CN103211785B - Acipimox film-controlled slow-release micro pill capsule - Google Patents
Acipimox film-controlled slow-release micro pill capsule Download PDFInfo
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- CN103211785B CN103211785B CN201210014352.3A CN201210014352A CN103211785B CN 103211785 B CN103211785 B CN 103211785B CN 201210014352 A CN201210014352 A CN 201210014352A CN 103211785 B CN103211785 B CN 103211785B
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- sustained release
- film
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- capsule core
- release
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- 239000002775 capsule Substances 0.000 title claims abstract description 115
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical compound CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960003526 acipimox Drugs 0.000 title claims abstract description 48
- 239000006187 pill Substances 0.000 title claims abstract description 36
- 238000013268 sustained release Methods 0.000 claims abstract description 51
- 239000012730 sustained-release form Substances 0.000 claims abstract description 51
- 238000000576 coating method Methods 0.000 claims abstract description 30
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims abstract description 29
- 239000011248 coating agent Substances 0.000 claims abstract description 27
- 230000032683 aging Effects 0.000 claims abstract description 18
- 239000008188 pellet Substances 0.000 claims abstract description 14
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000004584 weight gain Effects 0.000 claims abstract description 10
- 235000019786 weight gain Nutrition 0.000 claims abstract description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 9
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000013769 triethyl citrate Nutrition 0.000 claims abstract description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 7
- 239000008101 lactose Substances 0.000 claims abstract description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 7
- 239000001069 triethyl citrate Substances 0.000 claims abstract description 7
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000006641 stabilisation Effects 0.000 claims abstract description 5
- 238000011105 stabilization Methods 0.000 claims abstract description 5
- 239000004014 plasticizer Substances 0.000 claims abstract description 4
- 239000006185 dispersion Substances 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- 239000007888 film coating Substances 0.000 claims description 14
- 238000009501 film coating Methods 0.000 claims description 14
- 230000002459 sustained effect Effects 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 26
- 230000035699 permeability Effects 0.000 abstract description 11
- 230000003578 releasing effect Effects 0.000 description 29
- 238000002360 preparation method Methods 0.000 description 16
- 239000003814 drug Substances 0.000 description 15
- 239000007788 liquid Substances 0.000 description 14
- 238000005516 engineering process Methods 0.000 description 13
- 210000002784 stomach Anatomy 0.000 description 13
- 238000003556 assay Methods 0.000 description 11
- 229940079593 drug Drugs 0.000 description 8
- 239000012530 fluid Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- 239000012467 final product Substances 0.000 description 7
- 210000000936 intestine Anatomy 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000001828 Gelatine Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 150000003626 triacylglycerols Chemical class 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 210000001187 pylorus Anatomy 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000011122 softwood Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- -1 hydroxypropyl Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000627 niacin group Chemical group 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of Acipimox film-controlled slow-release micro pill capsule, the sustained release clothing film of its micropill is using Eurdragit NE 30D as filmogen, low-substituted hydroxypropyl cellulose containing high-expansion in capsule core, and the conventional excipient of pharmaceutically acceptable sustained release pellet, excipient preferably microcrystalline cellulose and lactose, wherein, the percentage that low-substituted hydroxypropyl cellulose accounts for capsule core weight in capsule core is 10~40%.Sustained release clothing film includes Eurdragit NE 30D, plasticizer triethyl citrate and antiplastering aid talcum powder, and its ratio is preferably Eurdragit NE 30D: triethyl citrate: talcum powder=30: 2: 4, coating weight gain is preferably 20~39%.Due to containing the capsule core with the low-substituted hydroxypropyl cellulose for meeting water high-expansion, can substantially be expanded after water suction, sustained release clothing film is caused to be stretched, thickness is thinning, and the aperture of permeable micropore becomes big, and permeability improves, the permeability that compensate for the aging generation of film declines, so that middle and later periods rate of release substantially constant, latter stage residual is small, can before the deadline remain the release performance of stabilization.
Description
Technical field
The present invention relates to a kind of Acipimox film-controlled slow-release micro pill capsule, it particularly relates to a kind of capsule core contains low taking
For the Acipimox film-controlled slow-release micro pill capsule of hydroxypropylcellulose, belong to field of pharmaceutical preparations.
Background technology
Acipimox is nicotinic acid derivates, can suppress the decomposition of adipose tissue, reduces free fatty and is released from adipose tissue
Put, so that synthesis of the triglycerides (TG) in liver is reduced, and by suppressing VLDL (VLDL) and low density lipoprotein
The synthesis of albumen (LDL), declines the concentration of triglycerides (TG) and T-CHOL (TC) in blood, for treating high glycerine three
Ester mass formed by blood stasis (IV types), hypercholesterolemia (IIa types), high triglyceride merge hypercholesterolemia (IIb types).Clinic is to this kind of
The basic demand of medicine is can long-acting control symptom.
Acipimox is slightly molten in water, and listing is ordinary preparation earliest, need to be taken 2-3 times daily, blood concentration fluctuation
Greatly, Cmax is too high, and adverse reaction is serious.The half-life short (1.5 hours) of Acipimox, suitably develops into sustained release agent.
Sustained release pellet is that medicine is made into multiunit slow-release system, general to load oral, capsule dissolving after capsule
Afterwards, sustained release pellet can extensively, be evenly distributed in intestines and stomach.Distribution area of the medicine on stomach and intestine surface increases, and is ensureing medicine
Thing can also effectively reduce stimulation of the medicine to intestines and stomach while uniformly release.Micropill preparation particle diameter is smaller, turning in intestines and stomach
Fortune is not influenceed by the food conveying rhythm and pace of moving things, though when pyloric sphincter is closed, remain to by pylorus, therefore particulate is in intestines and stomach
Absorption do not influenceed by gastric emptying typically.What is more important, the drug release behavior of micropill system is each of one dosage of composition
The summation of individual micropill drug release behavior, error or defect of indivedual micropills in preparation will not be produced to the drug release behavior of whole preparation
Have a strong impact on, therefore better than the slow, Dospan being made up of a unit in terms of the reappearance and uniformity of drug release rule.
Acipimox is suitable to be made sustained-release pellet preparation, and the effective blood drug concentration duration is long, blood concentration fluctuation is small, pair
The small, individual difference of effect is small, patient compliance is good.
The most frequently used implementation method of sustained release pellet is to use film controlling type, i.e., the outside solution coating method in capsule core wraps one
Layer sustained release clothing film, sustained release clothing film contains filmogen, plasticizer, antiplastering aid etc..It is many in one's early years that sustained release is prepared using organic solvent
The coating solution of clothing film, because organic solvent coating solution has pollution and safety issue, in order to overcome organic solvent coating solution
Defect, aqueous dispersion packaging technique is used widely, and conventional aqueous dispersion has Aquacoat, acrylic acid tree
Lipid aqueous dispersion, polyvinyl acetate ester aqueous dispersion etc., such as polyvinyl acetate ester aqueous dispersion Kollicoat SR 30D,
Crylic acid resin aqueous dispersion Eurdragit RL 30D, Eurdragit RS 30D, Eurdragit NE30D and ethyl
Cellulose aqueous dispersions Aquacoat and Surelease, however we have found that：The Acipimox for preparing is coated using aqueous dispersion
Film controlling type sustained-release micro-pill capsules, within a period of time for just having prepared, its release performance is good, but after storage a period of time,
Its release performance begins to decline, and storage time is more long, declines more obvious, the term of validity latter half for often specifying in medicine, release
Performance is decreased obviously.Analysis reason because coating membrane during placement because aqueous dispersion particulate continues to be combined with each other
Cause gradually to compact, cause membrane permeability to decline, make release slack-off, popular saying is aging.
The content of the invention
It is coated under the aging release for bringing of film of the Acipimox film controlling type sustained release pellet for preparing to solve aqueous dispersion
The problem of drop, the invention provides a kind of film controlling type Acipimox of the release performance that can before the deadline remain stabilization
Sustained-release micro-pill capsules, feature be micropill capsule core in containing have meet water high-expansion low-substituted hydroxypropyl cellulose, lead to
Water swelling is crossed so that sustained release coating film is deformed upon, so as to counteract the aging of film.
The conventional aqueous dispersion type coating material of the current slow controlled release micro pill of film controlling type, such as Eurdragit NE 30D, its
In macromolecular material it is in itself and water insoluble, but be dispersed in water in particulate form, and after the mixing such as plasticizer, antiplastering aid
Aqueous dispersion coating solution is obtained, micropill surface is sprayed on through spray gun, this operation is referred to as being coated；When being coated firm beginning, micropill table
These aqueous dispersions in face exist with substantial amounts of discontinuous particle shape, increase as coating solution is sprayed into, and these particles are mutual
Contact, deformation, cohesion, last mutually partial fusion, form a discontinuous film；Then it is heat-treated, after water volatilization, is gathered
Polymer beads are then connected with each other, fusion completely forms coating membrane.It is heat-treated releasing to the film-controlled slow-release micropill of aqueous dispersion coating
Put performance impact very big：Heat treatment not enough if, such as time is too short or temperature is too low, in coatings polymer beads it
Between also contain micro water, it may proceed to evaporate within follow-up storage period, continuing with film becomes more between particle
Compact, permeability declines causes release slack-off；In order to avoid such case, generally using the method for increasing heating strength come gram
Clothes, for example increase heat treatment time or improve heat treatment temperature, but it is this treatment easily lead to heat treatment it is excessive, cause
Film is excessively dried and compacted, even if initial stage release is qualified, but it is within follow-up storage period, the film for compacting originally can due to from
In environment water suction and film-forming high molecular material creep and become loose, permeability rise, cause release to accelerate.Practice have shown that,
For film controlling type slow-releasing acipimox micropill, because insoluble drug release is completely by spreading thus aging to film caused penetrating
Property declines very sensitive, and the just right release property to ensure to remain before the deadline stabilization is accomplished by Technology for Heating Processing
Can be highly difficult, the temperature and time being in most cases heat-treated is inadequate, and often later stage release is substantially slack-off.
For above-mentioned mechanism, the present inventor is surprised to find that by research：If the Acipimox film that aqueous dispersion is coated
Control type sustained release pellet uses the capsule core of the low-substituted hydroxypropyl cellulose containing high-expansion, due to low-substituted hydroxypropyl cellulose
Expansion rate of water absorption is up to 500%~700%, can substantially be expanded after capsule core water suction so that micropill volume becomes big, causes release membranes quilt
Support is big, and thickness is thinning, and the aperture of permeable micropore becomes big, and permeability improves, and can compensate heat treatment deficiency causes that film is aging to be produced
Raw permeability declines, so that middle and later periods rate of release substantially constant, latter stage remains small.Heat treatment can additionally be eliminated
The excessive influence for causing film too to compact, it is to avoid the day change of release performance that comes of caudacoria Relaxation Zone so that it is whole effectively
Drug releasing rate substantially constant in phase.The Acipimox film-controlled slow-release micropill of aqueous dispersion coating can so be greatly improved
Ageing resistace.Due to the high-expansion of low-substituted hydroxypropyl cellulose in capsule core, expansive force is very big, as standing time increases
Plus, the expansion rate after micropill water suction is basically unchanged, and no matter can cause that release membranes occur irreversible plastic deformation after being stretched
How film changes (become loose or become and compact) can support and arrive similar degree greatly, so as to ensure that the permeability of film is basically unchanged.
Preferably, Acipimox film-controlled slow-release micro pill capsule of the invention, the sustained release clothing film use of its micropill
Eurdragit NE30D as filmogen, the low-substituted hydroxypropyl cellulose containing high-expansion in capsule core, and pharmaceutically may be used
The conventional excipient of the sustained release pellet of receiving, excipient preferably microcrystalline cellulose and lactose, wherein, low-substituted hydroxypropyl is fine in capsule core
The percentage that dimension element accounts for capsule core weight is 10~40%.Sustained release clothing film includes Eurdragit NE 30D and antiplastering aid talcum powder,
Its ratio is preferably Eurdragit NE 30D: triethyl citrate: talcum powder=30: 2: 4, coating weight gain is preferably 20~
39%.
As one of the preferred embodiment of the present invention, at the micropill of Acipimox film-controlled slow-release micro pill capsule of the invention
Side is as follows：
First, capsule core prescription (1000 meters)
2nd, it is sustained clothing film prescription
It is preferred that sustained release clothing film coating weightening is 20~39%.
It is anti-aging invention also provides a kind of Acipimox film-controlled slow-release micro pill capsule for improving aqueous dispersion coating
The method of performance, it is characterized in that the sustained release clothing film of micropill uses aqueous dispersion Eurdragit NE 30D as filmogen, ball
Core contains low-substituted hydroxypropyl cellulose and the conventional excipient of sustained release pellet, excipient preferably microcrystalline cellulose and lactose.Wherein
The percentage that low-substituted hydroxypropyl cellulose accounts for capsule core weight in capsule core is 10~40%, and sustained release clothing film includes aqueous dispersion
Eurdragit NE 30D and antiplastering aid talcum powder, weight ratio are Eurdragit NE 30D: triethyl citrate: talcum powder=
30: 2: 4, coating weight gain is 20~39%.The above method it is preferred, be based on 1000 capsules, micropill use following prescription：
First, capsule core prescription (1000 meters)
2nd, it is sustained clothing film prescription
It is preferred that sustained release clothing film coating weightening is 20~39%.
The preparation method of film controlling type slow-releasing acipimox micropill of the present invention, can be according to film controlling type in the prior art
Delay the general technology of controlled release micro pill to prepare, including batch mixing, pill core, the slow clothing film of bag etc., it is preferred to use extrusion spheronization method
Prepare capsule core.The sustained release pellet that will be made loads common stomach dissolution type gelatine capsule, that is, obtain Acipimox film-controlled slow-release micropill glue
Capsule.
Film controlling type slow-releasing acipimox micro pill capsule of the present invention has the following advantages：
1) confrontation sustained release clothing film is aging：With aqueous dispersion Eurdragit NE 30D+ triethyl citrates+talcum powder group
Into sustained release clothing film can be aging, reason is that aqueous dispersion particulate is combined and promotes film aging, causes membrane permeability to reduce, and contain tool
There is the capsule core of the low-substituted hydroxypropyl cellulose for meeting water high-expansion, can substantially be expanded after water suction, cause sustained release clothing film to be stretched,
Thickness is thinning, and the aperture of permeable micropore becomes big, and permeability improves, and the permeability that compensate for the aging generation of film declines, so that
Middle and later periods rate of release substantially constant, latter stage residual is small, can before the deadline remain the release performance of stabilization.
2) supporting role：Using the capsule core of the low-substituted hydroxypropyl cellulose with water swelling, can be obvious after water suction
Expansion is played a supporting role, and medicine is dashed forward caused by can avoiding the extruding by intestines and stomach in intestines and stomach operation process in vivo
Release.
Specific embodiment
The slow-releasing acipimox micro pill capsule of the common capsule core of embodiment 1
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000
2nd, preparation technology：
1st, capsule core preparation technology：
(1) Acipimox is crossed into 60 mesh sieves；
(2) Acipimox, microcrystalline cellulose PH101, the lactose of recipe quantity are weighed, is put in wet granulator and is well mixed；
The ethanol solution softwood of (3) 1% sodium carboxymethylcellulose 10%；
(4) put and extruded on extruder, mesh size is 1.0mm, extruded velocity is 20~30rpm；
(5) round as a ball, round as a ball speed is 900~1000rpm, is dried in fluid bed；
(6) sieve, take the capsule core between 16~30 mesh.
2nd, it is sustained clothing film coating liquid preparing process：
The triethyl citrate for weighing recipe quantity puts the water of recipe quantity, stirs, and adds the talcum powder of recipe quantity,
Stirring shearing is uniform, is eventually adding Eurdragit NE 30D, stirs, and obtains final product.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 14.8%.
4th, it is heat-treated：
The micropill of extended release coatings will be wrapped in fluid bed, be heat-treated under the conditions of 40 DEG C/2h.
5th, capsule is filled
Coating micro-pill filling capsule is obtained final product.
3rd, release, assay and result
Assay is determined according to high effective liquid chromatography for measuring (two annex V D of China's coastal port).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler；Methyl alcohol -0.01mol/L
Tetrabutylammonium (20: 80) (with phosphorus acid for adjusting pH value to 6.0) is mobile phase, and Detection wavelength is 264nm, theoretical cam curve
Being calculated by Acipimox peak should be not less than 2000, and the separating degree at Acipimox peak and other impurities peak should meet regulation.
Determination method takes this product 10, pours out content, and accurately weighed content is finely ground, precision weigh fine powder it is appropriate (containing about
Acipimox 20mg), in putting 100ml measuring bottles, plus appropriate mobile phase, ultrasound dissolves main ingredient, constant volume, filtration, and precision measures continuous
Filtrate 5ml, is put in 50ml measuring bottles, and scale is diluted to mobile phase, and used as need testing solution, another precision weighs Acipimox control
Appropriate product, plus mobile phase is made into solution of the 1ml containing about the μ g of Acipimox 20, and used as reference substance solution, it is molten that precision measures test sample
Liquid and each 20 μ 1 of reference substance solution, inject liquid chromatograph, record chromatogram, by external standard method with calculated by peak area content, obtain final product.
Release takes this product, according to drug release determination method (two methods of annex XD first of China's coastal port), using molten
Out-degree determination method (two the first methods of annex X C of China's coastal port) device, with the hydrochloric acid solution 1000ml of 0.1mol/L
It is solvent, 100 turns per minute of rotating speed is operated in accordance with the law, separately sampled 10ml during through 1 hour, 3 hours, 5 hours, filtration, and in time
Mutually synthermal dissolution medium 10ml is supplemented in process container, precision measures subsequent filtrate 5ml, put in 100ml measuring bottles, used
The hydrochloric acid solution of 0.1mol/L is diluted to scale, used as need testing solution；Another precision weighs the Ah former times through 105 DEG C of dryings to constant weight
Department's reference substance is not appropriate, plus the hydrochloric acid solution of 0.1mol/L is made the solution containing 7.5 μ g in every 1ml, used as reference substance solution.Point
Need testing solution and reference substance solution are not taken, according to UV-VIS spectrophotometry (two annex of China's coastal port
IVA), determine trap respectively at the wavelength of 269nm, calculate every burst size in different time.This product every is small the 1st
When, 3 hours and burst size at 5 hours should be respectively 15~35%, 60~85% and more than the 80% of labelled amount, all should meet
Regulation.
Result such as table 1：
The releasing result of 1 embodiment of table 1
Result shows that slow-releasing acipimox micro pill capsule of the capsule core of embodiment 1 without intumescent material, initial release is good,
As standing time increases, film is constantly aging, and rate of release is slack-off, and residual substantially increases.
4th, expansion rate is determined
Assay method：37 DEG C of distillation appropriate amount of water is preheated to being added in 100ml measuring bottles, is dipped in 37 DEG C of water-baths and with steaming
Distilled water constant volume is to standby after scale；3 500ml beakers are taken, the distilled water that 300ml is preheated to 37 DEG C is separately added into, 37 are immersed in
It is standby in DEG C water-bath；Take capsule to be measured 10, remove capsule shells, micropill in capsule is poured out, it is fast in putting above-mentioned 100ml measuring bottles
Speed minimum scale value be 0.01ml pipette, extract measuring bottle in distilled water until liquid level is fallen after rise to measuring bottle scale, then accurately
The volume of water in pipette is read, the average external volume of micropill in every capsule is calculated, V is designated as0.30 capsules to be measured are taken, is divided into 3
Group, removes capsule shells by every group 10, and micropill in capsule is poured out, and immersion in above-mentioned 3 500ml beakers is put respectively, exists respectively
1h, 3h, 5h respectively take out 1 group, filtration, and the water of micropill surface residual is blotted with filter paper, and that has been put again that constant volume crosses is above-mentioned
In the measuring bottle of 100ml, rapidly with distilled water in above-mentioned pipette, extract measuring bottle until liquid level is fallen after rise to measuring bottle scale, then accurately
The volume of water in pipette is read, the average external volume of micropill in every capsule is calculated, V is designated asT.When being calculated as follows each sampling
Between put expansion rate, the results are shown in Table 2.
Computing formula：Expansion rate (%)=(VT-V0)/V0× 100%
Expansion rate result after the placement for a long time of the room temperature of table 2
Test result indicate that, slow-releasing acipimox micro pill capsule of the capsule core without intumescent material, micropill expansion rate is smaller,
And as room temperature is placed for a long time, expansion rate reduces therewith, the effect aging without sustained release clothing film is offset.
Slow-releasing acipimox micro pill capsule of the embodiment 2 containing 10% low-substituted hydroxypropyl cellulose
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription：With embodiment 1.
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000.
2nd, preparation technology：
1st, capsule core preparation technology：
(1) Acipimox is crossed into 60 mesh sieves；
(2) Acipimox, microcrystalline cellulose PH101, lactose, the low-substituted hydroxypropyl cellulose of recipe quantity are weighed, wet method is put
It is well mixed in granulator；
The ethanol solution softwood of (3) 1% sodium carboxymethylcellulose 10%；
(4) put and extruded on extruder, mesh size is 1.0mm, extruded velocity is 20~30rpm；
(5) round as a ball, round as a ball speed is 900~1000rpm, is dried in fluid bed；
(6) sieve, take the capsule core between 16~30 mesh.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 20.1%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：Coating micro-pill filling capsule is obtained final product.
3rd, release, assay and result
Assay method：With embodiment 1,3 are the results are shown in Table：
The releasing result of 3 embodiment of table 2
Result shows, at the beginning of the slow-releasing acipimox micro pill capsule of the capsule core containing low-substituted hydroxypropyl cellulose 10% of embodiment 2
Beginning release performance is good, and as standing time increases, still very well, end point discharges the equal very little of residual to releasing effect.
4th, swelling rate test
Experimental technique：With embodiment 1,4 are the results are shown in Table：
Expansion rate result after the placement for a long time of the room temperature of table 4
Result shows, the slow-releasing acipimox micro pill capsule of capsule core low-substituted hydroxypropyl cellulose containing intumescent material 10%,
Micropill expansion rate is larger, and under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Slow-releasing acipimox micro pill capsule of the embodiment 3 containing 20% low-substituted hydroxypropyl cellulose
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription：With embodiment 1
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000
2nd, preparation technology：
1st, capsule core preparation technology：With embodiment 2.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 26.2%, 31.6%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：Coating micro-pill filling capsule is obtained final product.
3rd, release, assay and result
Assay method：With embodiment 1,5 are the results are shown in Table：
The releasing result of 5 embodiment of table 3
Result shows that capsule core contains the slow-releasing acipimox micro pill capsule initial release performance of low-substituted hydroxypropyl cellulose 20%
Good, as standing time increases, still very well, the release equal very little of residual is put at end to releasing effect.
4th, expansion rate experiment
Experimental technique：With embodiment 1,6 are the results are shown in Table：
Expansion rate result after the placement for a long time of the room temperature of table 6
Result shows that capsule core contains the slow-releasing acipimox micro pill capsule of low-substituted hydroxypropyl cellulose 20%, micropill expansion rate
Larger, under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Slow-releasing acipimox micro pill capsule of the embodiment 4 containing 30% low-substituted hydroxypropyl cellulose
First, prescription
1. capsule core prescription (1000)
2. clothing film coating liquid prescription is sustained：With embodiment 1.
No. 3.0 stomach dissolution type gelatine capsule shells 1000.
2nd, preparation technology
1st, capsule core preparation technology：With embodiment 2.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 35.8%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：Coating micro-pill filling capsule is obtained final product.
3rd, release, assay and result
Assay method：With embodiment 1,7 are the results are shown in Table：
The releasing result of 7 embodiment of table 4
Result shows that capsule core contains the slow-releasing acipimox micro pill capsule initial release performance of low-substituted hydroxypropyl cellulose 30%
Good, as standing time increases, still very well, the release equal very little of residual is put at end to releasing effect.
4th, expansion rate experiment
Experimental technique：With embodiment 1,8 are the results are shown in Table：
Expansion rate after the placement for a long time of the room temperature of table 8
Result shows that slow-releasing acipimox capsule of the capsule core containing low-substituted hydroxypropyl cellulose 30%, expansion rate is larger, room temperature
Under long-term placement, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Slow-releasing acipimox micro pill capsule of the embodiment 5 containing 40% low-substituted hydroxypropyl cellulose
First, prescription
1. capsule core prescription (1000)
2. clothing film coating liquid prescription is sustained：With embodiment 1.
No. 3.0 stomach dissolution type gelatine capsule shells 1000.
2nd, preparation technology
1st, capsule core preparation technology：With embodiment 2.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 38.7%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：Coating micro-pill filling capsule is obtained final product.
3rd, release, assay and result
Assay method：With embodiment 1,9 are the results are shown in Table：
The releasing result of 9 embodiment of table 5
Result shows that capsule core contains the slow-releasing acipimox micro pill capsule initial release performance of low-substituted hydroxypropyl cellulose 40%
Good, as standing time increases, still very well, the release equal very little of residual is put at end to releasing effect.
4th, expansion rate experiment
Experimental technique：With embodiment 1,10 are the results are shown in Table：
Expansion rate after the placement for a long time of the room temperature of table 10
Result shows that capsule core contains the slow-releasing acipimox micro pill capsule of low-substituted hydroxypropyl cellulose 40%, micropill expansion rate
Larger, under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Claims (4)
1. a kind of Acipimox film-controlled slow-release micro pill capsule of the release performance that can before the deadline remain stabilization, it is special
Levy be micropill sustained release clothing film using Eurdragit NE 30D as filmogen, capsule core contain low-substituted hydroxypropyl cellulose and
The excipient of other pharmaceutically acceptable sustained release pellets, the excipient of other pharmaceutically acceptable sustained release pellets
It is microcrystalline cellulose and lactose, the percentage that low-substituted hydroxypropyl cellulose accounts for capsule core weight in the capsule core of micropill is 10~40%,
The sustained release clothing film of micropill includes Eurdragit NE 30D, plasticizer triethyl citrate and antiplastering aid talcum powder, is sustained clothing film
Composition weight ratio be Eurdragit NE 30D: triethyl citrate: talcum powder=30: 2: 4, coating weight gain be 20~
39%.
2. a kind of Acipimox film-controlled slow-release micro pill capsule as claimed in claim 1, it is characterized in that based on 1000 capsules, institute
Stating micropill has following prescription：
Capsule core prescription：
Sustained release clothing film prescription：
Sustained release clothing film coating weightening is 20~39%.
3. it is a kind of improve aqueous dispersion be coated Acipimox film-controlled slow-release micro pill capsule ageing resistace method, it is characterized in that
Using Eurdragit NE 30D as filmogen, the capsule core of micropill contains low-substituted hydroxypropyl cellulose to the sustained release clothing film of micropill
With the excipient of other pharmaceutically acceptable sustained release pellets, the figuration of other pharmaceutically acceptable sustained release pellets
Agent is microcrystalline cellulose and lactose, and the percentage that low-substituted hydroxypropyl cellulose accounts for capsule core weight in capsule core is 10~40%, micropill
Sustained release clothing film is comprising Eurdragit NE 30D and antiplastering aid talcum powder and weight ratio is Eurdragit NE 30D: talcum powder
=30: 4, coating weight gain is 20~39%.
4. method as claimed in claim 3, it is characterized in that based on 1000 capsules, the micropill uses following prescription：
Capsule core prescription：
Sustained release clothing film prescription：
Sustained release clothing film coating weightening is 20~39%.
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| CN103536595B (en) * | 2013-10-15 | 2015-04-22 | 海南卫康制药(潜山)有限公司 | Acipimox composition tablet |
| CN103893152A (en) * | 2014-03-28 | 2014-07-02 | 北京联合大学 | Method for preparing acipimox-ethylcellulose sustained release micro-capsule |
| WO2021042278A1 (en) * | 2019-09-04 | 2021-03-11 | 鲁南贝特制药有限公司 | Multi-unit sustained-release acipimox pellet tablet and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
| CN101732285A (en) * | 2010-02-01 | 2010-06-16 | 鲁南贝特制药有限公司 | Capsule of Acipimox |
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| GB2460915B (en) * | 2008-06-16 | 2011-05-25 | Biovascular Inc | Controlled release compositions of agents that reduce circulating levels of platelets and methods therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
| CN101732285A (en) * | 2010-02-01 | 2010-06-16 | 鲁南贝特制药有限公司 | Capsule of Acipimox |
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Denomination of invention: Acimox film controlled sustained-release pellets capsules Effective date of registration: 20220929 Granted publication date: 20170627 Pledgee: Beijing Zhongguancun bank Limited by Share Ltd. Pledgor: Beijing Tianheng Drug Research Institute Registration number: Y2022990000696 |
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