CN103479600A - Tacrolimus solid dispersion - Google Patents
Tacrolimus solid dispersion Download PDFInfo
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- CN103479600A CN103479600A CN201310424622.2A CN201310424622A CN103479600A CN 103479600 A CN103479600 A CN 103479600A CN 201310424622 A CN201310424622 A CN 201310424622A CN 103479600 A CN103479600 A CN 103479600A
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- tacrolimus
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- solid dispersion
- hydrate
- slow releasing
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- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 title claims abstract description 51
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 title claims abstract description 51
- 229960001967 tacrolimus Drugs 0.000 title claims abstract description 50
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 56
- 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 abstract description 10
- 229930195725 Mannitol Natural products 0.000 claims abstract description 10
- 239000000594 mannitol Substances 0.000 claims abstract description 10
- 235000010355 mannitol Nutrition 0.000 claims abstract description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
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- 239000000203 mixture Substances 0.000 claims description 10
- 239000001856 Ethyl cellulose Substances 0.000 claims description 9
- 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 9
- 229920001249 ethyl cellulose Polymers 0.000 claims description 9
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 9
- 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 7
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 3
- 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 2
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
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- 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 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 101100309716 Arabidopsis thaliana SD18 gene Proteins 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
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- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 description 1
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- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
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- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a tacrolimus solid dispersion. The tacrolimus solid dispersion contains tacrolimus or hydrate of tacrolimus, a solid matrix and an excipient, wherein the solid matrix and the excipient are used for dispersing the tacrolimus or the hydrate of tacrolimus. Moreover, the invention relates to an oral sustained release preparation of tacrolimus and a preparation method of a new sustained release system. The solid dispersion technology is adopted for the method, the water-insoluble solid matrix and the water-soluble solid matrix are mixed to serve as a carrier, the excipient of mannitol is added, and thus the medicine is not only consistent with a reference preparation in extracorporeal dissolution but also good in oral absorption and has high bioavailability.
Description
Technical field
The slow releasing preparation that the present invention relates to a kind of solid dispersion of tacrolimus and contain this solid dispersion.
Background technology
Tacrolimus, English tacrolimus(FK506 by name), be a kind of novel potent inhibitive ability of immunity macrolide antibiotics.To the selective inhibitory action of T cell, mainly by with intracellular immunity, having a liking for plain FK, be combined albumen (FKBP) in conjunction with suppressing Th cell release IL-2, IL-3, IFN-γ and suppressing IL-2R and express, strong 100 times than ciclosporin (CsA).Be mainly used in clinically the resisting transplant rejection reaction, also can be used for the autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis.
One class is by suppressing cell and humoral immune reaction, and the chemistry that tissue injury is alleviated or biological substance.It has immunosuppressive action, can suppress the abnormal immunoreation of body, is widely used at present the treatment of the anti-rejection of organ transplantation and autoimmune disease.Immunosuppressant class medicine in the market mainly contains ciclosporin, tacrolimus, rapamycin etc., immunosuppressant to time-to-live of Organ Transplantation Patients, keep the aspect such as transplant organ good function all to play an important role.Tacrolimus determined curative effect, side effect are little, within the short time of Discussion on Chinese Listed, sell rapidly and rise, and have become the first-line drug of anti-rejection after liver and renal transplantation, and Ministry of Public Health has been classified tacrolimus as clinical first-selected fundamental immunity and suppressed medicine.
Compliance is one of influence factor who transplants receptor's long-term prognosis, and the immunosuppressant of using at present all needs one day twice or repeatedly takes medicine." the SCIENTIFIC DISCUSSION " that announce the EMA website points out, compliance is poor is one of correlative factor of chronic graft mistake merit, studies show that the therapeutic scheme of renal transplantation recipients administration once a day has the compliance of statistical significance than taking twice show every day.Therefore the slow releasing preparation that preparation can make the patient reduce medicining times becomes one of significant problem of filed of organ transplantation.
Summary of the invention
For solving the problems of the technologies described above, break through an exploitation difficult problem, the object of the present invention is to provide a kind of slow releasing preparation of tacrolimus, allow the patient take tacrolimus every day one time, thereby improve the compliance that the patient takes medicine.In tacrolimus slow releasing preparation provided by the invention and preparation method thereof, the stripping of tacrolimus is slowly to discharge, the effective blood drug concentration that can maintain the long period, and pharmaceutical active maintains the long period, according to the present invention, can reduce the administration frequency of medicine.
For obtaining slow releasing preparation of the present invention, first prepared a kind of solid dispersion that contains tacrolimus or its hydrate.
The invention provides a kind of solid dispersion, wherein tacrolimus or its hydrate are scattered in the mixture of hydroxypropyl methylcellulose and ethyl cellulose, it is characterized in that also containing mannitol.
In the preferred solid dispersion of the present invention, the weight ratio of tacrolimus or its hydrate and mannitol is 1:5～1:30, preferably 1:10～1:20.
In the preferred embodiment of the invention, tacrolimus or its hydrate are 1:0.3～1 with the mixture weight ratio of hydroxypropyl methylcellulose and ethyl cellulose.
In more preferred embodiment, the weight ratio of tacrolimus and hydroxypropyl methylcellulose is 1:0.2～1:0.4; The weight ratio of tacrolimus and ethyl cellulose is 1:0.1～1:5.
The present invention adopts solid dispersion technology, for accelerating and increase the stripping of medicine, improves its bioavailability.
Resulting solid dispersion granule preferably is less than or equal to 250 μ m.
The solid dispersion compositions of producing by said method or its microgranule can be used as slow releasing preparation, consider the ease for operation of preparation, the dispersibility in water and the dispersibility after oral administration, more preferably by conventional formulation method (as compression moulding) by as described in compositions be prepared as the slow releasing preparation of powder, microgranule, granule, tablet or capsule form.
Dosage form involved in the present invention is slow releasing preparation, preferably in solid dispersion, does not substantially contain any disintegrating agent.
In preferred embodiments, slow releasing preparation of the present invention, except solid dispersion, also contains lubricant, is selected from magnesium stearate, micropowder silica gel, Pulvis Talci, preferably magnesium stearate.
In a preferred embodiment, slow releasing preparation of the present invention also contains lactose
Can preparing as follows of the slow releasing preparation of tacrolimus described in the present invention:
1, raw material pre-treatment: the mannitol of the amount of taking fully, cross 200 mesh sieves, collect the powder that sieves standby.
2, the preparation of solid dispersion:
1) take ethyl cellulose and the principal agent of recipe quantity, stir and be dissolved in dehydrated alcohol.
2) take the hypromellose of recipe quantity, slowly add in solution, keep stirring.
When 3) range estimation hypromellose swelling is without block colloid, keep stirring, standby as binding agent.
4) taking the colloidal silica of recipe quantity and the mannitol fine powder that sieved, add in wet granulator, mix, by 3) gradation slowly adds, granulates.After the wet granulate of 80 mesh sieves, the stand dish, 50 ℃ of vacuum drying ovens are dried, the dry granulate of 80 order.
5) by granule sealed packing, keep in Dark Place, survey content, molten residual, related substance.
3, the preparation of capsule:
1) total mixed: as according to after cubage, solid dispersion, vertical compression lactose, magnesium stearate to be put in total mixed machine and mixed;
2) 4# capsule-filling;
3) packing: adopt aluminium-plastic bubble plate packing.
In the present invention, related preparation process all needs the lucifuge operation.
The dissolution test related in the present invention adopts two appendix XC the second methods of Chinese Pharmacopoeia version in 2005: the device of dissolution method carries out.
The accompanying drawing explanation
In conjunction with the following drawings, above and other purpose of the present invention and feature will become apparent, and these accompanying drawings mean respectively:
Figure 1 shows that the dissolution test curve chart of tacrolimus slow release capsule, the tacrolimus slow-released system makes medicine continuous and effective in 12-24h, can under physiological condition, slowly discharge.
Figure 2 shows that the average blood drug level-time graph of tacrolimus.
The specific embodiment
Embodiment 1:
Tacrolimus slow release capsule prescription
SD1
Preparation 1
The mannitol of the amount of taking fully, cross 200 mesh sieves, collects the powder that sieves standby.Tacrolimus and ethyl cellulose stirring are dissolved in dehydrated alcohol.Take hypromellose, slowly add in solution, keep stirring.While estimating hypromellose E3 swelling without block colloid, keep stirring, standby as binding agent.The mannitol fine powder that takes colloidal silica and sieved, add in wet granulator, mixes, and the binding agent gradation is slowly added, and granulates.After the wet granulate of 80 mesh sieves, the stand dish, 50 ℃ of vacuum drying ovens are dried, the SD1 of the dry granulate of 80 order.SD1, lactose, magnesium stearate are put in total mixed machine and be mixed with preparation 1; Preparation 1 is packed into to the 4# capsule.
Embodiment 2:
Tacrolimus slow release capsule prescription
SD2
Preparation 2
Method with similar to embodiment 1, prepare preparation 2; Preparation 2 is packed into to the 4# capsule.
Embodiment 3:
Tacrolimus slow release capsule prescription
SD3
Preparation 3
Method with similar to embodiment 1, prepare preparation 3; Preparation 3 is packed into to the 4# capsule.
Embodiment 4:
Tacrolimus slow release capsule prescription
SD4
Preparation 4
Method with similar to embodiment 1, prepare preparation 4; Preparation 4 is packed into to the 4# capsule.
Embodiment 5:
Tacrolimus slow release capsule prescription
SD5
Method with similar to embodiment 1, prepare preparation 5; Preparation 5 is packed into to the 4# capsule.
Embodiment 6:
Tacrolimus slow release capsule prescription
SD6
Preparation 6
Method with similar to embodiment 1, prepare preparation 6; Preparation 6 is packed into to the 4# capsule.
Embodiment 7:
Tacrolimus slow release capsule prescription
SD7
Preparation 7
Method with similar to embodiment 1, prepare preparation 7; Preparation 7 is packed into to the 4# capsule.
Embodiment 8:
Tacrolimus slow release capsule prescription
SD18
Method with similar to embodiment 1, prepare preparation 8; Preparation 8 is packed into to the 4# capsule.
Embodiment 9:
SD9
Preparation 9
Method with similar to embodiment 1, prepare preparation 9; Preparation 9 is packed into to the 4# capsule.
Embodiment 10:
Tacrolimus slow release capsule prescription
SD10
Take ethyl cellulose and the tacrolimus of recipe quantity, stir the dehydrated alcohol that is dissolved in recipe quantity.After the clarification of range estimation solution, take the hypromellose E3 of recipe quantity, slowly add in solution, keep stirring.While estimating the abundant swelling of hypromellose E3 without block colloid, take the mannitol of recipe quantity, slowly add in this suspension.Keeping under stirring, dry this suspension of water-bath (about 40-50 ℃) vacuum decompression, then take out solid, and the abrasive solid dispersion becomes fine powder fast, to passing through 80 mesh sieves.After fine powder is carried out to assay, mix with lactose, then add a certain amount of magnesium stearate, total mixed, fill the 4# capsule.
Embodiment 11:
Dissolution test: the dissolution test related in the present invention adopts two appendix XC the second methods of Chinese Pharmacopoeia version in 2005: the device of dissolution method carries out, solution (the Japanese Pharmacopoeia Ph4.5 acetate buffer) 900ml of 0.005% hydroxypropyl cellulose (1 → 20 liter) of take is tested as release medium, at 1h, preparation and the reference preparation the data obtained of 2h, 6h, 12h, 24h embodiment 7 are shown in Fig. 1.In the present invention, related reference preparation derives from the former An Silaitai Pharmacy stock Co., Ltd of company of grinding, and adding adjuvant in solid dispersion in former triturate is lactose.
Embodiment 12:
Use preparation and the contrast of former triturate of embodiment 7, the experimenter advanced unified light diet in test the evening day before yesterday, and after supper, fasting, to morning next day, was used 200ml warm water oral test medicine early morning on the same day on an empty stomach in testing.6 routine subject age 22～27(23.5 ± 1.9) year, height 1.68～1.78(1.75 ± 0.04) rice, Body Mass Index 19.88～23.99(23.05 ± 1.57), health examination and routine blood test, Hepatitis B virus, Electrocardioscopy, hepatic and renal function, all no abnormal.After the experimenter took medicine in two cycles, by the EXPERIMENTAL DESIGN time point, take venous blood, adopt LC-MS/MS record TCS in whole blood through the time blood drug level, average blood drug level-time graph is shown in Fig. 2.
As seen from Figure 1, tacrolimus slow releasing preparation of the present invention makes medicine continuous and effective in 12-24h, can under physiological condition, slowly discharge, thereby make patient to take every day once, improves patient's drug compliance.
From Fig. 2, can significantly find out, tacrolimus slow releasing preparation bioavailability of the present invention, apparently higher than control formulation, as calculated, is compared AUC with former triturate
0-24hrbe about its 125%.
Claims (8)
1. a solid dispersion, wherein tacrolimus or its hydrate are scattered in the mixture of hydroxypropyl methylcellulose and ethyl cellulose, it is characterized in that also containing mannitol.
2. solid dispersion according to claim 1, wherein the weight ratio of tacrolimus or its hydrate and mannitol is 1:5～1:30, preferably 1:10～1:20.
3. solid dispersion according to claim 1 and 2, wherein tacrolimus or its hydrate with the mixture weight of hydroxypropyl methylcellulose and ethyl cellulose than being 1:0.3～1.
4. according to the described solid dispersion of any one in claims 1 to 3, wherein the weight ratio of tacrolimus and hydroxypropyl methylcellulose is 1:0.2～1:0.4.
5. according to the described solid dispersion of any one in claims 1 to 3, wherein the weight ratio of tacrolimus and ethyl cellulose is 1:0.1～1:5.
6. the slow releasing preparation of a tacrolimus, it is containing the described solid dispersion of any one in good grounds claim 1 to 5.
7. the slow releasing preparation of tacrolimus according to claim 6, it also contains lubricant, and described lubricant is selected from magnesium stearate, micropowder silica gel, Pulvis Talci, preferably magnesium stearate.
8. the slow releasing preparation of tacrolimus according to claim 6, is characterized in that it also contains lactose.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104940334A (en) * | 2015-06-24 | 2015-09-30 | 绍兴文理学院元培学院 | Hawthorn leaf extract solid dispersion sustained release capsule and preparation method thereof |
| CN105828827A (en) * | 2014-11-21 | 2016-08-03 | 杭州领业医药科技有限公司 | Solid preparation comprising tofogliflozin and method for producing same |
| CN106137971A (en) * | 2015-11-17 | 2016-11-23 | 南京瑞捷医药科技有限公司 | A kind of tacrolimus dispersion and slow releasing composition thereof and preparation method |
| CN107595784A (en) * | 2017-08-29 | 2018-01-19 | 杭州中美华东制药有限公司 | Tacrolimus slow releasing medicinal compositions |
| CN110639020A (en) * | 2019-08-15 | 2020-01-03 | 浙江工业大学 | Solid dispersion matrix and preparation method and application thereof |
| US11752104B2 (en) | 2019-05-31 | 2023-09-12 | Medical And Pharmaceutical Industry Technology And | Oral composition and methods for manufacturing the same and treatment |
| US11839605B2 (en) | 2018-10-11 | 2023-12-12 | Alivio Therapeutics, Inc. | Non-injectable hydrogel formulations for smart release |
Citations (3)
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| WO2006083130A1 (en) * | 2005-02-04 | 2006-08-10 | Hanmi Pharm. Co., Ltd. | Amorphous taclolimus solid dispersion having an enhanced solubility and pharmaceutical composition comprising same |
| CN1820759A (en) * | 2006-03-20 | 2006-08-23 | 复旦大学 | Tacrolimus solid dispersion and preparation method thereof |
| CN101537184A (en) * | 2009-04-30 | 2009-09-23 | 杭州中美华东制药有限公司 | Composition containing water-insoluble high-activity drug and preparation method thereof |
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| CN105828827A (en) * | 2014-11-21 | 2016-08-03 | 杭州领业医药科技有限公司 | Solid preparation comprising tofogliflozin and method for producing same |
| CN104940334A (en) * | 2015-06-24 | 2015-09-30 | 绍兴文理学院元培学院 | Hawthorn leaf extract solid dispersion sustained release capsule and preparation method thereof |
| CN104940334B (en) * | 2015-06-24 | 2018-04-10 | 绍兴文理学院元培学院 | A kind of hawthorne leaf P.E solid dispersions spansule and preparation method thereof |
| CN106137971A (en) * | 2015-11-17 | 2016-11-23 | 南京瑞捷医药科技有限公司 | A kind of tacrolimus dispersion and slow releasing composition thereof and preparation method |
| CN107595784A (en) * | 2017-08-29 | 2018-01-19 | 杭州中美华东制药有限公司 | Tacrolimus slow releasing medicinal compositions |
| CN107595784B (en) * | 2017-08-29 | 2018-09-28 | 杭州中美华东制药有限公司 | Tacrolimus slow releasing medicinal compositions |
| US11839605B2 (en) | 2018-10-11 | 2023-12-12 | Alivio Therapeutics, Inc. | Non-injectable hydrogel formulations for smart release |
| US11752104B2 (en) | 2019-05-31 | 2023-09-12 | Medical And Pharmaceutical Industry Technology And | Oral composition and methods for manufacturing the same and treatment |
| CN110639020A (en) * | 2019-08-15 | 2020-01-03 | 浙江工业大学 | Solid dispersion matrix and preparation method and application thereof |
| CN110639020B (en) * | 2019-08-15 | 2022-07-08 | 浙江工业大学 | A kind of solid dispersion matrix and its preparation method and application |
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