CN114917201A - Trifloxuridinedipirimid tablet and preparation method thereof - Google Patents
Trifloxuridinedipirimid tablet and preparation method thereof Download PDFInfo
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- CN114917201A CN114917201A CN202210668115.2A CN202210668115A CN114917201A CN 114917201 A CN114917201 A CN 114917201A CN 202210668115 A CN202210668115 A CN 202210668115A CN 114917201 A CN114917201 A CN 114917201A
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- Prior art keywords
- trifluridine
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- tablet
- aluminum
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- 238000002360 preparation method Methods 0.000 title description 39
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 claims abstract description 75
- 229960003962 trifluridine Drugs 0.000 claims abstract description 74
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000002131 composite material Substances 0.000 claims abstract description 19
- 229920003023 plastic Polymers 0.000 claims abstract description 17
- 239000004033 plastic Substances 0.000 claims abstract description 17
- 239000002274 desiccant Substances 0.000 claims abstract description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 23
- 229910052782 aluminium Inorganic materials 0.000 claims description 23
- 239000011248 coating agent Substances 0.000 claims description 18
- 238000000576 coating method Methods 0.000 claims description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 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 13
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 13
- 229960000913 crospovidone Drugs 0.000 claims description 13
- 239000011888 foil Substances 0.000 claims description 13
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- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 13
- 239000004698 Polyethylene Substances 0.000 claims description 12
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 8
- 239000004800 polyvinyl chloride Substances 0.000 claims description 8
- JWIXXNLOKOAAQT-UHFFFAOYSA-N tipepidine Chemical compound C1N(C)CCCC1=C(C=1SC=CC=1)C1=CC=CS1 JWIXXNLOKOAAQT-UHFFFAOYSA-N 0.000 claims description 8
- 229960000896 tipepidine Drugs 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 229920000881 Modified starch Polymers 0.000 claims description 5
- 235000021355 Stearic acid Nutrition 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 5
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 5
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- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 description 2
- 239000007888 film coating Substances 0.000 claims description 2
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- 230000002496 gastric effect Effects 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 22
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- 239000003826 tablet Substances 0.000 description 36
- 230000000052 comparative effect Effects 0.000 description 24
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- VPXSYLFGBHFLCF-VWZUFWLJSA-N 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)pyrimidine-2,4-dione hydrochloride Chemical compound C1[C@@H]([C@H](O[C@H]1N2C=C(C(=O)NC2=O)C(F)(F)F)CO)O.Cl VPXSYLFGBHFLCF-VWZUFWLJSA-N 0.000 description 1
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
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- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
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- 230000000259 anti-tumor effect Effects 0.000 description 1
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
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- 239000007941 film coated tablet Substances 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical group C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
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- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
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- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 description 1
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- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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Abstract
The invention provides a trifluridine pirimidine tablet, which comprises: trifluridine pirimidyl tablets; an aluminum-plastic blister containing the trifluridine primidine tablet; the medicinal composite bag is sleeved outside the aluminum-plastic bubble cap; and the drying agent is arranged between the aluminum-plastic bubble cap and the medicinal composite bag. The invention adopts the aluminum-plastic bubble cap as an inner packaging material which is directly contacted with the trifluridine tipidine tablet, coats the medicinal composite bag and adds the drying agent in the middle, thereby improving the condition of high humidity instability of the hydrochloric acid tipidine tablet, improving the stability of key quality attributes of related substances of the trifluridine tipidine tablet and the like, and particularly ensuring that the trifluridine tipidine tablet has a similar dissolution curve with the initial trifluridine tipidine tablet after being stored.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a trifluridine pirimidine tablet and a preparation method thereof.
Background
Trifloxuridine is an antitumor nucleoside drug, comprises two components of trifluridine and tipepimidine hydrochloride, the molar ratio of the two components is 1:0.5, the dosage form is a film-coated tablet, the dosage form has two specifications of 15mg and 20mg, and the drug mainly treats the prior chemotherapy based on perfluropyrimidine, oxaliplatin and irinotecan, and the prior treatment or the treatment unsuited to the prior treatment of anti-Vascular Endothelial Growth Factor (VEGF), anti-Epidermal Growth Factor Receptor (EGFR) (RAS wild type)Patients with metastatic colorectal cancer (mCRC). The recommended starting dose for an adult is about 35mg/m 2 Once/twice daily within 1 hour after breakfast and dinner, on days 1-5 and 8-12 of each course, with 28 days as a course, and should be taken until disease progression or intolerable toxicity occurs. The dose was calculated based on Body Surface Area (BSA), with the highest dose being 80 mg/dose.
In the trifluridine tipiramidine tablet, one of active ingredients, namely tipiramidine hydrochloride is easy to hydrolyze. To achieve the stability, the university of Roc drug corporation developed a method of using "sugars with critical humidity of 85% or more at 25 ℃ as 100% excipients, and a drug composition technique that prevents degradation of the drug during long-term storage was used. However, after the drug is left for a long period of time, the dissolution profile of the drug greatly changes from that of the original drug, and the absorption and utilization of the drug effect are impaired.
Disclosure of Invention
In view of the above, the invention provides a trifluridine pirimidine tablet and a preparation method thereof, the trifluridine pirimidine tablet provided by the invention is not degraded after long-term storage, and the dissolution curve of the trifluridine pirimidine tablet is consistent with that of an initial drug after long-term storage.
The invention provides a trifluridine pirimidine tablet, which comprises: trifluridine pirimidyl tablets; an aluminum-plastic blister containing the trifluridine primidine tablet; the medicinal composite bag is sleeved outside the aluminum-plastic bubble cap; and the drying agent is arranged between the aluminum-plastic bubble cap and the medicinal composite bag.
The invention adopts the aluminum plastic bubble cap as an inner packaging material which is in direct contact with the trifluridine substituted pyrimidine tablet, coats the medicinal composite bag and adds the drying agent in the middle, thereby improving the condition of high humidity instability of the hydrochloric acid substituted pyrimidine, improving the stability of key quality attributes of related substances of the trifluridine substituted pyrimidine tablet and the like, and particularly ensuring that the trifluridine substituted pyrimidine tablet has a similar dissolution curve with the initial trifluridine substituted pyrimidine tablet after being stored. In addition, the packaging form used by the invention greatly improves the safety and the effectiveness of the preparation, and simultaneously, sugar with the critical humidity of more than 85 percent at 25 ℃ does not need to be adopted as 100 percent excipient, thereby widening the composition of the pharmaceutical prescription of the trifluridine tipirimid tablets.
The aluminum-plastic blister is used for containing trifluridine pirimidine tablets, and in one embodiment, the aluminum-plastic blister is a polyvinyl chloride/aluminum foil blister, namely a blister package formed by a rigid polyvinyl chloride tablet for medicine and an aluminum foil. In one embodiment, the polyvinyl chloride/aluminum foil blister has a water vapor transmission rate of the polyvinyl chloride hard sheet of less than 2.5g/m2.24h and a water vapor transmission rate of the aluminum foil of less than 0.5g/m 2.24h. In one embodiment, the polyvinyl chloride/aluminum foil blister is a PTP blister.
The medicinal composite bag is used for wrapping an aluminum-plastic bubble cap containing trifluridine pirimidine tablets. In one embodiment, the pharmaceutical composite bag is a polyester/aluminum/polyethylene pharmaceutical composite bag.
And the drying agent is used for keeping the moisture in the aluminum-plastic bubble cap, can not be excessively wetted to influence the water absorption and degradation of the trifluridine tepirimidine tablet, and can not be excessively dried to cause the cracking of the trifluridine tepirimidine tablet. In one embodiment, the desiccant is one or more of a silica gel desiccant, a fiber desiccant, or calcium chloride.
When the packaging method provided by the application is adopted to package the trifluridine tipiramidine tablets, the sugar with the critical humidity of more than 85% at 25 ℃ does not need to be necessarily adopted as a 100% excipient, so that the composition of the pharmaceutical prescription of the trifluridine tipiramidine tablets is widened.
In one embodiment, the trifluridine thiopirimid tablet comprises: trifluridine, tipepidine hydrochloride and pharmaceutically acceptable auxiliary materials. Wherein the molar ratio of the trifluridine to the tipepidine hydrochloride is 1: 0.5.
In one embodiment, the pharmaceutically acceptable excipients include excipients, disintegrants, lubricants and coating materials. The excipient may be a saccharide having a critical humidity at 25 ℃ of 85% or more, or may be another common solid formulation excipient having a critical humidity at 25 ℃ of 85% or less. In one embodiment, the excipient is selected from one or more of lactose, mannitol, microcrystalline cellulose, or sucrose. In one embodiment, the disintegrant is selected from one or more of pregelatinized starch or crospovidone. In one embodiment, the lubricant is selected from one or more of stearic acid or magnesium stearate. In one embodiment, the coating material is selected from gastric-soluble film coating premix available in the market, and mainly comprises hypromellose, polyethylene glycol, titanium dioxide and the like, and has no water-resisting/waterproof function.
A typical composition of trifluridine pirimidyl tablets comprises:
20 parts by mass of trifluridine;
9.42 parts by mass of tipepimidine hydrochloride;
120.98 parts by mass of lactose;
8 parts by mass of pregelatinized starch;
1.6 parts by mass of stearic acid;
a typical composition of trifluridine pirimidyl tablets comprises:
20 parts by mass of trifluridine;
9.42 parts by mass of tipepidine hydrochloride;
114.98 parts by mass of mannitol;
14 parts by mass of crospovidone;
1.6 parts by mass of magnesium stearate;
a typical composition of trifluridine pirimidyl tablets comprises:
20 parts by mass of trifluridine;
9.42 parts by mass of tipepimidine hydrochloride;
120.98 parts by mass of lactose;
8 parts by mass of crospovidone;
1.6 parts by mass of magnesium stearate;
a typical composition of trifluridine pirimidyl tablets comprises:
20 parts by mass of trifluridine;
9.42 parts by mass of tipepimidine hydrochloride;
60.98 parts by mass of lactose;
60 parts by mass of microcrystalline cellulose;
8 parts by mass of crospovidone;
1.6 parts by mass of magnesium stearate.
In order to avoid the increase of high-humidity degradation products of the trifluridine tipiramidine hydrochloride in the granulation process, the intermediate granule of the trifluridine tipiramidine hydrochloride is prepared by directly mixing raw materials and auxiliary materials, namely, the trifluridine hydrochloride tipiramidine hydrochloride and pharmaceutically acceptable auxiliary materials are directly mixed and tableted.
The invention adopts the aluminum plastic bubble cap as an inner packaging material which is in direct contact with the trifluridine substituted pyrimidine tablet, coats the medicinal composite bag and adds the drying agent in the middle, thereby improving the condition of high humidity instability of the hydrochloric acid substituted pyrimidine, improving the stability of key quality attributes of related substances of the trifluridine substituted pyrimidine tablet and the like, particularly improving the physical and chemical stability of the floxuridine substituted pyrimidine tablet in the stable placing process, greatly reducing the change of the dissolution behavior of the trifluridine substituted pyrimidine tablet during the placing process, and having a dissolution curve similar to that of the initial trifluridine substituted pyrimidine tablet. In addition, the packaging form used by the invention greatly improves the safety and the effectiveness of the preparation, and simultaneously, the sugar with the critical humidity of more than 85 percent at 25 ℃ does not need to be adopted as a 100 percent excipient, thereby widening the prescription composition of the trifluridine pirimidine tablet medicament. The test result shows that the packaging form provided by the invention can ensure that the trifluridine pirimidine tablet still has better stability and lower related substance level under a high-humidity environment, and related substances do not obviously change and dissolution curves do not obviously change in the placing process, so that the production, transportation and use of the trifluridine pirimidine tablet are facilitated, the administration safety of the product is greatly improved, and the clinical use of patients is safer and more stable.
Drawings
FIG. 1 is an HPLC chromatogram of a packaged formulation of example 1 after standing at high temperature and high humidity for 30 days;
FIG. 2 is an HPLC chromatogram of the packaged formulation of example 2 after being left at high temperature and high humidity for 30 days;
FIG. 3 is an HPLC chromatogram of the packaged formulation of example 3 after being left at high temperature and high humidity for 30 days;
FIG. 4 is an HPLC chromatogram of the packaged formulation of example 4 after being left at high temperature and high humidity for 30 days;
FIG. 5 is an HPLC chromatogram of a packed formulation of comparative example 2 after standing at high temperature and high humidity for 30 days;
FIG. 6 is an HPLC chromatogram of a packed formulation of comparative example 3 after standing at high temperature and high humidity for 30 days;
FIG. 7 is an HPLC chromatogram of a packed formulation of comparative example 4 after 30 days of high temperature and high humidity;
FIG. 8 is a dissolution profile of the finished formulations provided in examples 1-4;
FIG. 9 is a graph showing the dissolution curves of the formulations packed in examples and comparative examples after being left for 30 days at high temperature and high humidity.
Detailed Description
The invention provides a trifluridine tipiramidine tablet and a preparation method thereof. Those skilled in the art can modify the process parameters appropriately in view of the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and modifications in the methods and applications disclosed herein, or appropriate variations and combinations thereof, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The present invention provides a trifluridine derivative tablet and a method for preparing the same, which are further described below with reference to the following examples.
The materials used in the present invention are all commercially available unless otherwise specified.
Example 1
The formulation composition of the formulation is shown in table 1:
table 1 formulation provided in example 1
| Composition (I) | Amount of the composition |
| Trifluridine | 20g |
| Hydrochloric acid substituted pirimid | 9.42g |
| Lactose | 120.98g |
| Pregelatinized starch | 8g |
| Stearic acid | 1.6g |
| Coating powder | The weight is increased by 2 to 3 percent |
The preparation method comprises the following steps:
mixing the two raw materials with adjuvants, tabletting, and coating to obtain final product;
packaging the finished preparation product by using a PTP (polyethylene film/aluminum foil) blister, externally coating a polyester/aluminum/polyethylene medicinal composite bag, and adding a fiber desiccant in the middle.
Example 2
The formulation composition of the formulation is shown in table 2:
table 2 formulation provided in example 2
| Composition (I) | Dosage of |
| Trifluridine | 20g |
| Hydrochloric acid substituted pirimid | 9.42g |
| Mannitol | 114.98 |
| Crospovidone | 14g |
| Magnesium stearate | 1.6g |
| Coating powder | The weight is increased by 2 to 3 percent |
The preparation method comprises the following steps:
mixing the two raw materials with adjuvants, tabletting, and coating to obtain final product;
packaging the finished preparation product by a PTP (polyethylene film/aluminum foil) blister, externally coating a polyester/aluminum/polyethylene medicinal composite bag, and adding a fiber drying agent in the middle.
Example 3
The formulation composition is shown in table 3:
table 3 formulation provided in example 3
| Composition (I) | Amount of the composition |
| Trifluridine | 20g |
| Hydrochloric acid substituted pirimid | 9.42g |
| Lactose | 120.98g |
| Crospovidone | 8g |
| Magnesium stearate | 1.6g |
| Coating powder | The weight is increased by 2 to 3 percent |
The preparation method comprises the following steps:
mixing the two raw materials with adjuvants, tabletting, and coating to obtain final product;
packaging the finished preparation product by a PTP (polyethylene film/aluminum foil) bubble cap, externally coating a polyester/aluminum/polyethylene medicinal composite bag, and adding a silica gel desiccant in the middle.
Example 4
The formulation composition is shown in table 4:
table 4 formulation provided in example 4
| Composition (A) | Dosage of |
| Trifluridine | 20g |
| Hydrochloric acid substituted pirimid | 9.42g |
| Lactose | 60.98g |
| Microcrystalline cellulose | 60g |
| Crospovidone | 8g |
| Magnesium stearate | 1.6g |
| Coating powder | The weight is increased by 2 to 3 percent |
The preparation method comprises the following steps:
mixing the two raw materials with adjuvants, tabletting, and coating to obtain final product;
packaging the finished preparation product by a PTP (polyethylene film/aluminum foil) blister, externally coating a polyester/aluminum/polyethylene medicinal composite bag, and adding a calcium chloride drying agent in the middle.
Comparative example 1
The formulation composition of the formulation is shown in table 5:
table 5 formulation provided in comparative example 1
| Composition (I) | Amount of the composition |
| Trifluridine | 20g |
| Hydrochloric acid substituted pirimid | 9.42g |
| Lactose | 60.98g |
| Microcrystalline cellulose | 60g |
| Crospovidone | 8g |
| Magnesium stearate | 1.6g |
| Coating powder | The weight is increased by 2 to 3 percent |
The preparation method comprises the following steps:
mixing the two materials with lactose, microcrystalline cellulose and crospovidone, adding purified water, wetting, granulating, drying, adding magnesium stearate, mixing, tabletting, and coating to obtain final product.
Comparative example 2
The finished formulation prepared in example 1 was stored in a high density polyethylene bottle.
Comparative example 3
The finished formulation prepared in example 2 was stored in a high density polyethylene bottle.
Comparative example 4
The finished formulation prepared in example 1 was blister-packaged using PTP (polyethylene film/aluminum foil) with a polyester/aluminum/polyethylene pharmaceutical composite bag without desiccant in the middle.
Test example 1
The finished preparation products prepared in the examples 1-4 and the comparative example 1 are detected, the levels of relevant substances are inspected, and the detection method of the relevant substances comprises the following steps: octadecylsilane chemically bonded silica is used as a filler, a chromatographic column is Inertsil ODS-3(4.6mm multiplied by 250mm,5 mu m) or other similar chromatographic columns, phosphate buffer solution (1.4 g of sodium dihydrogen phosphate dihydrate and 0.9g of sodium heptanesulfonate are taken and 900ml of water is added for dissolution, and the pH value is adjusted to 2.7 by phosphoric acid) is used as a mobile phase A, and acetonitrile is used as a mobile phase B; the detection wavelength is 210 nm; the column temperature was 40 ℃; the flow rate was 1.0 ml/min. The dissolution rate detection method comprises the following steps: octadecylsilane chemically bonded silica is used as a filling agent; taking 0.025mol/L disodium hydrogen phosphate solution-methanol (76: 24) as a mobile phase; the detection wavelength is 276nm, the column temperature is 40 ℃, the flow rate is 1.0ml/min, and the peak emergence sequence is the order of the hydrochloric acid tipepidine and the trifluridine.
The finished products of the preparations prepared in the embodiments 1 to 4 are detected, the dissolution curve is tested, and the dissolution conditions are as follows: the dissolution method comprises the following steps: paddle method, rotational speed: 50rpm, dissolution medium: purified water, volume 900 ml;
the results are shown in Table 6, and Table 6 shows the detection results of the relevant substances of the finished preparation products prepared in examples 1-4 and comparative example 1.
TABLE 6 detection results of related substances of the finished preparations prepared in examples 1 to 4 and comparative example 1
| Impurity content (%) | Limit of | Example 1 | Example 2 | Example 3 | Example 4 | Comparative example 1 |
| TPI-impurity A | ≤0.1％ | N.D | N.D | N.D | N.D | N.D |
| TPI-impurity B | ≤0.2％ | 0.04 | 0.03 | 0.06 | 0.03 | 0.03 |
| TPI-impurity C | ≤0.2％ | N.D | N.D | N.D | N.D | 0.14 |
| TPI-impurity D | ≤0.2％ | 0.03 | 0.03 | 0.03 | N.D | 0.02 |
| TPI-impurity E | ≤0.2％ | N.D | N.D | N.D | N.D | N.D |
| Single unknown impurity | ≤0.2％ | N.D | N.D | N.D | N.D | 0.08 |
Note that: since high humidity conditions only affect the level of the tipepidine hydrochloride impurity, the table only counts the impurities of the tipepidine hydrochloride.
As can be seen from the tests on the substances in the examples 1-4 and the comparative example 1, the product is more suitable for the direct compression process, and the comparative example 1 is implemented by tabletting after wet granulation, and the tests on the substances show that the product has degradation impurities after wet granulation, which indicates that the product is suitable for the direct compression process production.
The finished products of the preparations prepared in the embodiments 1 to 4 are detected, the dissolution curve is tested, and the dissolution conditions are as follows: the dissolution method comprises the following steps: paddle method, rotational speed: 50rpm, dissolution medium: purified water, volume 900 ml;
the packaged preparations prepared in examples 1 to 4 and comparative examples 2 to 4 were placed at 25 ℃ and 90% +/-5% humidity for 30 days, and the conditions and dissolution curves of the relevant substances were examined according to the above-mentioned methods, and the results are shown in FIGS. 1 to 9, 7 and 8, where FIG. 1 is an HPLC profile of the packaged preparation of example 1 at high temperature and high humidity for 30 days, FIG. 2 is an HPLC profile of the packaged preparation of example 2 at high temperature and high humidity for 30 days, FIG. 3 is an HPLC profile of the packaged preparation of example 3 at high temperature and high humidity for 30 days, FIG. 4 is an HPLC profile of the packaged preparation of example 4 at high temperature and high humidity for 30 days, FIG. 5 is an HPLC profile of the packaged preparation of comparative example 2 at high temperature and high humidity for 30 days, FIG. 6 is an HPLC profile of the packaged preparation of comparative example 3 at high temperature and high humidity for 30 days, FIG. 7 is an HPLC profile of the packaged preparation of comparative example 4 at high temperature and high humidity for 30 days, fig. 8 is a dissolution curve of the finished preparations provided in examples 1 to 4, fig. 9 is a dissolution curve of the packaged preparations of examples and comparative examples after being left for 30 days under high temperature and high humidity, table 7 is a dissolution curve of the finished preparations and packaged preparations prepared in examples and comparative examples, and table 8 is a substance statistics table of the packaged preparations prepared in examples and comparative examples after being stored for 30 days under high humidity.
TABLE 7 dissolution curves of finished preparations and packaged preparations prepared in examples and comparative examples
TABLE 8 statistics of the substances in the packaged formulations prepared in examples and comparative examples after 30-day high-humidity storage
Note that: since high humidity conditions only affect the level of the tipepimidine hydrochloride impurity, the table only counts the impurities of tipepimidine hydrochloride.
As is clear from fig. 1 to 9, table 6, table 7 and table 8, the substance levels in examples 1, 2, 3 and 4 were kept at low levels even in the 0-time test, regardless of whether a saccharide having a critical humidity at 25 ℃ of 85% or more was used or other common solid formulation excipients having a critical humidity at 25 ℃ of 85% or less were used. Meanwhile, by adopting the packaging form of the invention, the medicine has good physical and chemical stability, especially the dissolution curve is the same as that of the initial preparation, no matter the medicine is combined with the saccharide excipient with the critical humidity of more than 85% at 25 ℃, or is combined with other common solid preparation excipients with the critical humidity of less than 85% at 25 ℃. In the case of other packaging forms, even when a combination with a saccharide excipient having a critical humidity of 85% or more at 25 ℃ is used in the preparation, the amount of impurities may increase and the dissolution rate may be greatly improved during the stability period.
In conclusion, the packaging form of the invention can improve the quality and safety of the medicine.
The above examples are only preferred embodiments of the present invention, and a number of improvements, modifications or improvements can be made on the basis of the present invention without departing from the principle of the present invention, and these should also be construed as the protection scope of the present invention.
Claims (10)
1. A trifluridine tipyrimidine tablet comprising: trifluridine pirimidyl tablets; an aluminum-plastic blister containing the trifluridine pirimidyl tablet; the medicinal composite bag is sleeved outside the aluminum-plastic bubble cap; and the drying agent is arranged between the aluminum-plastic bubble cap and the medicinal composite bag.
2. A trifluridine primidine tablet according to claim 1, wherein the aluminum plastic blister is a polyvinyl chloride/aluminum foil blister.
3. A trifluridine pirimidine tablet according to claim 2, wherein said polyvinyl chloride/aluminum foil blister has a water vapor transmission rate of said polyvinyl chloride hard tablet lower than 2.5g/m 2 24h, the water vapor transmission capacity of the aluminum foil is less than 0.5g/m 2 .24h。
4. A trifluridine tipopyrimidine tablet according to claim 1, characterized in that said pharmaceutical composite pouch is a polyester/aluminum/polyethylene pharmaceutical composite pouch.
5. A trifluridine telapropyrimidine tablet according to claim 1, wherein said desiccant is one or more of silica gel desiccant, fiber desiccant or calcium chloride.
6. A trifluridine pirimidyl tablet according to claim 1, wherein said trifluridine pirimidyl tablet comprises: trifluridine, tipepidine hydrochloride and pharmaceutically acceptable auxiliary materials.
7. A trifluridine telipimidine tablet according to claim 6, wherein the pharmaceutically acceptable excipients comprise an excipient, a disintegrant, a lubricant and a coating material.
8. A trifluridine primidine tablet according to claim 7, characterized in that the excipient is selected from one or more of lactose, mannitol, microcrystalline cellulose or sucrose;
the disintegrant is selected from one or more of pregelatinized starch or crospovidone;
the lubricant is selected from one or more of stearic acid or magnesium stearate;
the coating material is selected from gastric soluble film coating premix.
9. A trifluridine tegpirimidine tablet according to claim 6, comprising:
20 parts by mass of trifluridine;
9.42 parts by mass of tipepimidine hydrochloride;
120.98 parts by mass of lactose;
8 parts by mass of pregelatinized starch;
1.6 parts by mass of stearic acid;
or comprises the following steps:
20 parts by mass of trifluridine;
9.42 parts by mass of tipepidine hydrochloride;
114.98 parts by mass of mannitol;
14 parts by mass of crospovidone;
1.6 parts by mass of magnesium stearate;
or comprises the following steps:
20 parts by mass of trifluridine;
9.42 parts by mass of tipepimidine hydrochloride;
120.98 parts by mass of lactose;
8 parts by mass of crospovidone;
1.6 parts by mass of magnesium stearate;
or comprises the following steps:
20 parts by mass of trifluridine;
9.42 parts by mass of tipepimidine hydrochloride;
60.98 parts by mass of lactose;
60 parts by mass of microcrystalline cellulose;
8 parts by mass of crospovidone;
1.6 parts by mass of magnesium stearate.
10. A trifluridine tipopyrimidine tablet according to any one of claims 6-9, wherein said trifluridine tipopyrimidine tablet is prepared by mixing and tabletting trifluridine, tipopyrimidine hydrochloride and pharmaceutically acceptable excipients.
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Citations (4)
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| CN104105490A (en) * | 2012-02-15 | 2014-10-15 | 大鹏药品工业株式会社 | Oral pharmaceutical composition |
| CN105395497A (en) * | 2015-12-04 | 2016-03-16 | 杭州新诺华医药有限公司 | Stable alpha-crystalline form perindopril tert-butylamine tablet and preparation method thereof |
| CN111186632A (en) * | 2018-11-15 | 2020-05-22 | 珠海润都制药股份有限公司 | Package for improving stability of medicine |
| US20200405741A1 (en) * | 2018-03-03 | 2020-12-31 | Natco Pharma Limited | Stable pharmaceutical compositions comprising trifluridine and tipiracil hydrochloride |
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| CN104105490A (en) * | 2012-02-15 | 2014-10-15 | 大鹏药品工业株式会社 | Oral pharmaceutical composition |
| CN105395497A (en) * | 2015-12-04 | 2016-03-16 | 杭州新诺华医药有限公司 | Stable alpha-crystalline form perindopril tert-butylamine tablet and preparation method thereof |
| US20200405741A1 (en) * | 2018-03-03 | 2020-12-31 | Natco Pharma Limited | Stable pharmaceutical compositions comprising trifluridine and tipiracil hydrochloride |
| CN111186632A (en) * | 2018-11-15 | 2020-05-22 | 珠海润都制药股份有限公司 | Package for improving stability of medicine |
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