CN104490848B - A kind of Raltitrexed colon-specific pellets and preparation method thereof - Google Patents
A kind of Raltitrexed colon-specific pellets and preparation method thereof Download PDFInfo
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- CN104490848B CN104490848B CN201410844733.3A CN201410844733A CN104490848B CN 104490848 B CN104490848 B CN 104490848B CN 201410844733 A CN201410844733 A CN 201410844733A CN 104490848 B CN104490848 B CN 104490848B
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- raltitrexed
- plasticizer
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- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 title claims abstract description 97
- 229960004432 raltitrexed Drugs 0.000 title claims abstract description 97
- 210000001072 colon Anatomy 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 239000008188 pellet Substances 0.000 title claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 44
- 238000000926 separation method Methods 0.000 claims abstract description 43
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims description 73
- 239000004014 plasticizer Substances 0.000 claims description 67
- 239000003795 chemical substances by application Substances 0.000 claims description 61
- 239000000853 adhesive Substances 0.000 claims description 53
- 230000001070 adhesive effect Effects 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- 238000000576 coating method Methods 0.000 claims description 35
- 239000011248 coating agent Substances 0.000 claims description 33
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 29
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 29
- 238000005282 brightening Methods 0.000 claims description 22
- 239000003605 opacifier Substances 0.000 claims description 22
- 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 description 20
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 19
- 239000006185 dispersion Substances 0.000 claims description 19
- 239000004408 titanium dioxide Substances 0.000 claims description 19
- 239000001069 triethyl citrate Substances 0.000 claims description 19
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 19
- 235000013769 triethyl citrate Nutrition 0.000 claims description 19
- 239000002775 capsule Substances 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
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- 235000010981 methylcellulose Nutrition 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 239000012530 fluid Substances 0.000 claims description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 9
- 229920003081 Povidone K 30 Polymers 0.000 claims description 9
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 9
- 239000001856 Ethyl cellulose Substances 0.000 claims description 8
- 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 claims description 8
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 8
- 229920001249 ethyl cellulose Polymers 0.000 claims description 8
- -1 phthalic acid carboxylic ester Chemical class 0.000 claims description 8
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- QZCLKYGREBVARF-UHFFFAOYSA-N Acetyl tributyl citrate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)(OC(C)=O)CC(=O)OCCCC QZCLKYGREBVARF-UHFFFAOYSA-N 0.000 claims description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 6
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000006850 spacer group Chemical group 0.000 claims description 6
- 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 description 5
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 5
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 5
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- 239000008101 lactose Substances 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
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- 229920002689 polyvinyl acetate Polymers 0.000 claims description 5
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- MUZDXNQOSGWMJJ-UHFFFAOYSA-N 2-methylprop-2-enoic acid;prop-2-enoic acid Chemical group OC(=O)C=C.CC(=C)C(O)=O MUZDXNQOSGWMJJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004925 Acrylic resin Substances 0.000 claims description 4
- 239000004375 Dextrin Substances 0.000 claims description 4
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- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 239000000470 constituent Substances 0.000 claims description 4
- 235000019425 dextrin Nutrition 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
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- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 229920000136 polysorbate Polymers 0.000 claims description 4
- 229950008882 polysorbate Drugs 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 235000005979 Citrus limon Nutrition 0.000 claims description 3
- 238000012840 feeding operation Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- 240000000111 Saccharum officinarum Species 0.000 claims 2
- 235000007201 Saccharum officinarum Nutrition 0.000 claims 2
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 claims 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 claims 2
- 235000000346 sugar Nutrition 0.000 claims 2
- 244000131522 Citrus pyriformis Species 0.000 claims 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims 1
- 238000005516 engineering process Methods 0.000 abstract description 2
- 210000000936 intestine Anatomy 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 210000002784 stomach Anatomy 0.000 abstract 1
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- 239000000243 solution Substances 0.000 description 22
- 239000000203 mixture Substances 0.000 description 17
- 206010009944 Colon cancer Diseases 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 238000001259 photo etching Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000003405 delayed action preparation Substances 0.000 description 3
- 239000012055 enteric layer Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 244000248349 Citrus limon Species 0.000 description 2
- XEPCTMQKNYGHQR-UHFFFAOYSA-N N=NC=NN.N=NC=NN.C1=CC=CC=C1.C(C)(=O)O Chemical compound N=NC=NN.N=NC=NN.C1=CC=CC=C1.C(C)(=O)O XEPCTMQKNYGHQR-UHFFFAOYSA-N 0.000 description 2
- 108010020346 Polyglutamic Acid Proteins 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
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- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920002643 polyglutamic acid Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012913 prioritisation Methods 0.000 description 2
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- 210000000813 small intestine Anatomy 0.000 description 2
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- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
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- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
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- 102000003960 Ligases Human genes 0.000 description 1
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- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N Thymine Natural products CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to pharmaceutical field, is related to a kind of pharmaceutical preparation using Raltitrexed as active component, more particularly to a kind of Raltitrexed colon-specific pellets and preparation method thereof.Its each structure sheaf be arranged in order from the inside to the outside for：Carry medicine body, medicated layer, separation layer and site specific DDS for colon layer.Micropill of the present invention, has the characteristics of oral enteric, site specific DDS for colon, it is oral after mainly in colon site dissolving, absorb.Compared with the prior art, the multiple-unit preparation that the technology of the present invention ultimately forms can reach consistent Plasma Drug Level, reduce the risk of burst drug release intestines and stomach distribution is good, passage time is consistent.Bioavilability can be improved, be provided simultaneously with more preferable security performance.
Description
Technical field
The invention belongs to pharmaceutical field, it is related to a kind of pharmaceutical preparation using Raltitrexed as active component, more particularly to one
Kind Raltitrexed colon-specific pellets and preparation method thereof.
Background technology
Colorectal cancer is one of most commonly seen malignant tumour of gastrointestinal system, and the second of tumor mortality is occupied in west.
With the change of expanding economy, people life style and diet structure, its incidence of disease is increasing year by year, especially in recent years,
With 4% speed increase.
Operative treatment is the main method for the treatment of of colorectal cancer, and its success rate depends on advancing of disease degree；Post operation
Generally require chemotherapy.For the colorectal cancer patients of Locally Advanced, preoperative or postoperative adjuvant radiotherapy, local relapse is than outer merely
Section's operation has obvious reduction.In past more than 40 years, fluorouracil is always the most frequently used chemotherapeutic, but fluorouracil
There is the dosage regimen of heavier toxic reaction and complexity, prolonged application can cause nervous system toxicity, and some patients there is also
The adverse reactions such as myocardial ischemia, angina pectoris, thus application clinically is limited by very large.
Raltitrexed (Raltitrexed) is the new anticancer drug developed by Britain Ze Neika (Zeneca) company, its
Chemical name:N- { 5- { N- { (3,4- dihydro -2- methyl -4- oxygen -6- quinazolyls)-methyl }-N- methylaminos } -2- thiophene
Base }-Pidolidone.Molecular formula:C21H22N4O6S.Molecular weight：458.49.
Structural formula：
The medicine is a kind of quinazoline folate analog, is mainly used in the treatment of late period colorectal cancer, it antitumor
Effect is and caused by the single-minded suppression to thymidylate synthase.In the treatment to colorectal cancer, the effect of Raltitrexed
It is similar to fluorouracil, and fluorouracil is better than to the inhibitory action of colon carcinoma cell line, but avoid caused by fluorouracil
The medication of toxicity and complexity.In vitro study shows that Raltitrexed active transports enter intracellular a large amount of quickly
A series of polyglutamic acid class compounds are metabolized to, these polyglutamic acid class compounds are more stronger than female medicine Raltitrexed
Thymine synthetase (TS) inhibitor, so as to suppress the synthesis of cell DNA, play cytotoxicity, and can be in cell the Lushui River
Stay, play inhibitory action for a long time.The life quality of colorectal cancer patients can be significantly improved, therefore, especially late
In the treatment of colorectal cancer, the alternative fluorouracils of Raltitrexed.
At present, the Raltitrexed preparations of clinical practice only have injection (freeze-dried powder), enter body by blood circulation
It is interior, treat colon carcinoma.But the medication amount for reaching Colon and rectum position is fewer, thereby increases and it is possible to hematotoxicity and gastrointestinal discomfort occurs
Etc. systemic side effects.
A kind of thunder disclosed in Chinese patent 200610022370.0 " a kind of sustained release formulation of raltitrexed and preparation method thereof "
Sustained release preparation preparation method is filled in for song：The sustained release preparation includes label and enteric solubility coatings, label by effective dose main ingredient thunder
Formed for Qu Sai and pharmaceutic adjuvant, wherein pharmaceutic adjuvant mainly includes slow-release material, filler, lubricant and adhesive；Enteric
Type coatings are enteric solubility polymer material layer.Also disclose the preparation method of sustained release formulation of raltitrexed：Supplementary material is weighed to mix
It is even, single-deck core will be pressed into after direct powder compression or granulation, be coated.Thunder made of Chinese patent 200610022370.0 is for song
Plug sustained release preparation is unit preparation, is existed certain by active component content deviation or enteric layer thickness deviation（Influence release control
System）Caused validity and security risks；Said preparation is complete larger chip solid before colon site is reached, and is arrived
Up to drug release position（Colon）Required time is longer, and could be discharged completely after need to being disintegrated, and drug effect is slower.
The content of the invention
In order to solve the above technical problems, the present invention provides a kind of Raltitrexed colon-specific pellets and preparation method, tool
There is the characteristics of oral enteric, site specific DDS for colon, be administered orally, carry, be convenient to take；Medicine is mainly molten in colon site
Solution, absorb, it is with strong points, bioavilability can be improved, and substantially reduce toxic side effect.Meanwhile with the rapid, security that works
With validity height, steady quality feature.
Present invention also offers the preparation method of above-mentioned Raltitrexed colon-specific pellets.
Solve a kind of Raltitrexed colon-specific pellets in the present invention of its technical problem, be followed successively by load medicine from the inside to the outside
Body, medicated layer, separation layer and site specific DDS for colon layer, load medicine body are capsule core, and medicated layer parcel carries medicine body and forms Raltitrexed medicated layer
Base ball, separation layer parcel Raltitrexed medicated layer base ball form Raltitrexed separation layer base ball, and site specific DDS for colon layer parcel thunder is for song
Fill in separation layer base ball and form Raltitrexed colon-specific pellets, it is characterised in that：The load medicine body is sucrose, starch, crystallite fibre
One or more in dimension element, dextrin and lactose；
To carry medicine body 80-200 parts to calculate, medicated layer is made up of following parts by weight of component：Raltitrexed 1-5 parts, bonding
Agent 2-10 parts, solvent 40-200 parts；Described adhesive is that PVP K30, methylcellulose, HPMC and ethyl are fine
Dimension element is one or more kinds of；The solvent is that water and ethanol are one or two kinds of；
Using Raltitrexed medicated layer base ball 80-220 parts to calculate, separation layer parts by weight of component and content are：Plasticizer
0.5-3 parts, opacifier brightening agent 1-6 parts, adhesive 5-30 parts, solvent 80-250 parts；The plasticizer is water-soluble plasticizer
Polyethylene glycol, propane diols, water-insoluble Dibutyl Sebacate, triethyl citrate, diethyl phthalate and lemon
It is one or more kinds of in lemon acid tributyl；The opacifier or brightening agent are one kind or two in medicinal talcum powder, titanium dioxide
More than kind；Described adhesive is one kind or two in PVP K30, methylcellulose, HPMC and ethyl cellulose
More than kind；The solvent is one or two kinds of in water and ethanol；Using Raltitrexed separation layer base ball 80-250 parts as calculating, colon
Alignment layers parts by weight of component and content are：Film forming agent 10-50 parts, antiplastering aid 3-15 parts, plasticizer 0.7-15 parts, solvent 40-125
Part；The film forming agent is methacrylic acid-acrylic acid resin copolymer constituents or its aqueous dispersion, polyvinyl acetate benzene diformazan
It is one or more kinds of in acid esters, the third methylcellulose of phthalic acid carboxylic ester, CAP；The plasticizer is water
Dissolubility plasticizer polyethylene glycol, propane diols, polysorbate are one or more kinds of；Or the plasticizer is water-insoluble plasticizer
It is one or more kinds of in dibutyl sebacate, triethyl citrate, diethyl phthalate and ATBC；It is described
Antiplastering aid is one or more kinds of in medicinal talcum powder, titanium dioxide, magnesium stearate, silica；The solvent is water, second
It is one or more kinds of in alcohol, acetone.
Prioritization scheme is：To carry medicine body 90-150 parts to calculate, medicated layer is made up of following parts by weight of component：Raltitrexed
2-4 parts, adhesive 2.5-7 parts, solvent 45-150 parts；Described adhesive is PVP K30, methylcellulose, hydroxypropyl fibre
Dimension element and ethyl cellulose are one or more kinds of；The solvent is that water and ethanol are one or two kinds of；
Using Raltitrexed medicated layer base ball 90-180 parts to calculate, separation layer parts by weight of component and content are：Plasticizer
0.6-2 parts, opacifier brightening agent 1.3-4 parts, adhesive 6-25 parts, solvent 85-200 parts；The plasticizer is water soluble plasticizers
Agent polyethylene glycol, propane diols, water-insoluble Dibutyl Sebacate, triethyl citrate, diethyl phthalate and
It is one or more kinds of in ATBC；The opacifier or brightening agent be medicinal talcum powder, it is a kind of in titanium dioxide or
It is two or more；Described adhesive be it is a kind of in PVP K30, methylcellulose, HPMC and ethyl cellulose or
It is two or more；The solvent is one or two kinds of in water and ethanol；Using Raltitrexed separation layer base ball 90-200 parts to calculate, tie
Intestines alignment layers parts by weight of component and content are：Film forming agent 20-50 parts, antiplastering aid 5-12 parts, plasticizer 1-10 parts, solvent 40-100
Part；The film forming agent is methacrylic acid-acrylic acid resin copolymer constituents or its aqueous dispersion, polyvinyl acetate benzene diformazan
It is one or more kinds of in acid esters, the third methylcellulose of phthalic acid carboxylic ester, CAP；The plasticizer is water
Dissolubility plasticizer polyethylene glycol, propane diols, polysorbate are one or more kinds of；Or the plasticizer is water-insoluble plasticizer
It is one or more kinds of in dibutyl sebacate, triethyl citrate, diethyl phthalate and ATBC；It is described
Antiplastering aid is one or more kinds of in medicinal talcum powder, titanium dioxide, magnesium stearate, silica；The solvent is water, second
It is one or more kinds of in alcohol, acetone.
Further prioritization scheme is：To carry 100 parts of medicine body to calculate, medicated layer is made up of following parts by weight of component：Thunder replaces
2 parts of song plug, 2.5 parts of adhesive, 45.5 parts of solvent；Described adhesive is HPMC, and the solvent is water；
With Raltitrexed medicated layer base ball, 100 parts are calculating, and separation layer parts by weight of component and content are：0.7 part of plasticizer,
1.4 parts of opacifier or brightening agent, 7 parts of adhesive, 90 parts of solvent；The plasticizer is polyethylene glycol, the opacifier or is brightened
Agent is titanium dioxide, and described adhesive is HPMC, and the solvent is water；With Raltitrexed separation layer base ball 100
To calculate, site specific DDS for colon layer weight part component and content are part：50 parts of film forming agent, 9 parts of antiplastering aid, 1 part of plasticizer, solvent 40
Part；The film forming agent is aqueous dispersion, and the plasticizer triethyl citrate, the antiplastering aid is medicinal talcum powder, described molten
Agent is water.
The aqueous dispersion is methacrylic acid, methyl acrylate and methyl methacrylate with 1:1:1 ratio is mixed with water
Close and formed, solid content 30%.Aqueous dispersion or " Utech " that German Romo Co., Ltd's production is bought in the market.
HPMC is adhesive, and its mass property is adhesiveness；Titanium dioxide is opacifier and antitack agent, its
Mass property is opaqueness, resistance to bond；Its characteristic of the film forming agent of site specific DDS for colon layer is just to dissolve in the basic conditions.
A kind of preparation method of Raltitrexed colon-specific pellets in the present invention, it is characterised in that：Comprise the following steps：
（1）Capsule core is weighed, places fluid bed preheat, 40 ~ 70 DEG C of temperature, 15 ~ 45min of time；
（2）It is prepared by Raltitrexed medicated layer base ball：Weigh, taking adhesive adds stirring to solution in solvent and clarified；By thunder
Fill in add in solution for song and stir to clarify, open coating medicine-feeding operation, carry out fluidized coating parcel capsule core；
Coating medicine-feeding operation is fluidized coating, and solution atomization is sprayed onto in capsule core, and spray speed is not lumpd with material for degree, temperature
30 ~ 50 DEG C of degree, untill liquid has sprayed.Fluidized coating operation is the same in later step.
(3) prepared by Raltitrexed medicated layer base ball：Weigh, taking adhesive adds stirring solvent to solution and clarified, then takes screening
Photo etching and plasticizer, add in solution and stir, it is in suspension state to make solution, and spacer layer coating liquid is made, then to Raltitrexed
Medicated layer base ball carries out fluidized coating；
(4) preparation of site specific DDS for colon layer micropill：Weigh, take antiplastering aid, plasticizer mixing solubilizer stirring and dissolving, then pour into
In film forming agent, site specific DDS for colon layer coating solution is made, then fluidized coating is carried out to Raltitrexed medicated layer base ball.
（5）Capsule filling, packaging.
The step（4）The step of be：Solvent, antiplastering aid and plasticizer are placed in container high speed shearing homogeneous 10-
30min, this suspension is poured into film forming agent under agitation, cross 0.5mm sieves, be made into the coating solution of solid contents about 25%, then
Fluid bed is opened, input Raltitrexed separation layer micropill is coated operation into fluid bed, until site specific DDS for colon layer coating solution
It has been sprayed that, rewinding.
The beneficial effects of the invention are as follows：
Equal oral enteric, site specific DDS for colon, medicine is mainly dissolved in colon site, absorbed, with strong points;With existing thunder
Compared for song plug injection, carry, be convenient to take.Meanwhile Raltitrexed colon-specific pellets provided by the invention can be on demand
Load capsule, oral rear capsule shells complete dissolving on alimentary canal top so as to release micropill therein, due to the volume of micropill
It is small, duodenum, small intestine etc. can be run through and reach colon, the dissolving of site specific DDS for colon layer can release medicine, rapid-onset；By
The micropill eventually form for multiple-unit preparation, even if inclined with the presence of a small amount of micropill active component content deviation or enteric layer thickness
Difference, to the overall influence of preparation also very little, the security and validity of preparation are high.
The micropill can load capsule on demand, and oral rear capsule shells complete dissolving so as to release wherein on alimentary canal top
Micropill, due to the small volume of micropill, duodenum, small intestine etc. can be run through and reach colon, after the dissolving of site specific DDS for colon layer i.e.
It can release medicine, rapid-onset；By the micropill eventually form for multiple-unit preparation, even if with the presence of a small amount of micropill activity into
Divide content deviation or enteric layer thickness deviation, to the overall influence of preparation also very little, the security and validity of preparation are high.
Embodiment
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
Embodiment 1, Raltitrexed colon-specific pellets
Medicated layer consists of the following composition：
Separation layer consists of the following composition：
Site specific DDS for colon layer consists of the following composition：
（Note：Methacrylic acid, methyl acrylate and the methyl methacrylate of German Romo Co., Ltd's production（1:1:1）Altogether
Polymers aqueous dispersion, solid content 30%, similarly hereinafter.）
The Raltitrexed colon-specific pellets preparation method of the present invention is as follows：
1st, weigh, stock up：Material is weighed by recipe quantity, it is standby.
2nd, the preparation of Raltitrexed medicated layer base ball：
HPMC is sprinkled into partial purification water by A, is configured to the HPMC aqueous solution；
Raltitrexed is added in the step A aqueous solution prepared and is configured to the aqueous solution by B；Fluid bed is opened, puts into medicine
Operation is coated into fluid bed with fine pellet core, until upper aqueous solution has sprayed, rewinding.
3rd, prepared by Raltitrexed separation layer base ball：
HPMC is sprinkled into portion of pure water by A, is configured to the HPMC aqueous solution；
Polyethylene glycol, titanium dioxide are added in the step A aqueous solution prepared and are configured to spacer layer coating liquid by B, open
Fluid bed is opened, input Raltitrexed pastille micropill is coated operation into fluid bed, until spacer layer coating liquid has sprayed, receives
Material.
4th, prepared by Raltitrexed colon-specific pellets
Water, talcum powder and triethyl citrate are placed in container high speed shearing 10 ~ 30min of homogeneous by A, under agitation by this
Suspension pours into UtechIn FS30D, 0.5mm sieves are crossed, are made into the coating solution of solid contents about 25%；
B opens fluid bed, and input Raltitrexed separation layer micropill is coated operation into fluid bed, until colon is determined
Position layer coating solution has sprayed, rewinding；
5th, capsule is filled：The loading of every capsule is calculated according to detection level, is filled with hard capsule case；
6th, inner packing：Carry out plastic-aluminum；
7th, outer packing：Carry out outer packing.
Embodiment 2, Raltitrexed colon-specific pellets
Medicated layer consists of the following composition：
Preparation method is the same as embodiment 1.
Embodiment 3, Raltitrexed colon-specific pellets
Medicated layer consists of the following composition：
Preparation method is the same as embodiment 1.
Embodiment 4, Raltitrexed colon-specific pellets
Medicated layer consists of the following composition：
Preparation method is the same as embodiment 1.
Embodiment 5, Raltitrexed colon-specific pellets
Medicated layer consists of the following composition：
Preparation method is the same as embodiment 1.
Embodiment 6, Raltitrexed colon-specific pellets
Medicated layer, separation layer, preparation method（Except site specific DDS for colon layer coating liquid making method）With embodiment 1.
Site specific DDS for colon layer consists of the following composition：
Content such as embodiment 1 in other preparation methods, wherein site specific DDS for colon layer are coated liquid making method：
The desired amount of water is heated, then addition Tween 80, glycerin monostearate, triethyl citrate, homogeneous 10min,
The suspension of solid content 15% is made.Suspension is diluted with remaining water and is cooled to room temperature, stirs, suspension is poured into especially
It is special strangeFS30D, 0.5mm sieves are crossed, be made into the coating solution of solid contents about 25%.
Embodiment 7, Raltitrexed colon-specific pellets
Medicated layer, separation layer, preparation method（Except site specific DDS for colon layer coating liquid making method）With embodiment 1.
Site specific DDS for colon layer consists of the following composition：
The methacrylic acid and methyl methacrylate of [note] German Romo Co., Ltd's production（1:2）Copolymer.Similarly hereinafter.
Content such as embodiment 1 in other preparation methods, wherein site specific DDS for colon layer are coated liquid making method：
Water is poured into container, adds Utech under agitationS100,5min is stirred, add 1mol/L ammoniacal liquor, after
Continuous stirring 60min, then adds triethyl citrate and talcum powder, continues to stir 60min, crosses 0.5mm sieves, is made into solids and contains
The coating solution of amount about 25%.
Embodiment 8, Raltitrexed colon-specific pellets
Medicated layer, separation layer, preparation method（Except site specific DDS for colon layer coating liquid making method）With embodiment 1.
Site specific DDS for colon layer consists of the following composition：
[note] UtechL100[note]For the methacrylic acid and methyl methacrylate of the production of German Romo Co., Ltd（1:1）
Copolymer, similarly hereinafter.
Content such as embodiment 1 in other preparation methods, wherein site specific DDS for colon layer are coated liquid making method：
Water is poured into container, adds Utech under agitationS100,5min is stirred, add 1mol/L ammoniacal liquor, after
Continuous stirring 60min, prepares UtechS100 dispersions；With method operation preparation UtechL100 dispersions.In stirring at low speed
Under, by UtechS100 dispersions pour into UtechL100 dispersions, continue to stir 15min, then add citron triethylenetetraminehexaacetic acid
Ester and talcum powder, continue to stir 60min, cross 0.5mm sieves, be made into the coating solution of solid contents about 25%.
Embodiment 9
Control group：Raltitrexed site specific DDS for colon piece
Label consists of the following composition：
Separation layer is the same as embodiment 1.
Site specific DDS for colon layer consists of the following composition：
Raltitrexed colon-specific pellets preparation method is as follows：
1st, weigh, stock up：Material is weighed by recipe quantity, it is standby.
2nd, the preparation of label：
HPMC is sprinkled into partial purification water by A, is configured to HPMC solution；
B weighs Raltitrexed, microcrystalline cellulose, lactose, the PVPP of the deal, mixes, and adds hydroxypropyl first
Base cellulose solution, mix, pelletize, dry, whole grain, add superfine silica gel powder and magnesium stearate mixes, tabletting, be made every containing master
Medicine 2mg label.
3rd, it is coated：
HPMC is sprinkled into portion of pure water by A, is configured to the HPMC aqueous solution；Add poly- second
Glycol, titanium dioxide, it is configured to spacer layer coating liquid；
Water is poured into container by B, adds Utech under agitationS100,5min is stirred, add 1mol/L ammoniacal liquor, after
Continuous stirring 60min, then adds triethyl citrate and talcum powder, continues to stir 60min, crosses 0.5mm sieves, is made into solids and contains
The site specific DDS for colon layer coating solution of amount about 15%.
Raltitrexed label is placed in coating pan by C, start, preheating, when label temperature is about 35 ~ 40 DEG C, spray into every
Absciss layer coating solution, continue to be blown into hot-air 30min after having sprayed.Site specific DDS for colon layer coating solution is sprayed into, continues to be blown into hot sky after having sprayed
Gas 30min.Then by coating tablet in drying box 35 ~ 40 DEG C of dry solidifications 6 ~ 8 hours.It is aluminum-plastic packaged, outer packing, produce.
Embodiment 10
Other contents such as embodiment 1, to carry 80 parts of medicine body to calculate, medicated layer is made up of following parts by weight of component：Thunder replaces
1 part of song plug, 2 parts of adhesive, 40 parts of solvent；Described adhesive is ethyl cellulose, and the solvent is ethanol；
With Raltitrexed medicated layer base ball, 80 parts are calculating, and separation layer parts by weight of component and content are：0.5 part of plasticizer,
1 part of opacifier or brightening agent, 5 parts of adhesive, 80 parts of solvent；The plasticizer is propane diols, and the opacifier or brightening agent are
Medicinal talcum powder, described adhesive are PVP K30, and the solvent is water；With Raltitrexed separation layer base ball, 80 parts are calculating,
Site specific DDS for colon layer weight part component and content are：10 parts of film forming agent, 3 parts of antiplastering aid, 0.7 part of plasticizer, 80 parts of solvent；It is described into
Film is polyvinyl acetate phthalic acid ester, and the Dibutyl Sebacate, the antiplastering aid is titanium dioxide, described molten
Agent is ethanol.
Embodiment 11
Other contents such as embodiment 1, to carry 200 parts of medicine body to calculate, medicated layer is made up of following parts by weight of component：Thunder replaces
5 parts of song plug, 10 parts of adhesive, 200 parts of solvent；Described adhesive is HPMC, and the solvent is water；
With Raltitrexed medicated layer base ball, 220 parts are calculating, and separation layer parts by weight of component and content are：3 parts of plasticizer, hide
6 parts of photo etching or brightening agent, 30 parts of adhesive, 250 parts of solvent；The plasticizer is polyethylene glycol, the opacifier or brightening agent
For titanium dioxide, described adhesive is HPMC, and the solvent is water；With 250 parts of Raltitrexed separation layer base ball
To calculate, site specific DDS for colon layer weight part component and content are：50 parts of film forming agent, 15 parts of antiplastering aid, 15 parts of plasticizer, solvent 250
Part；The film forming agent is aqueous dispersion, and the plasticizer triethyl citrate, the antiplastering aid is medicinal talcum powder, described molten
Agent is water.
Embodiment 12
Other contents such as embodiment 1, to carry 90 parts of medicine body to calculate, medicated layer is made up of following parts by weight of component：Thunder replaces
2 parts of song plug, 2.5 parts of adhesive, 45 parts of solvent；Described adhesive is HPMC, and the solvent is water and ethanol；
With Raltitrexed medicated layer base ball, 90 parts are calculating, and separation layer parts by weight of component and content are：0.6 part of plasticizer,
1.3 parts of opacifier or brightening agent, 6 parts of adhesive, 85 parts of solvent；The plasticizer is triethyl citrate, phthalic acid two
Ethyl ester and ATBC mixture, the opacifier or brightening agent are medicinal talcum powder and titanium dioxide, described adhesive
For ethyl cellulose, the solvent is water；With Raltitrexed separation layer base ball, 90 parts are to calculate, site specific DDS for colon layer weight part component
And content is：20 parts of film forming agent, 5 parts of antiplastering aid, 1 part of plasticizer, 90 parts of solvent；The film forming agent is aqueous dispersion, the increasing
Modeling agent is polyethylene glycol or propylene glycol mixture, and the antiplastering aid is silica, and the solvent is water, ethanol and acetone mixing
Thing.
Embodiment 13
Other contents such as embodiment 1, to carry 150 parts of medicine body to calculate, medicated layer is made up of following parts by weight of component：Thunder replaces
4 parts of song plug, 7 parts of adhesive, 150 parts of solvent；Described adhesive is HPMC, and the solvent is water；
With Raltitrexed medicated layer base ball, 180 parts are calculating, and separation layer parts by weight of component and content are：2 parts of plasticizer, hide
4 parts of photo etching or brightening agent, 25 parts of adhesive, 200 parts of solvent；The plasticizer is polyethylene glycol, the opacifier or brightening agent
For titanium dioxide, described adhesive is HPMC, and the solvent is water；With 200 parts of Raltitrexed separation layer base ball
To calculate, site specific DDS for colon layer weight part component and content are：40 parts of film forming agent, 12 parts of antiplastering aid, 10 parts of plasticizer, solvent 200
Part；The film forming agent is aqueous dispersion, and the plasticizer triethyl citrate, the antiplastering aid is medicinal talcum powder, described molten
Agent is water.
Embodiment 14
Other contents such as embodiment 1, to carry 110 parts of medicine body to calculate, medicated layer is made up of following parts by weight of component：Thunder replaces
3 parts of song plug, 5 parts of adhesive, 80 parts of solvent；Described adhesive is HPMC, and the solvent is water；
With Raltitrexed medicated layer base ball, 120 parts are calculating, and separation layer parts by weight of component and content are：1 part of plasticizer, hide
3 parts of photo etching or brightening agent, 10 parts of adhesive, 120 parts of solvent；The plasticizer is polyethylene glycol, the opacifier or brightening agent
For titanium dioxide, described adhesive is HPMC, and the solvent is water；With 120 parts of Raltitrexed separation layer base ball
To calculate, site specific DDS for colon layer weight part component and content are：30 parts of film forming agent, 8 parts of antiplastering aid, 4 parts of plasticizer, 105 parts of solvent；
The film forming agent is aqueous dispersion, and the plasticizer triethyl citrate, the antiplastering aid is medicinal talcum powder, and the solvent is
Water.
Embodiment 15
Other contents such as embodiment 1, to carry 120 parts of medicine body to calculate, medicated layer is made up of following parts by weight of component：Thunder replaces
2.5 parts of song plug, 4 parts of adhesive, 70 parts of solvent；Described adhesive is HPMC, and the solvent is water；
With Raltitrexed medicated layer base ball, 120 parts are calculating, and separation layer parts by weight of component and content are：1.5 parts of plasticizer,
2 parts of opacifier or brightening agent, 15 parts of adhesive, 130 parts of solvent；The plasticizer is polyethylene glycol, the opacifier or is brightened
Agent is titanium dioxide, and described adhesive is HPMC, and the solvent is water；With Raltitrexed separation layer base ball 120
To calculate, site specific DDS for colon layer weight part component and content are part：25 parts of film forming agent, 10 parts of antiplastering aid, 6 parts of plasticizer, solvent 120
Part；The film forming agent is aqueous dispersion, and the plasticizer triethyl citrate, the antiplastering aid is medicinal talcum powder, described molten
Agent is water.
By the encapsulated rear and embodiment 9 of the Raltitrexed colon-specific pellets of above-described embodiment 1 ~ 8（Control group）Thunder replace
Song plug site specific DDS for colon piece carries out disintegration time limited detection in 0.01mol/L hydrochloric acid solutions.As a result show, the thunder of embodiment 1 ~ 8 replaces
Song plug colon-specific pellets capsule is all disintegrated into 0.5 ~ 0.8mm micropill, Raltitrexed site specific DDS for colon piece in 5 ~ 8min
It is then unchanged in 120min outers.The former is prompted to be more easy to release after reaching colon site by the way that alimentary canal is rapid than the latter
Medicine.
Again by the encapsulated rear and embodiment 9 of the Raltitrexed colon-specific pellets of above-described embodiment 1 ~ 8（Control group）Thunder
Vitro release measure is carried out for song plug site specific DDS for colon piece.As a result show, in 0.01mol/L hydrochloric acid solutions more than 2 hours
Do not release the drug；In pH7.4 phosphate buffer, the former is complete in 10 ~ 15min drug releases, and the latter then just releases in 30 ~ 45min
Medicine is complete, and its In Vitro Dissolution curve see the table below 1.
The Raltitrexed colon-specific pellets of table 1（It is encapsulated）It is bent with control group Raltitrexed site specific DDS for colon piece In Vitro Dissolution
Line
（Note：Dissolution medium：PH7.4 phosphate buffer）
The encapsulated rear and embodiment 9 of Raltitrexed colon-specific pellets in the present invention（Control group）Raltitrexed colon
Insoluble in acidic gastric juice after spacer is oral, just dissolving discharges active component in intestinal juice, reaches oral enteric, colon
The effect of positioning, medicine is just discharged after reaching focus so as to play therapeutic action, be advantageous to improve curative effect；Colon-specific pellets
Capsule need not be disintegratable in colon site, the former drug release rate more faster than the latter, colon-specific pellets glue in the present invention
Capsule can play therapeutic effect faster.
Claims (4)
1. a kind of Raltitrexed colon-specific pellets, it is followed successively by carries medicine body, medicated layer, separation layer and site specific DDS for colon from the inside to the outside
Layer, load medicine body are capsule core, and medicated layer parcel carries medicine body and forms Raltitrexed medicated layer base ball, separation layer parcel Raltitrexed drug containing
Layer base ball forms Raltitrexed separation layer base ball, and site specific DDS for colon layer parcel Raltitrexed separation layer base ball forms Raltitrexed colon
Position micropill, it is characterised in that：The medicine body that carries is one kind or more in sucrose, starch, microcrystalline cellulose, dextrin and lactose
Kind；
To carry medicine body 80-200 parts to calculate, medicated layer is made up of following parts by weight of component：Raltitrexed 1-5 parts, adhesive 2-
10 parts, solvent 40-200 parts；Described adhesive is PVP K30, methylcellulose, HPMC and ethyl cellulose
It is one or more kinds of；The solvent is that water and ethanol are one or two kinds of；
Using Raltitrexed medicated layer base ball 80-220 parts to calculate, separation layer parts by weight of component and content are：Plasticizer 0.5-3
Part, opacifier or brightening agent 1-6 parts, adhesive 5-30 parts, solvent 80-250 parts；The plasticizer is the poly- second of water-soluble plasticizer
Glycol, propane diols, water-insoluble Dibutyl Sebacate, triethyl citrate, diethyl phthalate and citric acid
It is one or more kinds of in tributyl；The opacifier or brightening agent be medicinal talcum powder, in titanium dioxide one or two with
On；Described adhesive be in PVP K30, methylcellulose, HPMC and ethyl cellulose one or two with
On；The solvent is one or two kinds of in water and ethanol；Using Raltitrexed separation layer base ball 80-250 parts as calculating, site specific DDS for colon
Layer weight part component and content are：Film forming agent 10-50 parts, antiplastering aid 3-15 parts, plasticizer 0.7-15 parts, solvent 40-125 parts；
The film forming agent is methacrylic acid-acrylic acid resin copolymer constituents or its aqueous dispersion, polyvinyl acetate phthalic acid
It is one or more kinds of in ester, the third methylcellulose of phthalic acid carboxylic ester, CAP；The plasticizer is water-soluble
Property plasticizer polyethylene glycol, propane diols, polysorbate it is one or more kinds of；Or the plasticizer is the water-insoluble plasticizer last of the ten Heavenly stems
It is one or more kinds of in adipate, triethyl citrate, diethyl phthalate and ATBC；It is described anti-
Stick is one or more kinds of in medicinal talcum powder, titanium dioxide, magnesium stearate, silica；The solvent is water, second
It is one or more kinds of in alcohol, acetone；
The aqueous dispersion is methacrylic acid, methyl acrylate and methyl methacrylate with 1:1:1 ratio mixes shape with water
Into solid content 30%.
A kind of 2. Raltitrexed colon-specific pellets according to claim 1, it is characterised in that：The load medicine body is sugarcane
One or more in sugar, starch, microcrystalline cellulose, dextrin and lactose；
To carry medicine body 90-150 parts to calculate, medicated layer is made up of following parts by weight of component：Raltitrexed 2-4 parts, adhesive
2.5-7 parts, solvent 45-150 parts；Described adhesive is that PVP K30, methylcellulose, HPMC and ethyl are fine
Dimension element is one or more kinds of；The solvent is that water and ethanol are one or two kinds of；
Using Raltitrexed medicated layer base ball 90-180 parts to calculate, separation layer parts by weight of component and content are：Plasticizer 0.6-2
Part, opacifier or brightening agent 1.3-4 parts, adhesive 6-25 parts, solvent 85-200 parts；The plasticizer gathers for water-soluble plasticizer
Ethylene glycol, propane diols, water-insoluble Dibutyl Sebacate, triethyl citrate, diethyl phthalate and lemon
It is one or more kinds of in sour tributyl；The opacifier or brightening agent are one or two kinds of in medicinal talcum powder, titanium dioxide
More than；Described adhesive is one or two kinds of in PVP K30, methylcellulose, HPMC and ethyl cellulose
More than；The solvent is one or two kinds of in water and ethanol；Using Raltitrexed separation layer base ball 90-200 parts to calculate, colon is fixed
Position layer weight part component and content are：Film forming agent 20-50 parts, antiplastering aid 5-12 parts, plasticizer 1-10 parts, solvent 40-100 parts；
The film forming agent is methacrylic acid-acrylic acid resin copolymer constituents or its aqueous dispersion, polyvinyl acetate phthalic acid
It is one or more kinds of in ester, the third methylcellulose of phthalic acid carboxylic ester, CAP；The plasticizer is water-soluble
Property plasticizer polyethylene glycol, propane diols, polysorbate it is one or more kinds of；Or the plasticizer is the water-insoluble plasticizer last of the ten Heavenly stems
It is one or more kinds of in adipate, triethyl citrate, diethyl phthalate and ATBC；It is described anti-
Stick is one or more kinds of in medicinal talcum powder, titanium dioxide, magnesium stearate, silica；The solvent is water, second
It is one or more kinds of in alcohol, acetone.
A kind of 3. Raltitrexed colon-specific pellets according to claim 2, it is characterised in that：The load medicine body is sugarcane
One or more in sugar, starch, microcrystalline cellulose, dextrin and lactose；
To carry 100 parts of medicine body to calculate, medicated layer is made up of following parts by weight of component：2 parts of Raltitrexed, 2.5 parts of adhesive are molten
45.5 parts of agent；Described adhesive is HPMC, and the solvent is water；
With Raltitrexed medicated layer base ball, 100 parts are calculating, and separation layer parts by weight of component and content are：0.7 part of plasticizer, shading
1.4 parts of agent or brightening agent, 7 parts of adhesive, 90 parts of solvent；The plasticizer is polyethylene glycol, and the opacifier or brightening agent are
Titanium dioxide, described adhesive are HPMC, and the solvent is water；With Raltitrexed separation layer base ball, 100 parts are
Calculate, site specific DDS for colon layer weight part component and content are：50 parts of film forming agent, 9 parts of antiplastering aid, 1 part of plasticizer, 40 parts of solvent；Institute
It is aqueous dispersion to state film forming agent, and the plasticizer triethyl citrate, the antiplastering aid is medicinal talcum powder, and the solvent is
Water.
4. according to a kind of preparation method of Raltitrexed colon-specific pellets of claim 1 or 2 or 3, it is characterised in that：Bag
Include following steps：
（1）Capsule core is weighed, places fluid bed preheat, 40 ~ 70 DEG C of temperature, 15 ~ 45min of time；
（2）It is prepared by Raltitrexed medicated layer base ball：Weigh, taking adhesive adds stirring to solution in solvent and clarified；By thunder for song
Plug is added in solution and stirred to clarify, and opens coating medicine-feeding operation, carries out fluidized coating parcel capsule core；
(3) prepared by Raltitrexed separation layer base ball：Weigh, taking adhesive adds stirring solvent to solution and clarified, then takes opacifier
And plasticizer, add in solution and stir, it is in suspension state to make solution, and spacer layer coating liquid is made, then to Raltitrexed drug containing
Layer base ball carries out fluidized coating；
(4) preparation of colon-specific pellets：Weigh, take antiplastering aid, plasticizer mixing solubilizer stirring and dissolving, then pour into film forming agent
In, be made site specific DDS for colon layer coating solution, then fluidized coating, rewinding are carried out to Raltitrexed separation layer base ball；
（5）Capsule filling, packaging.
Priority Applications (1)
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| CN201410844733.3A CN104490848B (en) | 2014-12-31 | 2014-12-31 | A kind of Raltitrexed colon-specific pellets and preparation method thereof |
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| CN201410844733.3A CN104490848B (en) | 2014-12-31 | 2014-12-31 | A kind of Raltitrexed colon-specific pellets and preparation method thereof |
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| Publication Number | Publication Date |
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| CN104490848A CN104490848A (en) | 2015-04-08 |
| CN104490848B true CN104490848B (en) | 2018-01-30 |
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| CN1543953A (en) * | 2003-11-21 | 2004-11-10 | 复旦大学 | Colon targeted fluorouracil minipills prepartion |
| CN100525769C (en) * | 2006-11-30 | 2009-08-12 | 成都耐切尔生物技术有限公司 | Sustained release formulation of raltitrexed and preparation method thereof |
| CN101209246A (en) * | 2006-12-29 | 2008-07-02 | 天津医科大学 | Novel pH-dependent colon-specific drug delivery system |
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Address after: 614000 Yingbin Avenue, Central District, Sichuan, Leshan, No. 6 Applicant after: Emei Mountain in Sichuan Pharmaceutical Co.,Ltd. Address before: 614000 Yingbin Avenue, Central District, Sichuan, Leshan, No. 6 Applicant before: SICHUAN EMEISHAN PHARMACEUTICAL Co.,Ltd. |
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| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Raltitrexed colon specific pellet and preparation method thereof Effective date of registration: 20200421 Granted publication date: 20180130 Pledgee: Science and Technology Branch of Leshan Commercial Bank Co.,Ltd. Pledgor: Emei Mountain in Sichuan Pharmaceutical Co.,Ltd. Registration number: Y2020980001669 |
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| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20210414 Granted publication date: 20180130 Pledgee: Science and Technology Branch of Leshan Commercial Bank Co.,Ltd. Pledgor: Emei Mountain in Sichuan Pharmaceutical Co.,Ltd. Registration number: Y2020980001669 |
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| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A raltitrexed colon specific pellets and its preparation method Effective date of registration: 20210521 Granted publication date: 20180130 Pledgee: Science and Technology Branch of Leshan Commercial Bank Co.,Ltd. Pledgor: Emei Mountain in Sichuan Pharmaceutical Co.,Ltd. Registration number: Y2021510000072 |
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| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Granted publication date: 20180130 Pledgee: Science and Technology Branch of Leshan Commercial Bank Co.,Ltd. Pledgor: Emei Mountain in Sichuan Pharmaceutical Co.,Ltd. Registration number: Y2021510000072 |