chinese Pharmacopoeia 2010 edition second with the detection of the second methods of Chinese Pharmacopoeia (2010 editions) annex VI G
In the quality standard of hydroxypropyl methylcellulose).Inventor had found by many experiments, the high viscosity hydroxypropyl in the range of particular viscosity
Methylcellulose I and low viscosity hydroxypropyl methylcellulose II are used in mixed way, and when ensureing in the range of certain proportion, the hydroxyl of gained mixing
Third methylcellulose can be several on preparation dissolution rate without influence while coating efficiency is ensured, and under extreme storage conditions still
Preferable isolation effect can be realized.It is preferred that, the hydroxypropyl methylcellulose I and hydroxypropyl methylcellulose II mass ratio is 1:2
~4.
The coating prescription can further contain opacifier, and the opacifier is the common opacifier in this area, such as two
Titanium oxide, zinc oxide, iron oxide etc., the consumption of the opacifier defer to consumption customary in the art, it is preferred that the opacifier
Consumption and hydroxypropyl methylcellulose I mass ratio be 1~2:1.
Foregoing coatings prescription can solve to improve bisulfate clopidogrel and A Lishatan ester formulations in extreme condition
The technical problem of lower storage quality, but for further optimisation technique scheme, the coating prescription can also further contain
The auxiliary materials such as plasticizer, antiplastering aid, the plasticizer is plasticizer commonly used in the art, such as Macrogol 6000, lemon triethylenetetraminehexaacetic acid
Ester etc., the consumption of the plasticizer defers to consumption customary in the art, it is preferred that the consumption and hypromellose of the plasticizer
Plain I mass ratio is 0.1~0.5:1；The antiplastering aid is antiplastering aid commonly used in the art, such as talcum powder, the antiplastering aid
Consumption defer to consumption customary in the art.
The preferred technical scheme of the present invention, the prescription is as follows：
| Title | Consumption (mass parts) |
| Hydroxypropyl methylcellulose I | 1.0 |
| Hydroxypropyl methylcellulose II | 3.0 |
The preferred technical scheme of the present invention, the prescription is as follows：
The preferred technical scheme of the present invention, the prescription is as follows：
| Title | Consumption (mass parts) |
| Hydroxypropyl methylcellulose I | 1.0 |
| Hydroxypropyl methylcellulose II | 3.0 |
| Titanium dioxide | 1.5 |
| Triethyl citrate | 0.4 |
The prescription of the present invention that is coated is used for the bisulfate clopidogrel and A Lishatan ester labels of all prior arts
In can reach and improve the technique effect that bisulfate clopidogrel and A Lishatan ester formulations store quality under extreme conditions,
It is preferred that, it is of the present invention coating prescription can be used for patent CN200610063151.7, CN200710129305.2,
What formulation and technology disclosed in CN201010579305.4, CN201010543097.2, CN201410324788.1 etc. was prepared
Clopidogrel bisulfate tablet core, and the A Lishatan that formulation and technology disclosed in patent CN200880001668.0 etc. is prepared
In ester label.The label of bisulfate clopidogrel and the A Lishatan ester can be common Clinical practice specification, specifically, institute
The label for stating bisulfate clopidogrel can be 25mg, 75mg, 300mg equal-specification, the labels of the A Lishatan esters can for 80mg,
240mg equal-specifications.
Second object of the present invention is to provide a kind of art for coating, the art for coating in bisulfate clopidogrel or
Used in A Lishatan ester formulations, be conducive to aiding in, coordinate foregoing coatings prescription to realize coating effect, and solve to improve hydrogen sulfate
Clopidogrel and A Lishatan ester formulations store the technical problem of quality under extreme conditions.
The above-mentioned beneficial effect of the technique is achieved through the following technical solutions：
A kind of art for coating, the art for coating is comprised the following steps：
1st, it will be uniformly dispersed in addition to hydroxypropyl methylcellulose in the ethanol of other auxiliary materials addition recipe quantity；
2nd, the hydroxypropyl methylcellulose for adding recipe quantity is uniformly dispersed；
3rd, the purified water for adding recipe quantity stirs, and obtains coating solution；
4th, label is added in seed-coating machine, preheated, EAT, coating pan rotating speed are set, spray into step
3 gained coating solutions are coated, and coating weight gain is 0.5%-5%.
For the ethanol in abovementioned steps 1, its object is to dispersed other auxiliary materials, step in addition to hydroxypropyl methylcellulose
1 ethanol uses percentage by volume for 95% and the ethanol of the above, such as absolute ethyl alcohol, 95% ethanol etc.；To make coating effect more
It is good, step 1 gained alcohol mixeding liquid can be crossed into 80-100 mesh sieves after being uniformly dispersed.
The purpose that purified water is added in step 3 is to dissolve hydroxypropyl methylcellulose.For bisulfate clopidogrel and A Li
Husky smooth ester active ingredient, the used in amounts of coating solution reclaimed water will be controlled, therefore ethanol in the final gained coating solution of the step 3 (with
Absolute ethyl alcohol meter) it should be 1~9 with the mass ratio of water:1；The concentration of hydroxypropyl methylcellulose described in step 3 can influence to be coated work
Skill, specifically, the hydroxypropyl methylcellulose of excessive concentrations can make it that coating fluid viscosity is excessive, it is impossible to realize spraying and be coated, and mistake
The excessive solvent of hydroxypropyl methylcellulose correspondence of low concentration is used so that the coating membrane compactness of formation is not good and Coating times
Long, coating efficiency is low.Therefore it is 5%~10% that the hydroxypropyl methylcellulose mass percent in coating solution, which need to be controlled,.
EAT described in step 4, coating pan rotating speed are the conventional coating process parameters in this area, it is preferred that institute
State EAT be 35~60 DEG C, coating pan rotating speed be 3~15r/min.
According to being actually needed for tablet, the technique that multiple coatings can be used, i.e. repeat step 1-3, and it is right in step 4
Corresponding coating solution is coated successively, to realize more preferable coating effect.Specifically, the coatings can be individual layer bag
Clothing or multiple coatings, wherein multiple coatings can preferably solve to improve bisulfate clopidogrel and A Lishatan esters
Preparation stores the technical problem of quality under extreme conditions, but the coating for crossing multilayer no longer corresponds to substantially carrying for storage quality
Height, in addition, excessive art for coating can also extend overall preparation process, improves preparation cost, therefore, the tablet coating is excellent
1-3 layers of coating are selected, more preferably 2 layers coating, different coatings can be coated prescription and technique using identical, can also basis
It is coated purpose and uses different coating prescription and technique.The coating weight gain preferably 1~4% of each layer of coating.
The preferred art for coating of the present invention, using double-layer coatings, wherein coatings I is internal layer coating, is only used
Hydroxypropyl methylcellulose, because the film forming and adhesion of hydroxypropyl methylcellulose are good, it is ensured that the humidity resistance of tablet, also causes piece
Face is smooth, suitable for further coating；Coatings II is outer layer coating, and it is further added on the basis of first layer clothing film prescription
It is other to be coated auxiliary material such as opacifier, plasticizer etc..The preferred art for coating uses foregoing coatings step and technological parameter.
The prescription of the coatings I is as follows：
| Title | Consumption (mass parts) |
| Hydroxypropyl methylcellulose I | 1.0 |
| Hydroxypropyl methylcellulose II | 3.0 |
The prescription of the coatings II is as follows：
| Title | Consumption (mass parts) |
| Hydroxypropyl methylcellulose I | 1.0 |
| Hydroxypropyl methylcellulose II | 3.0 |
| Titanium dioxide | 1.5 |
Or
The prescription of the coatings I is as follows：
| Title | Consumption (mass parts) |
| Hydroxypropyl methylcellulose I | 1.0 |
| Hydroxypropyl methylcellulose II | 2.0 |
The prescription of the coatings II is as follows：
| Title | Consumption (mass parts) |
| Hydroxypropyl methylcellulose I | 1.0 |
| Hydroxypropyl methylcellulose II | 3.0 |
| Titanium dioxide | 1.5 |
| Triethyl citrate | 0.4 |
The present invention has the following advantages and beneficial effect relative to prior art：
1st, provide a kind of while suitable for bisulfate clopidogrel or the coating prescription of A Lishatan esters, the prescription have compared with
Prior art has more preferable isolation effect so that preparation can also keep stable in extreme circumstances, and then cause preparation normal
The preservation of longer time can be realized under rule condition of storage, is conducive to extending keeping life；
2nd, a kind of art for coating is provided, the art for coating makes in bisulfate clopidogrel or A Lishatan ester formulations
With being conducive to aiding in, coordinate the present invention to be coated prescription to realize coating effect, and solve to improve bisulfate clopidogrel and A Lisha
Smooth ester formulation stores the technical problem of quality under extreme conditions.
Brief description of the drawings
Outward appearance comparison diagram of Fig. 1 embodiments 1 with the gained tablet of comparative example 1 after stability experiment is carried out 7 days
Embodiment
With reference to embodiment and accompanying drawing, the present invention is described in further detail, but the embodiment of invention is not limited to
This.
Embodiment 1
Clopidogrel bisulfate tablet core is prepared using method disclosed in patent CN200710129305.2 embodiments 1
(75mg), is coated using the following prescription that is coated to gained label.
1st, coating solution is prepared
Coatings I：Hydroxypropyl methylcellulose I (HPMC 60RT50) and hydroxypropyl methylcellulose II (HPMC606) are sequentially added
It is uniformly dispersed in 90.0g absolute ethyl alcohols；30.0g purified water is added, is stirred,
It is standby；
Coatings II：90.0g absolute ethyl alcohols are taken, titanium dioxide is added while stirring, 100 mesh sieves are crossed after being uniformly dispersed, after
Sequentially add recipe quantity hydroxypropyl methylcellulose I (HPMC 60RT50) and hydroxypropyl methylcellulose II (HPMC 606) is uniformly dispersed, most
30.0g purified waters are added afterwards to stir, it is standby.
2nd, it is coated
1000 labels are added in seed-coating machine, preheated, to set EAT be 40~50 DEG C, coating pan rotating speed be 5~
10r/min, the coating solution that coatings I and coatings II is sprayed into successively is coated, and obtains bisulfate clopidogrel coated tablet.
Wherein coatings I coating weight gain is 1%-2%, and coatings II coating weight gain is 1%-3%.
Embodiment 2
Clopidogrel bisulfate tablet core is prepared using method disclosed in patent CN200710129305.2 embodiments 1
(75mg), is coated using the following prescription that is coated to gained label.
1st, coating solution is prepared
Coatings I：Hydroxypropyl methylcellulose I (HPMC E50) and hydroxypropyl methylcellulose II (HPMC E5) are sequentially added
It is uniformly dispersed in 75.0g absolute ethyl alcohols；37.5g purified waters are added, are stirred, it is standby；
Coatings II：150g absolute ethyl alcohols are taken, titanium dioxide and triethyl citrate are added while stirring, after being uniformly dispersed
Cross 100 mesh sieves, after sequentially add recipe quantity hydroxypropyl methylcellulose I (HPMC E50) and hydroxypropyl methylcellulose II (HPMC E5) point
Dissipate uniform, be eventually adding 52.5g purified waters and stir, it is standby.
2nd, it is coated
Using double-layer coatings technique same as Example 1,1000 bisulfate clopidogrel coated tablets are obtained.It is coated
Layer I coating weight gain is 1%-2%, and coatings II coating weight gain is 1%-3%.
Embodiment 3
Clopidogrel bisulfate tablet core is prepared using method disclosed in patent CN200710129305.2 embodiments 1
(75mg), is coated using the following prescription that is coated to gained label.
1st, coating solution is prepared
Coatings I：Hydroxypropyl methylcellulose I (HPMC 60RT50) and hydroxypropyl methylcellulose II (HPMC606) are sequentially added
It is uniformly dispersed in 80.0g absolute ethyl alcohols；40.0g purified waters are added, are stirred, it is standby；
Coatings II：Hydroxypropyl methylcellulose I (HPMC 60RT50) and hydroxypropyl methylcellulose II (HPMC606) are added successively
Enter and be uniformly dispersed in 90.0g absolute ethyl alcohols；30.0g purified waters are added, are stirred, it is standby.
2nd, it is coated
Using double-layer coatings technique same as Example 1,1000 bisulfate clopidogrel coated tablets are obtained.It is coated
Layer I coating weight gain is 1%-2%, and coatings II coating weight gain is 1%-3%.
Embodiment 4
Clopidogrel bisulfate tablet core is prepared using method disclosed in patent CN200710129305.2 embodiments 1
(75mg), is coated using the following prescription that is coated to gained label.
| Title | Consumption (mass parts) | Consumption (g) |
| Hydroxypropyl methylcellulose I | 1.0 | 3.0 |
| Hydroxypropyl methylcellulose II | 2.5 | 7.5 |
1st, coating solution is prepared
By hydroxypropyl methylcellulose I (HPMC 60RT50) and hydroxypropyl methylcellulose II (HPMC 606) sequentially add 80.0g without
It is uniformly dispersed in water-ethanol；45.0g purified waters are added, are stirred, it is standby；
2nd, it is coated
1000 labels are added in seed-coating machine, preheated, to set EAT be 40~50 DEG C, coating pan rotating speed be 5~
10r/min, sprays into coating solution and is coated, obtain bisulfate clopidogrel coated tablet, coating weight gain is 3%-4%.
Comparative example 1
Clopidogrel bisulfate tablet core is prepared using method disclosed in patent CN200710129305.2 embodiments 1
(75mg), is coated using the following prescription that is coated to gained label.
Using commercially available stomach dissolved film coating pre-mix dose Opadry 295F680001 (Opadry295F680001) to 1000
Label obtained by piece is coated, using mass fraction be 75% ethanol as solvent, coating powder is prepared into 8% coating solution, adopted
With double-layer coatings technique same as Example 1, bisulfate clopidogrel coated tablet is obtained.Coatings I coating weight gain is
1%-2%, coatings II coating weight gain are dried for 1%-3%.
Comparative example 2
Clopidogrel bisulfate tablet core is prepared using method disclosed in patent CN200710129305.2 embodiments 1
(75mg), is coated using the following prescription that is coated to gained label.
1000 gained labels are wrapped using hydroxypropyl methylcellulose I (HPMC 60RT50) same as Example 1
Clothing, using mass fraction be 75% ethanol as solvent, coating powder is prepared into 8% coating solution, using same as Example 1
Double-layer coatings technique, obtains bisulfate clopidogrel coated tablet.Coatings I coating weight gain is 1%-2%, coatings II's
Coating weight gain is 1%-3%.
Embodiment 5
A Lishatan ester labels are prepared using method disclosed in patent CN200880001668.0 embodiments D5
(240mg), is coated using the following prescription that is coated to gained label.
| Title | Consumption (mass parts) | Consumption (g) |
| Hydroxypropyl methylcellulose I | 1.0 | 5.0 |
| Hydroxypropyl methylcellulose II | 3.5 | 17.5 |
| Titanium dioxide | 1.5 | 7.5 |
1st, coating solution is prepared
Coatings：Take 162.5g absolute ethyl alcohols, titanium dioxide added while stirring, after being uniformly dispersed cross 100 mesh sieves, after according to
Secondary addition recipe quantity hydroxypropyl methylcellulose I (HPMC 60RT50) and hydroxypropyl methylcellulose II (HPMC 606) are uniformly dispersed, finally
112.5g purified waters are added to stir, it is standby.
2nd, it is coated
Using art for coating same as Example 1, single coats, bag are carried out to 1000 gained A Lishatan esters labels
Clothing weightening is 2-4%.
Embodiment 6
A Lishatan ester labels are prepared using method disclosed in patent CN200880001668.0 embodiments D5
(240mg), is coated using the following prescription that is coated to gained label.
| Title | Consumption (mass parts) | Consumption (g) |
| Hydroxypropyl methylcellulose I | 1.0 | 5.0 |
| Hydroxypropyl methylcellulose II | 5.0 | 25.0 |
| Macrogol 6000 | 0.5 | 2.5 |
| Talcum powder | 4.0 | 20.0 |
| Titanium dioxide | 1.5 | 7.5 |
1st, coating solution is prepared
Coatings：Talcum powder, titanium dioxide, Macrogol 6000 are successively added and be uniformly dispersed in 300.0g absolute ethyl alcohols
100 mesh sieves are crossed afterwards；Sequentially add hydroxypropyl methylcellulose I (HPMC E50) and hydroxypropyl methylcellulose II (HPMC E5) is uniformly dispersed
150.0g purified waters are added afterwards, are stirred, it is standby；
2nd, it is coated
Using art for coating same as Example 1, single coats, bag are carried out to 1000 gained A Lishatan esters labels
Clothing weightening is 2-4%.
Comparative example 3
A Lishatan ester labels are prepared using method disclosed in patent CN200880001668.0 embodiments D5
(240mg), is coated using the following prescription that is coated to gained label.
| Title | Consumption (mass parts) | Consumption (g) |
| Hydroxypropyl methylcellulose I | 1.5 | 7.5 |
| Titanium dioxide | 1.5 | 7.5 |
1st, coating solution is prepared
Coatings：100.0g absolute ethyl alcohols are taken, titanium dioxide is added while stirring, 100 mesh sieves are crossed after being uniformly dispersed, it is rear to add
Enter hydroxypropyl methylcellulose I (HPMC 60RT50) same as Example 5 to be uniformly dispersed, be eventually adding the stirring of 40.0g purified waters equal
It is even, it is standby.
2nd, it is coated
Using art for coating same as Example 1, single coats, bag are carried out to 1000 gained A Lishatan esters labels
Clothing weightening is 2-4%.
Embodiment 7
Study on the stability
By embodiment 1-4, clopidogrel hydrogen sulfate tablet obtained by comparative example 1-2, which is removed, is placed in high temperature height after outer packing
Under the conditions of wet (RH75%, 40 DEG C), its steadiness under extreme storage environment is observed, it is as a result as follows：
* the outward appearance is to be measured after removing coatings
By to above Analysis of test results, hot and humid condition to the Color influences of clopidogrel coated tablet compared with
Greatly, specifically, coating prescription of the present invention keeps color to be basically unchanged in experimentation, it is possible to achieve in hot and humid bar
Storage-stable under part；
Comparative example 1 is coated using commercially available fixed prescription, because coating membrane ruptures under the conditions of hot and humid, causes production
Product gradually turn yellow in experimentation, and unilateral spot occur (embodiment 1 and the gained tablet of comparative example 1 are real in stability
The outward appearance comparison diagram tested after carrying out 7 days is as shown in Figure 1), impurity has also substantially increased in addition；
Comparative example 2 is coated using single hydroxypropyl methylcellulose, and it is equally coated under the conditions of hot and humid
Film ruptures so that product label after experiment 7 days is in buff, and it is unilateral there is more spot, impurity content, which is also corresponded to, to be increased.
By embodiment 5-6, the gained A Lishatan esters tablet of comparative example 3 is placed in hot and humid condition after removing outer packing
Under (RH75%, 40 DEG C), observe its steadiness under extreme storage environment, it is as a result as follows：
* the outward appearance is to be measured after removing coatings
By to above Analysis of test results, impurity situation of the hot and humid condition to A Lishatan ester coated tablets
Influence is larger, specifically, coating prescription of the present invention keeps total miscellaneous content to be basically unchanged in experimentation, it is possible to achieve
Storage-stable under the conditions of hot and humid；
Comparative example 3 is coated using single hydroxypropyl methylcellulose, and it easily occurs coating membrane under the conditions of hot and humid
Rupture so that product total miscellaneous content in experimentation is in the trend gradually increased, and is accelerated with the growth of experimental period
Increase.
Dissolving out capability is investigated
Using《Chinese Pharmacopoeia》(2010 editions) annex XC the second methods of dissolution determination method slurry processes respectively to embodiment 1-4 and
The dissolution rate of clopidogrel hydrogen sulfate tablet is detected that acquired results are as follows obtained by comparative example 1-2：
| Project | 30min dissolution rates (%) |
| Embodiment 1 | 97.6 |
| Embodiment 2 | 98.0 |
| Embodiment 3 | 97.4 |
| Embodiment 4 | 98.3 |
| Comparative example 1 | 97.5 |
| Comparative example 2 | 98.1 |
By the way that to above Analysis of test results, coatings influence for the dissolving out capability of clopidogrel hydrogen sulfate tablet
Smaller, coating prescription of the present invention can realize effective dissolution.
Using《Chinese Pharmacopoeia》(2010 editions) annex XC the second methods of dissolution determination method slurry processes respectively to embodiment 5-6 and
The dissolution rate of the gained A Lishatan ester tablets of comparative example 3 is detected that acquired results are as follows：
| Project | 45min dissolution rates (%) |
| Embodiment 5 | 87.6 |
| Embodiment 6 | 88.0 |
| Comparative example 3 | 87.5 |
By to above Analysis of test results, coatings for A Lishatan ester tablets dissolving out capability influence compared with
Small, coating prescription of the present invention can realize effective dissolution.
Above-described embodiment is preferably embodiment, but embodiments of the present invention are not by above-described embodiment of the invention
Limitation, other any Spirit Essences without departing from the present invention and the change made under principle, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (5)
1. a kind of clopidogrel bisulfate solid preparation, it is characterised in that the clopidogrel bisulfate solid preparation is made to be coated
Agent, the coating prescription is that viscosity is 30 comprising hydroxypropyl methylcellulose I and hydroxypropyl methylcellulose II, the hydroxypropyl methylcellulose I
~60mPa.s hydroxypropyl methylcellulose, the hydroxypropyl methylcellulose II is the hydroxypropyl methylcellulose that viscosity is 2.2~10mPa.s；
It is characterized in that the coatings of the clopidogrel bisulfate solid preparation are 2 layers, the prescription of the coatings I is as follows：
The prescription of the coatings II is as follows：
Or
The prescription of the coatings I is as follows：
The prescription of the coatings II is as follows：
2. clopidogrel bisulfate solid preparation according to claim 1, it is characterised in that the bisulfate clopidogrel
The prescription of solid pharmaceutical preparation is as follows：
3. the clopidogrel bisulfate solid preparation according to claim 1-2 any one, it is characterised in that the hydroxypropyl
Methylcellulose I is HPMC 60RT50, HPMC E50 any one or two or more mixtures, the hydroxypropyl methylcellulose
II for HPMC 606, HPMC E5, HPMC E6, HPMC VLV any one or two or more mixtures.
4. a kind of art for coating of the clopidogrel bisulfate solid preparation as described in claim 1-3 any one, the coating
Technique is comprised the following steps：
(1) it will be uniformly dispersed in addition to hydroxypropyl methylcellulose in the ethanol of other auxiliary materials addition recipe quantity；
(2) hydroxypropyl methylcellulose for adding recipe quantity is uniformly dispersed；
(3) purified water for adding recipe quantity stirs, and obtains coating solution；
(4) label is added in seed-coating machine, preheated, EAT, coating pan rotating speed are set, spray into coating solution obtained by step (3)
It is coated, coating weight gain is 0.5%-5%；
The ethanol of the step (1) uses percentage by volume for 95% and the ethanol of the above, alcohol mixeding liquid mistake obtained by step (1)
The mass ratio of ethanol and water is 1~9: 1 in 80-100 mesh sieves, the final gained coating solution of the step (3)；In the step (3)
Hydroxypropyl methylcellulose mass percent in coating solution is 5%~10%；In the step (4) EAT be 35~60 DEG C,
Coating pan rotating speed is 3~15r/min.
5. art for coating according to claim 4, it is characterised in that the coating weight gain is 1~4%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710132953.7A CN107213131A (en) | 2015-09-08 | 2015-09-08 | Packaging technique for treating angiocardiopathy solid pharmaceutical preparation |
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| CN201710132953.7A CN107213131A (en) | 2015-09-08 | 2015-09-08 | Packaging technique for treating angiocardiopathy solid pharmaceutical preparation |
| CN201510564484.7A CN105168166A (en) | 2015-09-08 | 2015-09-08 | Coating technique of solid preparation for treating cardiovascular diseases |
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| CN105168166A (en) * | 2015-09-08 | 2015-12-23 | 深圳信立泰药业股份有限公司 | Coating technique of solid preparation for treating cardiovascular diseases |
| CN108420798B (en) * | 2017-02-15 | 2021-03-02 | 江苏威凯尔医药科技有限公司 | Quick-release medicinal preparation of anticoagulant and preparation method thereof |
| EP3782621A4 (en) | 2018-04-16 | 2021-12-22 | Jiangsu Vcare Pharmatech Co., Ltd | Instant release pharmaceutical preparation of anticoagulant and preparation method therefor |
| CN115212180B (en) * | 2022-09-03 | 2024-05-10 | 深圳市信宜特科技有限公司 | Compound preparation of aspirin and clopidogrel bisulfate and preparation method thereof |
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| AU2005313262B2 (en) * | 2004-12-07 | 2010-08-19 | Les Laboratoires Servier | Tablets for the sustained release of indapamide and preparation method thereof |
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| JP5946641B2 (en) * | 2008-09-25 | 2016-07-06 | アイエスピー インヴェストメンツ インコーポレイテッドＩｓｐ Ｉｎｖｅｓｔｍｅｎｔｓ Ｉｎｃ． | Smooth, high solid tablet coating composition |
| CN103893773B (en) * | 2014-04-04 | 2016-10-05 | 成都科特包衣技术有限公司 | A kind of oil resistivity stomach dissolution type film-coating premixing auxiliary material and preparation method thereof |
| CN105168166A (en) * | 2015-09-08 | 2015-12-23 | 深圳信立泰药业股份有限公司 | Coating technique of solid preparation for treating cardiovascular diseases |
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- 2015-09-08 CN CN201510564484.7A patent/CN105168166A/en active Pending
- 2015-09-08 CN CN201710132953.7A patent/CN107213131A/en active Pending
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| AU2005313262B2 (en) * | 2004-12-07 | 2010-08-19 | Les Laboratoires Servier | Tablets for the sustained release of indapamide and preparation method thereof |
| CN101690719A (en) * | 2007-07-01 | 2010-04-07 | 深圳信立泰药业股份有限公司 | Bisulfate clopidogrel solid preparation, particles and preparation method thereof |
| CN101176723A (en) * | 2007-12-18 | 2008-05-14 | 严洁 | Ranolazine sustained release tablets |
| CN102247333A (en) * | 2010-05-18 | 2011-11-23 | 山东方明药业股份有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
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| CN103768063A (en) * | 2012-10-19 | 2014-05-07 | 深圳信立泰药业股份有限公司 | Moxifloxacin hydrochloride pharmaceutical composition and preparation method thereof |
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| CN105168166A (en) | 2015-12-23 |
| WO2016161990A2 (en) | 2016-10-13 |
| WO2016161990A3 (en) | 2016-11-24 |
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