CN105853367B - The preparation method and its pharmaceutical preparation of Deferasirox solid dispersions - Google Patents
The preparation method and its pharmaceutical preparation of Deferasirox solid dispersions Download PDFInfo
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- CN105853367B CN105853367B CN201610309213.1A CN201610309213A CN105853367B CN 105853367 B CN105853367 B CN 105853367B CN 201610309213 A CN201610309213 A CN 201610309213A CN 105853367 B CN105853367 B CN 105853367B
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- deferasirox
- solid dispersions
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- pharmaceutically acceptable
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The preparation method and its pharmaceutical preparation of present invention offer Deferasirox solid dispersions, the method be by Deferasirox and pharmaceutically acceptable carrier after mixing, heating melting, it cools down again, crushing obtains Deferasirox solid dispersions, and wherein pharmaceutically acceptable carrier is selected from povidone, hypromellose, copolyvidone.The invention also discloses the Deferasirox pieces for containing the solid dispersions.Preparation method of the invention facilitates the pressure of the risk for reducing safety and environmental protection without using organic solvent, and reduces and produce cost, conducive to commercially producing for product is realized.
Description
Technical field
The present invention relates to the preparation method of Deferasirox solid dispersions and its pharmaceutical preparations
Background technique
Deferasirox (deferasirox) is oral active chelators, with iron (Fe3+) there is high selectivity.By Novartis
Company's exploitation, in 2005 in U.S.'s Initial Public Offering, trade name Exjade.It is mainly used for treatment 2 years old or more due to blood transfusion
Caused by chronic iron overload disease；The chronic iron overload of 10 years old or more non-transfusion dependent thalassemia (NTDT) patients is controlled
It treats.
Deferasirox is irony chelating agent, has high affinity for ferric ion, 2 molecules can be with 1 Fe3+Knot
It closes.It can substitute the irony that organ removes accumulation, the complications caused by can be reduced because of the accumulation of long-term irony.
Entitled 4- [3,5- bis--(2- hydroxy phenyl) -1H- [1,2, the 4]-triazol-1-yl] benzoic acid of Deferasirox chemistry, tool
Just like flowering structure:
Carrying out domestic unique available row's iron medicine over the years is de-iron ammonium (deferoxamine), since it can not mouth
Clothes absorb and half-life short, it is therefore necessary to h inf, 5-7 days weekly, every time infusion 8-12 hours, use more time-consuming and not
Just, and there are more adverse reactions, cause patient's long-term administration poor compliance, also limit being widely used for they.Health
Portion's oral row iron medicine Deferasirox new in January, 2007 approval, for treatment 6 years old or less children and other transfusion dependent diseases
The overload of iron caused by disease.
Recent study shows deferasirox as the effect that deferoxamine is used for chronic canker disease.
For oral row's chalybeate because easy to use, injecting row's chalybeate compared with conventional subcutaneous has higher acceptance and satisfaction, and can promote trouble
The quality of the life of person needs using the patient of row's chalybeate to be that the compliance of patient's long-term administration can be improved compared with good news to long-term.
Deferasirox is first public by Novartis Co., Ltd in US64655504.
In international patent publications WO97/49395 (on December 31st, 1997 is open, and which is incorporated herein by reference)
Disclose free acid form, the mixture I of salt and its crystal form.
Summary of the invention
The purpose of the present invention is to provide a kind of hot-melt extruded preparation method of Deferasirox solid dispersions, main features
It is with hydrophilic high molecular material copolyvidone (PVP-VA64, Kollidon VA64), povidone (PVP-K30) or hydroxypropyl first
Base cellulose (HPMC-AS) is used as main dispersible carrier material, glycitols auxiliary material is added when necessary as plasticizer, easyization is squeezed
Technical process out is effectively improved dispersity of the drug in solid dispersions, improves the dissolution rate of Deferasirox.
The present invention is achieved by the following measures:
(a) Deferasirox is uniformly mixed with pharmaceutically acceptable carrier:
(b) mixture of heating stepses (a) melts it completely:
(c) fusant of cooling step (b), crushing obtain Deferasirox solid dispersions:
Wherein pharmaceutically acceptable carrier is selected from povidone, copolyvidone, hypromellose.
According to the present invention, sufficiently high temperature should be heated the mixture to during step (b), so that mixture is complete
Melting, forms uniform solution.
The Deferasirox solid dispersions being prepared according to the method for the present invention are that solid solution or glassy solids are molten
Body, Deferasirox exist in the form of molecule or amorphous substance in solid dispersions, show as Deferasirox in XRPD map
Crystal form characteristic peak disappear.
Solubility very little of the Deferasirox in most of solvents, and fusing point is very high (about 261 DEG C), conventional fusion method
It is difficult that Deferasirox is made to melt or be dissolved in polymer support completely, so that solid solution or glassy state solid solution be prepared
Body.The present inventor passes through a large amount of experimental study, and discovery is using povidone, copolyvidone or hypromellose object as load
Body can obtain uniform melt solution by heating mixture, without decomposing or being carbonized.
According to the present invention, pharmaceutically acceptable carrier is preferably copolyvidone.
According to the present invention, the mass ratio of Deferasirox and carrier is 1:0.3-1:3, preferably 1:0.4-1:2, more preferable 1:
0.5-1:1。
According to the present invention, Deferasirox solid dispersions using hot-melt extrusion process prepare, specifically, by Deferasirox with
Pharmaceutically acceptable carrier be uniformly mixed, be placed in hot-melt extruded machine, heating and temperature control within the scope of 150 DEG C to 260 DEG C,
After hot-melt extruded machine extrusion, cooling condenses into solid, and the solid is crushed to obtain Deferasirox solid dispersions.
According to the present invention, the heating temperature of hot-melt extruded machine can be adjusted according to material properties, make Deferasirox and carry
The mixture of body melts completely.When heating temperature is too low, mixed material does not melt completely, is unable to get uniform solid point
Granular media, part is undissolved to obtain uniform solution in the carrier of melting, obtains uniform solid dispersions after cooling；Work as heating
When the temperature is excessively high, the degradation that can accelerate drug increases product in relation to the content of substance, does not meet drug quality requirement.
According to the present invention, heating temperature is preferably 160 DEG C to 250 DEG C.
A specific example according to the present invention completes hot melt using the silent winged 11 twin screw hot melt extruder of Pharma of match
Squeeze out operation.In conjunction with substantive content of the invention, the single screw rod or double with similar functions is can be used in those skilled in the art
Screw rod hot-melt extruded machine, the model of hot-melt extruded machine, screw speed etc. can be selected according to the requirement of batch and production efficiency.
The present invention also provides a kind of Deferasirox piece, the Deferasirox solid obtained containing method produced according to the present invention
Dispersion and pharmaceutically acceptable additive, pharmaceutically acceptable additive include filler, disintegrating agent and lubrication
Agent.
According to the present invention, every Deferasirox piece contain Deferasirox amount be 100-1000mg, preferably 125-500mg,
Specially 125mg, 250mg and 500mg.
According to the present invention, filler is selected from lactose, microcrystalline cellulose, crospovidone, hypromellose, colloidal state two
Silica, magnesium stearate, lauryl sodium sulfate.It is one or more.According to the present invention, filler loading accounts for total weight of tablet
20-80%.
According to the present invention, disintegrating agent is in crospovidone, croscarmellose sodium or sodium carboxymethyl starch
It is one or more.Disintegrating agent dosage accounts for the 2%-20% of total weight of tablet according to the present invention.
According to the present invention, lubricant in talcum powder, colloidal silicon dioxide, magnesium stearate or sodium stearyl fumarate one
Kind is a variety of.According to the present invention, lubricant quantity accounts for the 0.1%-5% of total weight of tablet.
The present invention also provides a kind of preparation method of Deferasirox piece, the ground that method produced according to the present invention is obtained is drawn
Sieve department dispersion and pharmaceutically acceptable filler, disintegrating agent, mix lubricant are uniform, tabletted.
The Deferasirox solid dispersions being prepared according to the method for the present invention are that solid solution or glassy solids are molten
Body, Deferasirox exist in the form of molecule or amorphous substance in solid dispersions.Further with the solid dispersions
The Deferasirox piece being prepared has higher dissolution rate relative to commercial product.
Detailed description of the invention
Fig. 1: the X-ray powder diffraction pattern of Deferasirox bulk pharmaceutical chemicals
Fig. 2: the Deferasirox solid dispersions X-ray powder diffraction pattern of embodiment 1
Fig. 3: the Deferasirox piece of embodiment 1 is compared with the dissolution curve of commercially available product Deferasirox dispersible tablet 125mg
Specific embodiment
Invention is further illustrated combined with specific embodiments below, but the scope of the present invention is not limited to following embodiment.
Embodiment 1
| Name of material | Dosage/1000 piece |
| Deferasirox | 125g |
| Crospovidone | 100 |
| Lactose monohydrate | 110 |
| Microcrystalline cellulose | 50 |
| Copolyvidone VA64 | 280 |
| Colloidal silicon dioxide | 10 |
| Magnesium stearate | 40 |
| Dodecyl sodium sulfate | 160 |
Deferasirox is uniformly mixed with povidone, is squeezed out using the silent winged 11 twin screw hot melt extruder of Pharma of match, spiral shell
Bar revolving speed 10-30rpm, the heating temperature of control such as following table, is ground into after extrudate is cooling using FITZ-MILL beater grinder
Particle, mesh size 1.0mm；Particle and crospovidone, lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, ten
Dialkyl sulfonates are uniformly mixed, tabletted.
Embodiment 2
| Name of material | Dosage/1000 piece |
| Deferasirox | 250 |
| Crospovidone | 150 |
| Lactose monohydrate | 150 |
| Microcrystalline cellulose | 80 |
| Copolyvidone VA64 | 500 |
| Superfine silica gel powder | 15 |
| Magnesium stearate | 50 |
| Dodecyl sodium sulfate | 180 |
Deferasirox is uniformly mixed with povidone, is squeezed out using the silent winged 11 twin screw hot melt extruder of Pharma of match, spiral shell
Bar revolving speed 10-30rpm, the heating temperature of control such as following table, is ground into after extrudate is cooling using FITZ-MILL beater grinder
Particle, mesh size 1.0mm；Particle and crospovidone, lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, ten
Dialkyl sulfonates are uniformly mixed, tabletted.
Embodiment 3
| Name of material | Dosage/1000 piece |
| Deferasirox | 500g |
| Crospovidone | 300g |
| Lactose monohydrate | 300g |
| Microcrystalline cellulose | 160g |
| Copolyvidone VA64 | 500g |
| Superfine silica gel powder | 30g |
| Magnesium stearate | 100g |
| Dodecyl sodium sulfate | 300g |
Deferasirox is uniformly mixed with povidone, is squeezed out using the silent winged 11 twin screw hot melt extruder of Pharma of match, spiral shell
Bar revolving speed 10-30rpm, the heating temperature of control such as following table, is ground into after extrudate is cooling using FITZ-MILL beater grinder
Particle, mesh size 1.0mm；Particle and crospovidone, lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, ten
Dialkyl sulfonates are uniformly mixed, tabletted.
Embodiment 4
The Deferasirox solid dispersions sample of Deferasirox bulk pharmaceutical chemicals, embodiment 1 is taken to carry out X-ray powder diffraction respectively
Detection, map are shown in Fig. 1 and Fig. 2 respectively
Embodiment 5
It is measured according to the second method of dissolution method (slurry processes) as defined in Chinese Pharmacopoeia four general rules 0931 in 2015, with
0.1mol/L hydrochloric acid 1000ml is dissolution medium, and temperature is 37 ± 0.5 DEG C, revolving speed 50rpm.The Deferasirox of Example 1
Sample, commercially available En Ruige(Deferasirox dispersible tablet 125mg) each 6 detects dissolution curve respectively, in 5min, 10min,
15min, 20min, 30min, 45min and 60min.5ml is respectively taken, 0.45 μm of filtering with microporous membrane is measured using HPLC method and dissolved out
As a result curve is shown in Fig. 3.The result shows that Deferasirox piece of the invention has the dissolution rate more considerably more rapid than commercially available product.
Claims (2)
1. a kind of Deferasirox piece, containing Deferasirox solid dispersions and pharmaceutically acceptable additive, wherein pharmaceutically
Acceptable additive includes filler, disintegrating agent and lubricant；
The Deferasirox piece prepares raw material are as follows:
The Deferasirox solid dispersions the preparation method comprises the following steps:
(a) Deferasirox is uniformly mixed with copolyvidone VA64；
(b) mixture of heating stepses (a) melts it completely；
(c) fusant of cooling step (b), crushing obtain Deferasirox solid dispersions；
The mixture of step (a) is set in hot-melt extruded machine, controls 130~260 DEG C of heating temperature.
2. Deferasirox piece as described in claim 1, which is characterized in that the heating temperature is 150-240 DEG C.
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| CN201610309213.1A CN105853367B (en) | 2016-05-10 | 2016-05-10 | The preparation method and its pharmaceutical preparation of Deferasirox solid dispersions |
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| CN105853367B true CN105853367B (en) | 2019-07-12 |
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| WO2018208242A1 (en) * | 2017-05-10 | 2018-11-15 | İlko Ilaç Sanayi Ve Ticaret Anonim Şirketi | Formulation of deferasirox tablet for oral suspension composition with better processability |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012003987A1 (en) * | 2010-07-08 | 2012-01-12 | Ratiopharm Gmbh | Oral dosage form of deferasirox |
| CN105377256A (en) * | 2013-05-10 | 2016-03-02 | 奇普拉股份有限公司 | Low dose pharmaceutical composition |
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2016
- 2016-05-10 CN CN201610309213.1A patent/CN105853367B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012003987A1 (en) * | 2010-07-08 | 2012-01-12 | Ratiopharm Gmbh | Oral dosage form of deferasirox |
| CN105377256A (en) * | 2013-05-10 | 2016-03-02 | 奇普拉股份有限公司 | Low dose pharmaceutical composition |
Non-Patent Citations (1)
| Title |
|---|
| 地拉罗司分散片的处方筛选研究;刘东等;《中国药房》;20131231;第24卷(第45期);参见全文 * |
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Effective date of registration: 20191211 Address after: No.7 Huiling Road, health base, Torch Development Zone, Zhongshan City, Guangzhou City, Guangdong Province Patentee after: Anshi Pharmaceutical (Zhongshan) Co., Ltd. Address before: 510003 Guangdong province Guangzhou International Biological Island four spiral Road No. 1 office second layer 202, 203 unit Patentee before: Jiadeen Medical Co., Ltd., Guangzhou |
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