CN106822041A - A kind of PTS Tivozanib oral sustained release micropills and preparation method thereof - Google Patents
A kind of PTS Tivozanib oral sustained release micropills and preparation method thereof Download PDFInfo
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- CN106822041A CN106822041A CN201611096938.3A CN201611096938A CN106822041A CN 106822041 A CN106822041 A CN 106822041A CN 201611096938 A CN201611096938 A CN 201611096938A CN 106822041 A CN106822041 A CN 106822041A
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- tivozanib
- sustained release
- pts
- oral sustained
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention belongs to field of medicaments, and in particular to a kind of PTS Tivozanib oral sustained release micropills and preparation method thereof.The oral sustained release micropill is made up of each raw material of following parts by weight：2~60 parts of Tivozanib medicines, 10~90 parts of diluent, 1~25 part of adhesive, 1~45 part of slow-release material, 0.5~10 part of pore-foaming agent, 0.5~10 part of plasticizer, 0.5~30 part of antiplastering aid.Its preparation method comprises the following steps, first, adhesive is added to be made capsule core after PTS Tivozanib and sustained release agent being mixed, then, the capsule core is coated with the compound of slow-release material, pore-foaming agent, plasticizer and antiplastering aid again, the sustained release pellet is obtained final product after the completion of coating.Oral sustained release micropill the invention provides PTS Tivozanib and preparation method thereof, makes the orally available PTS of patient, and it can gently stablize release in the acid solution close to human body hydrochloric acid in gastric juice.The preparation method that the present invention is provided is simple to operate, and technical maturity, low production cost, efficiency high is suitable for large-scale production.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of PTS Tivozanib oral sustained releases micropill and its preparation
Method.
Background technology
Tivozanib, also known as AV-951, chemical entitled N- { the chloro- 4- of 2- [(6,7- dimethoxy-4 's-quinolyl) epoxide]
Phenyl }-N'- (5- methyl -3- isoxazolyls) urea.
Structural formula：
Tivozanib is a kind of antineoplastic target medicine, is Mutiple Targets anti-angiogenesis inhibitor PTS, main
It is used to treat kidney, late shows preferable curative effect in the first-line treatment of kidney, the major target class of its effect is Ink vessel transfusing
Skin growth factor VEGFR1,2,3, by suppressing these three vascular endothelial growth factor receptors, so as to play treatment kidney cell
The effect of tumor patient, patient take mean survival time after Tivozanib be 11.8 months and it is no deteriorate, for hand
Art extracts the advanced renal cell cancer patient of part kidney, and curative effect can reach nearly 14.8 months.And latest news is announced, the U.S. in 2012
Whether III phase of Aveo Pharmaceuticals Inc. analyzes result of the test clinically by independent audit committee, it was demonstrated that no matter connect before patient
The antineoplaston of system is received, average for Wo Zhani treatment groups is all significantly better than Sorafenib pair without progression of disease survival period
According to group.Therefore, regard as treating the Orphan drug of clear-cell carcinoma by EMA, it was predicted that weight pound will be turned into after medicine listing frying
Ammunition thing.Will be produced with huge Social benefit and economic benefit after medicine listing.The current PTS does not have still
Orally available sustained-release pellet preparation.
The content of the invention
For the deficiencies in the prior art, the technical problems to be solved by the invention are to provide a kind of PTS
Tivozanib oral sustained release micropills, its have slow release effect more preferably, the features such as easily swallow.
The technical scheme that the present invention solves above-mentioned technical problem is as follows：A kind of PTS Tivozanib oral sustained releases are micro-
Ball, is made up of each raw material of following parts by weight：2~60 parts of Tivozanib medicines, 1~25 part of adhesive, slow-release material 1~
45 parts, 10~90 parts of diluent, 0.5~10 part of pore-foaming agent, 0.5~10 part of plasticizer, 0.5~30 part of antiplastering aid.
Specifically, described adhesive is the one kind in hydroxypropyl methyl cellulose, starch slurry, methylcellulose and PVP
Or it is various.
Specifically, the slow-release material is ethyl cellulose, hydroxypropyl methyl cellulose, acrylic resin and polyethylene pyrrole
One or more in pyrrolidone.
Preferably, the acrylic resin be Eudragit RS100, Eudragit RS30D, Eudragit RS PO,
Eudragit RL30D、Eudragit RL PO、Eudragit RL100、Eudragit NE 30D、Eudragit L30D-55
In one or more.
Specifically, the diluent is microcrystalline cellulose, cane sugar powder, lactose, mannitol, amylum pregelatinisatum, dextrin and nothing
One or more in machine calcium salt.Wherein, the inorganic calcium salt be calcium sulfate, calcium monohydrogen phosphate and medicinal calcium carbonate in one kind or
It is various.
Specifically, the pore-foaming agent is the one kind or many in hydroxypropyl methyl cellulose, Macrogol 4000 and PVP
Kind, the antiplastering aid is talcum powder, lauryl sodium sulfate, magnesium stearate, superfine silica gel powder, glycerin monostearate, titanium dioxide
One or more in silicon and titanium dioxide.
Specifically, the plasticizer is diethyl phthalate, the repefral, (2- of phthalic acid two
Ethylhexyl) it is ester, triethyl citrate, dibutyl sebacate, dibutyl phthalate, glycerol triacetate, castor oil, sweet
One or more in oil and propane diols.
Specifically, the Li Jing≤2.5mm of the sustained release pellet.
The present invention also provides a kind of preparation method of above-mentioned PTS Tivozanib oral sustained release micropills, and it includes
Following steps, first, will PTS Tivozanib and sustained release agent mix after add adhesive to be made capsule core, then, then with delaying
The compound for releasing material, pore-foaming agent, plasticizer and antiplastering aid is coated to the capsule core, and the sustained release is obtained final product after the completion of coating
Micropill.
Specifically, in above-mentioned preparation method, the preparation of the capsule core and the coating to capsule core pass through coating pan rolling
Any one method in method, centrifuge-fiuidization method, extrusion-throwing circule method, fluidized-bed spraying method and cyclone fluidized bed spraying process comes real
It is existing.
The beneficial effects of the invention are as follows：Oral sustained release micropill there is provided PTS Tivozanib and preparation method thereof,
Diluent, adhesive, slow-release material and other excipient mix by a certain percentage with Tivozanib can effectively regulating drug release
Speed, enables Tivozanib to slowly release in vivo, and blood concentration is more steady, effectively increases Clinical efficacy
And security, the orally available PTS of patient, and it can gently stablize release in the acid solution close to human body hydrochloric acid in gastric juice,
It is easy to doctor according to the concrete condition of patient, is administered according to quantity on time；The PTS Tivozanib oral sustained releases that the present invention is provided
The finished product of micropill is the less pellet of particle diameter, is easy to people to swallow.The PTS Tivozanib oral sustained releases that the present invention is provided
The preparation method of micropill is simple to operate, technical maturity, low production cost, and efficiency high is suitable for large-scale production.
Brief description of the drawings
Fig. 1 is the cumulative release curve in each solution of sustained release pellet prepared by the embodiment of the present invention 1；
Fig. 2 is the cumulative release curve in each solution of sustained release pellet prepared by the embodiment of the present invention 2；
Fig. 3 is the cumulative release curve in each solution of sustained release pellet prepared by the embodiment of the present invention 3；
Fig. 4 is the cumulative release curve in each solution of sustained release pellet prepared by the embodiment of the present invention 4.
Specific embodiment
Below in conjunction with drawings and the specific embodiments, the present invention is described in further detail, and example is served only for explaining
The present invention, is not intended to limit the scope of the present invention.
Embodiment 1
A kind of PTS Tivozanib oral sustained release micropills：
Including the coating outside capsule core and capsule core, wherein capsule core composition is：Tivozanib 2g, microcrystalline cellulose 10g, lactose
5g, hydroxypropyl methyl cellulose 1g；Coating constituents are：Eudragit RS100 1g, PEG4000 0.5g, triethyl citrate
0.5g, talcum powder 0.3g, titanium dioxide 0.2g.
Preparation method：Take and 100 mesh sieves are crossed after Tivozanib mixes with microcrystalline cellulose, lactose, be well mixed, in centrifugation
In formula layering pelletization machine, with Hydroxypropyl methylcellulose solution as adhesive, micropill is made, micropill is coated with coating constituents.
Obtained Tivozanib sustained release pellets are taken, diameter≤2.5mm is determined.Obtained Tivozanib sustained release pellets are taken, is determined respectively
The release profiles in water, 0.1M hydrochloric acid solutions, pH5.6 carbonate buffer solutions, pH7.2 phosphate buffers, are as a result shown in Fig. 1.Knot
Fruit shows that Tivozanib sustained release pellets are obtained can slowly be discharged in above dissolution medium.
Embodiment 2
A kind of PTS Tivozanib oral sustained release micropills：
Including the coating outside capsule core and capsule core, wherein capsule core composition is：Tivozanib 20g, microcrystalline cellulose 30g are sweet
Dew alcohol 5g, ethyl cellulose 8g；Coating constituents are：Polyvinylpyrrolidone 5g, Eudragit RL100 3g, PEG4000
0.1g, repefral 0.5g, talcum powder 5g.
Preparation method：Take and 100 mesh sieves are crossed after Tivozanib mixes with microcrystalline cellulose, polyvinylpyrrolidone, mixing is equal
It is even, in centrifugal layering pelletization machine, with ethyl cellulose solution as adhesive, micropill is made, micropill is entered with coating constituents
Row is coated.Obtained Tivozanib sustained release pellets are taken, diameter≤2.5mm is determined.Obtained Tivozanib sustained release pellets are taken, point
The release profiles in water, 0.1M hydrochloric acid solutions, pH5.6 carbonate buffer solutions, pH7.2 phosphate buffers are not determined, are as a result seen
Fig. 2.Result shows that Tivozanib sustained release pellets are obtained can slowly be discharged in above dissolution medium.
Embodiment 3
A kind of PTS Tivozanib oral sustained release micropills：
Including the coating outside capsule core and capsule core, wherein capsule core composition is：Tivozanib 45g, cane sugar powder 60g, compressibility
Starch 30g, medicinal calcium carbonate 10g, methylcellulose 6g；Coating constituents are：Eudragit NE 30D 25g, PEG4000 3g.
Triethyl citrate 3g, talcum powder 10g, lauryl sodium sulfate 20g.
Preparation method：Take and 100 are crossed after Tivozanib mixes with HPMC, microcrystalline cellulose, amylum pregelatinisatum
Mesh sieve, is well mixed, and in centrifugal layering pelletization machine, with methocel solution as adhesive, micropill is made, to be coated into
Divide and micropill is coated.Obtained Tivozanib sustained release pellets are taken, diameter≤2.5mm is determined.Take obtained Tivozanib
Sustained release pellet, determines discharged in water, 0.1M hydrochloric acid solutions, pH5.6 carbonate buffer solutions, pH7.2 phosphate buffers respectively
Curve, is as a result shown in Fig. 3.Result shows that Tivozanib sustained release pellets are obtained can slowly be discharged in above dissolution medium.
Embodiment 4
A kind of PTS Tivozanib oral sustained release micropills：
Including the coating outside capsule core and capsule core, wherein capsule core composition is：Tivozanib 60g, microcrystalline cellulose 90g, hydroxyl
Propyl methocel 15g, PVP 10g；Coating constituents are：Eudragit L30D-5520g, Eudragit NE 30D
25g, PEG400010g. diethyl phthalate 2g, glycerin monostearate 8g, lauryl sodium sulfate 30g.
Preparation method：Take and 100 mesh sieves are crossed after Tivozanib mixes with HPMC, microcrystalline cellulose, mixing is equal
It is even, in centrifugal layering pelletization machine, with povidone solution as adhesive, micropill is made, micropill is wrapped with coating constituents
Clothing.Obtained Tivozanib sustained release pellets are taken, diameter≤2.5mm is determined.Obtained Tivozanib sustained release pellets are taken, is surveyed respectively
Release profiles in water, 0.1M hydrochloric acid solutions, pH5.6 carbonate buffer solutions, pH7.2 phosphate buffers are scheduled on, Fig. 4 is as a result seen.
Result shows that Tivozanib sustained release pellets are obtained can slowly be discharged in above dissolution medium.
Knowable to the drug accumulation release profiles that Fig. 1 to Fig. 4 is obtained, sustained release pellet exists obtained in various embodiments of the present invention
There is good slow release effect in the hydrochloric acid solution of 0.1mol/L, in the aqueous solution of slightly acidic solution, micro alkaline solution and neutrality.
Wherein the hydrochloric acid solution of 0.1mol/L is approximate with the hydrochloric acid in gastric juice composition of normal person, and the line of the interval interior each points of 0-12h can be fitted to one
Bar straight line obliquely, the i.e. speed ratio of medicament slow release is more steady, and 12-25h insoluble drug releases are slower, it is seen that slow release effect is preferable,
Blood concentration can ensure more steady, side effects of pharmaceutical drugs be reduced, while medicining times can be reduced suitably.In desalination acid solution
In other outer solution, sustained drug release effect also be can guarantee that, therefore the sustained release pellet that the present invention is provided can not only obtained under one's belt
To release, also can effectively be discharged in the complex environment in enteron aisle.
The foregoing is only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all it is of the invention spirit and
Within principle, any modification, equivalent substitution and improvements made etc. should be included within the scope of the present invention.
Claims (10)
1. a kind of PTS Tivozanib oral sustained release micropills, it is characterised in that by each raw material group of following parts by weight
Into：2~60 parts of Tivozanib medicines, 1~25 part of adhesive, 1~45 part of slow-release material, 10~90 parts of diluent, pore-foaming agent
0.5~10 part, 0.5~10 part of plasticizer, 0.5~30 part of antiplastering aid.
2. a kind of PTS Tivozanib oral sustained release micropills according to claim 1, it is characterised in that described viscous
Mixture is one or more in hydroxypropyl methyl cellulose, starch slurry, methylcellulose and PVP.
3. a kind of PTS Tivozanib oral sustained release micropills according to claim 1, it is characterised in that described slow
It is one or more in ethyl cellulose, hydroxypropyl methyl cellulose, acrylic resin and polyvinylpyrrolidone to release material.
4. a kind of PTS Tivozanib oral sustained release micropills according to claim 3, it is characterised in that described third
Olefin(e) acid resin be Eudragit RS100, Eudragit RS30D, Eudragit RS PO, Eudragit RL30D,
One or more in Eudragit RL PO, Eudragit RL100, Eudragit NE 30D, Eudragit L30D-55.
5. a kind of PTS Tivozanib oral sustained release micropills according to claim 1, it is characterised in that described dilute
It is one or more in microcrystalline cellulose, cane sugar powder, lactose, mannitol, amylum pregelatinisatum, dextrin and inorganic calcium salt to release agent.
6. a kind of PTS Tivozanib oral sustained release micropills according to claim 1, it is characterised in that the cause
Hole agent be hydroxypropyl methyl cellulose, Macrogol 4000 and PVP in one or more, the antiplastering aid be talcum powder,
One kind in lauryl sodium sulfate, magnesium stearate, superfine silica gel powder, glycerin monostearate, silica and titanium dioxide or
It is various.
7. a kind of PTS Tivozanib oral sustained release micropills according to claim 1, it is characterised in that the increasing
Modeling agent is diethyl phthalate, repefral, phthalic acid two (2- ethylhexyls) ester, lemon triethylenetetraminehexaacetic acid
One kind or many in ester, dibutyl sebacate, dibutyl phthalate, glycerol triacetate, castor oil, glycerine and propane diols
Kind.
8. a kind of PTS Tivozanib oral sustained release micropills according to any one of claim 1 to 7, its feature exists
In the Li Jing≤2.5mm of the sustained release pellet.
9. the preparation method of a kind of PTS Tivozanib oral sustained release micropills as described in any one of claim 1 to 8,
It is characterised in that it includes following steps：After first PTS Tivozanib and sustained release agent being mixed by proportioning add adhesive
Be made capsule core, then again by proportioning with the compound being made up of slow-release material, pore-foaming agent, plasticizer and antiplastering aid to the capsule core
It is coated, the sustained release pellet is obtained final product after the completion of coating.
10. a kind of preparation method of PTS Tivozanib oral sustained release micropills according to claim 9, its feature
Be, the preparation of the capsule core and to the coating of capsule core by coating pan rolling method, centrifuge-fiuidization method, extrusion-throwing circule method,
Any one method in fluidized-bed spraying method and cyclone fluidized bed spraying process is realized.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611096938.3A CN106822041A (en) | 2016-12-02 | 2016-12-02 | A kind of PTS Tivozanib oral sustained release micropills and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611096938.3A CN106822041A (en) | 2016-12-02 | 2016-12-02 | A kind of PTS Tivozanib oral sustained release micropills and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108938584A (en) * | 2018-08-17 | 2018-12-07 | 湖北欣瑞康医药科技有限公司 | A kind of tablet and preparation method thereof of the Tivozanib of inhibitor containing vegf receptor salt |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105476963A (en) * | 2015-12-17 | 2016-04-13 | 北京科莱博医药开发有限责任公司 | Acotiamide hydrochloride sustained-release pellet and preparation method thereof |
| CN106176681A (en) * | 2016-08-25 | 2016-12-07 | 泰力特医药（湖北）有限公司 | A kind of anti-heart failure medicine LCZ696 oral sustained release micropill and preparation method thereof |
-
2016
- 2016-12-02 CN CN201611096938.3A patent/CN106822041A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105476963A (en) * | 2015-12-17 | 2016-04-13 | 北京科莱博医药开发有限责任公司 | Acotiamide hydrochloride sustained-release pellet and preparation method thereof |
| CN106176681A (en) * | 2016-08-25 | 2016-12-07 | 泰力特医药（湖北）有限公司 | A kind of anti-heart failure medicine LCZ696 oral sustained release micropill and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| ESKENS F.A.L.M ET AL: ""Biologic and Clinical Activity of Tivozanib (AV-951, KRN-951), a Selective Inhibitor of VEGF Receptor-1,-2,and -3 Tyrosine Kinases, in a 4-week-On, 2-Week-Off Schedule in Patients with Advanced Solid Tumors"", 《CLINICAL CANCER RESEARCH》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108938584A (en) * | 2018-08-17 | 2018-12-07 | 湖北欣瑞康医药科技有限公司 | A kind of tablet and preparation method thereof of the Tivozanib of inhibitor containing vegf receptor salt |
| CN108938584B (en) * | 2018-08-17 | 2021-01-26 | 湖北欣瑞康医药科技有限公司 | Tablet containing VEGF receptor inhibitor Tivozanib salt and preparation method thereof |
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Application publication date: 20170613 |