CN104042561A - Carbamazepine cocrystal solid dispersion and preparation method thereof - Google Patents
Carbamazepine cocrystal solid dispersion and preparation method thereof Download PDFInfo
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- CN104042561A CN104042561A CN201310082826.2A CN201310082826A CN104042561A CN 104042561 A CN104042561 A CN 104042561A CN 201310082826 A CN201310082826 A CN 201310082826A CN 104042561 A CN104042561 A CN 104042561A
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Abstract
The invention discloses a carbamazepine cocrystal solid dispersion and a preparation method thereof. According to the invention, a cocrystal ligand and a polymer carrier material are employed to prepare the carbamazepine cocrystal solid dispersion by a melting technique and a hot melting extrusion technique, thus improving the equilibrium solubility and dissolution rate of carbamazepine. By adding the cocrystal ligand to form the cocrystal with carbamazepine, the drug's melting point can be adjusted, the selection range of the temperature and polymer carrier material for preparation of the solid dispersion through the melting technique and the hot melting extrusion technique is expanded, and the problem that the melting technique and the hot melting extrusion technique are likely to cause drug thermal decomposition is effectively solved. The preparation method provided by the invention can improve the oral bioavailability of carbamazepine, lower the dosage of administration, and reduce adverse drug reaction. With high production efficiency, the method is suitable for industrial application.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of carbamazepine eutectic solid dispersion and preparation method thereof.
Background technology
Carbamazepine (carbamazepine is called for short CBZ) is the choice drug that is used for the treatment of epilepsy, is also usually used in treating the diseases such as trigeminal neuralgia, manic depression, arrhythmia, is clinical conventional medicine, and market is huge.Schneider by Switzerland in 1961 etc. are synthetic, nineteen sixty-eight, Novartis Co.,Ltd was with the listing of Tegretol～tablet, to so far in the world main brand have Tegretol@(Novartis Co.,Ltd), Carbatrol@(wishing Thunder God department), EquetroTM (wishing Thunder God department), Epitol@(TEVA company), Teril@(Taro company).The dosage form of listing also develops into chewable tablet, suspensoid and slow releasing preparation from simple tablet.1997, the slow releasing capsule Carbatrol～acquisition FDA by rapid release, slow release, enteric coated micropill combination that wishes the exploitation of Thunder God department ratified, and has promoted the formulation development of carbamazepine.2004, the carbamazepine sustained-release capsules Equetro of the uncommon Thunder God department U.S. FDA approval listing of getting back, this is current unique effective treatment bipolar affective disorder patient's molecusol-carbamazepine.
Carbamazepine almost insoluble (113mg/L, 25 DEG C) in water, Determination of oil-water partition coefficient theoretical value is 1.98, and experiment value is 2.45 (n-octyl alcohol/water), and the dissolubility in oil is also bad, and its pKa is 7, therefore dissolubility is not subject to the impact of pH.Low-solubility and high membrane permeability make after carbamazepine oral administration slow and irregular in gastrointestinal absorption, blood drug level individual variation is larger, and treatment window narrow (4-12mg/L), easily produce various toxic and side effects, such as sensitivity response, hepatic injury, hypertension etc.Therapeutic dose large (> 100mgd), and owing to there being the auto-induction effect of dose dependent, after long-term taking, need to strengthen therapeutic dose, and in liver, have first pass effect.
Oral administration is the first-selected approach of clinical administration, and due to indissoluble in carbamazepine water, the research and development of oral formulations focus on improving the dissolution in gastrointestinal tract, thereby improves bioavailability.The method that improves carbamazepine bioavailability comprises solid dispersions technique, clathrate technology, stomach flotation technique etc.
Solid dispersion refers to that medicine is dispersed in the system in solid carrier with molecule, amorphous or microcrystalline state height.From 1961, solid dispersion technology is first for since improving the dissolution rate and oral administration biaavailability of insoluble drug, many researcheres have carried out research extensively and profoundly to solid dispersion, further prove that it is one of method the most with potential applications improving its dissolubility and dissolution rate that insoluble drug is made to solid dispersion.Traditional preparation method of solid dispersion comprises fusion method, solvent method, solvent-fusion method.In recent years, hot-melt extruded method enjoys the concern of domestic and international pharmaceutics researcher as a kind of novel method of preparing solid dispersion.The method, by single screw rod or double screw extruder of heating piecemeal, realizes the transmission of material and carries, shear-mixed and melt extruded.With respect to traditional preparation method, it is high that hot-melt extruded method has production efficiency, without organic solvent, is suitable for the features such as suitability for industrialized production.But for medicine and the carrier with higher melt, fusion method and hot-melt extruded method easily cause the thermal decomposition of medicine and carrier, thereby have limited the extensive use of the method.
Eutectic (cocrystal) refers to that drug molecule and eutectic part pass through the effect of hydrogen bond or other non-covalent bonds in conjunction with the crystal of formation, wherein drug molecule and eutectic part are at room temperature solid, and have fixing stoichiometric proportion between each component.Eutectic can regulating drug physical and chemical parameter, comprise fusing point, dissolubility, hygroscopicity and powder property, there is the advantage such as chemical stability and bioavailability that improves medicine simultaneously.At present, utilize eutectic technology to improve slightly solubility, the dissolution properties of atomic dissolubility or microsolubility medicine and oral administration biaavailability are the focuses in eutectic research.In prior art, also do not prepare the relevant report of carbamazepine eutectic solid dispersion.
Summary of the invention
The object of the invention is to for the dissolution rate of carbamazepine oral formulations existence slow, assimilation effect is poor, the problem that bioavailability is low, a kind of indissolvable medicament cocrystallizing solid dispersoid is provided, increase dissolubility and the dissolution rate of insoluble drug, thereby improve the oral administration biaavailability of insoluble drug, reduce dosage and toxic and side effects.
For achieving the above object, the present invention has taked following technical scheme: a kind of indissolvable medicament cocrystallizing solid dispersoid, be prepared from by insoluble drug, eutectic part and polymer carrier, the mol ratio of described insoluble drug and eutectic part is 1～2: 1, and the quality percentage composition that polymer carrier accounts for described solid dispersion is 10%～90%.
Preferably, the mol ratio of described insoluble drug and eutectic part is 1: 1, and the quality percentage composition that polymer carrier accounts for described solid dispersion is 50%～90%.
Described eutectic part is selected from pharmaceutically acceptable nicotiamide, glycolic, adipic acid, salicylic acid, citric acid, succinic acid and other can form eutectic and eutectic melting point below or above one or more in the eutectic part of insoluble drug with insoluble drug.Eutectic part and insoluble drug form eutectic, after melting, are dispersed in polymer carrier with amorphous or molecular state.
Described polymer carrier is selected from one or more in the water-soluble high-molecular materials such as polyethylene glycols, poly(ethylene oxide)polymers class, polyvidone class, copolyvidone class, hypromellose class, hyprolose class, poloxamer class, novel adjuvant soluplus.
Described carbamazepine eutectic solid dispersion can be made into tablet, capsule, granule, drop pill or other solid orally ingestibles.
Another object of the present invention is also to overcome fusion method and the hot-melt extruded legal system defect for solid dispersion, a kind of preparation method of indissolvable medicament cocrystallizing solid dispersoid is provided, the fusing point of regulating drug, thereby expand fusion method and hot-melt extruded legal system for temperature and the carrier material range of choice of solid dispersion, avoid medicine and carrier thermal decomposition.
For achieving the above object, the present invention has taked following technical scheme:
The preparation method of indissolvable medicament cocrystallizing solid dispersoid---eutectic-fusion method, comprises the following steps:
(1) by after insoluble drug and eutectic part mix homogeneously, prepare eutectic by methods such as solvent method, heating and melting method, mechanical milling method, liquid feeding grindings;
(2) by the eutectic of step (1) and polymer carrier mix homogeneously, be heated to 50-300 DEG C, melting 3-10min, dry cooling, solidify, pulverize and sieve and get final product.
Or the preparation method of indissolvable medicament cocrystallizing solid dispersoid---eutectic-hot-melt extruded method, comprises the following steps:
(1) by after insoluble drug and eutectic part mix homogeneously, by solvent method, heating and melting method, mechanical milling method, the methods such as liquid feeding grinding are prepared eutectic;
(2) by the eutectic of step (1) and polymer carrier mix homogeneously, join in hot-melt extruded machine machine barrel, barrel section temperature setting is set to 50-300 DEG C, under condition at screw speed lower than 300 turn/min, material melt extrudes stop 2～4min in machine barrel after, dry cooling, solidify, pulverize and sieve and get final product.
Or, the preparation method of indissolvable medicament cocrystallizing solid dispersoid---fusion method, concrete grammar is:
By insoluble drug, eutectic part and polymer carrier mix homogeneously, be heated to 50-300 DEG C, melting 3-10min, dry cooling, solidify, pulverize and sieve and get final product.
Or, the preparation method of indissolvable medicament cocrystallizing solid dispersoid---hot-melt extruded method, concrete grammar is:
By insoluble drug, eutectic part and polymer carrier mix homogeneously, join in hot-melt extruded machine machine barrel, barrel section temperature setting is set to 50-300 DEG C, under condition at screw speed lower than 300 turn/min, material melt extrudes stop 2～4min in machine barrel after, dry cooling, solidify, pulverize and sieve and get final product.
Indissolvable medicament cocrystallizing solid dispersoid of the present invention is through evidence, and dissolubility that can significantly increasing medicament is accelerated the dissolution rate of medicine.
The present invention adopts differential scanning calorimetry, X-ray diffraction analysis, and fourier transform infrared spectroscopy method, PLM with heating stage is investigated eutectic solid dispersion.Differential scanning calorimetric analysis result shows that medicine and eutectic part form after eutectic under the condition of heating and melting, and melting is dispersed in polymer carrier.Thermal analysis curve shows that the melting absworption peak of pure medicine and insoluble drug eutectic all disappears, in the X ray diffracting spectrum of the eutectic solid dispersion of this ratio without crystal diffraction peak, show that this solid dispersion has become solid solution, eutectic is with molecular state or amorphous being scattered in carrier material.The demonstration of fourier transform infrared spectroscopy result, in eutectic solid dispersion, insoluble drug and eutectic part are with hydrogen bonded.Hot platform polarized light microscopy result demonstration, in heating and melting process, first medicine and eutectic part form eutectic, and melting is subsequently scattered in polymer carrier.
Compared with prior art, the present invention has following beneficial effect:
1. indissolvable medicament cocrystallizing solid dispersoid dissolubility of the present invention increases, and dissolution rate is fast, and dissolution is high, has improved the bioavailability of insoluble drug, reduces dosage, reduces adverse effect.
2. the present invention is by adding eutectic part, form eutectic with insoluble drug, thereby the fusing point of regulating drug, can significantly reduce processing temperature, fusion method, hot-melt extruded legal system are expanded for the temperature of solid dispersion and the range of choice of polymer carrier, efficiently solve fusion method, hot-melt extruded method easily causes drug fever resolution problem, preparation method is simple, is easy to the operation of suitability for industrialized production and seriality.
Brief description of the drawings
Fig. 1 is carbamazepine, nicotiamide, copolyvidone VA64, physical mixture, the hot-melt extruded legal system x-ray diffractogram of powder spectrum for eutectic solid dispersion;
Fig. 2 is carbamazepine and taking copolyvidone VA64 as carrier material, and hot-melt extruded legal system is for the In Vitro Dissolution curve of eutectic solid dispersion;
Fig. 3 is carbamazepine, nicotiamide, hypromellose E5, physical mixture, the hot-melt extruded legal system x-ray diffractogram of powder spectrum for eutectic solid dispersion;
Fig. 4 is carbamazepine and taking hypromellose E5 as carrier material, and hot-melt extruded legal system is for the In Vitro Dissolution curve of eutectic solid dispersion;
Fig. 5 is carbamazepine, nicotiamide, soluplus, physical mixture, the hot-melt extruded legal system x-ray diffractogram of powder spectrum for eutectic solid dispersion;
Fig. 6 is carbamazepine and taking soluplus as carrier material, and hot-melt extruded legal system is for the In Vitro Dissolution curve of eutectic solid dispersion.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further, it should be pointed out that these embodiment only need not limit the scope of the invention for the present invention is described.In addition, for those skilled in the art under the premise of not departing from the present invention, some improvement of doing and modification also belong to protection scope of the present invention.
Embodiment 1 carbamazepine eutectic solid dispersion
Be prepared from by following component:
Carbamazepine (insoluble drug, Wuhan Yuancheng Technology Development Co., Ltd.) 2.72g
Nicotiamide (eutectic part, Shanghai brilliant pure reagent company limited) 1.29g
Copolyvidone VA64 (polymer carrier, German BASF AG) 4.01g
The preparation method of the carbamazepine eutectic solid dispersion of embodiment 1 is eutectic-fusion method, comprises the following steps:
(1) prepare eutectic
Getting 0.0115mol (1.29g) nicotiamide is dissolved in 16ml dehydrated alcohol, add the carbamazepine of 0.0115mol (2.72g), be heated to 65 DEG C, until carbamazepine dissolves completely, be cooled to 55 DEG C, be beneficial to carbamazepine-nicotinamide eutectic precipitation, temperature is further down to 20 DEG C, promotes that crystallization further precipitates, and adopts buchner funnel sucking filtration to separate, ethyl acetate solution rinses, and is placed in air drying and obtains carbamazepine-nicotinamide eutectic.Adopt powder X-ray diffraction, differential scanning calorimetry is identified eutectic.
(2) prepare eutectic solid dispersion
Get the polymer carrier copolyvidone VA64 mix homogeneously of 0.5g carbamazepine-nicotinamide eutectic and 0.5g, be placed in temperature control electrical heating platform, be heated to 160 DEG C of melting 5min, fused mass room temperature natural cooling, solidify, be placed in mortar and grind, 80 mesh sieves obtain the eutectic solid dispersion of the present embodiment excessively.
Powder X-ray diffraction (Fig. 1) and fourier transform infrared spectroscopy result show that eutectic is dispersed in carrier material with amorphous or molecular state.High performance liquid chromatography testing result shows that medicament contg is without significant change.In Vitro Dissolution experimental result shows that the medicine accumulative total stripping percentage rate of this eutectic solid dispersion significantly improves (Fig. 2).
Embodiment 2 carbamazepine eutectic solid dispersion
Be prepared from by following component:
Carbamazepine (insoluble drug, Wuhan Yuancheng Technology Development Co., Ltd.) 2.72g
Nicotiamide (eutectic part, Shanghai brilliant pure reagent Co., Ltd) 1.29g
Copolyvidone VA64 (polymer carrier, German BASF AG) 4.01g
The preparation method of the carbamazepine eutectic solid dispersion of embodiment 2 is eutectic-hot-melt extruded method, comprises the following steps:
(1) prepare eutectic
The nicotiamide of getting 0.0115mol (1.29g) is dissolved in 16ml dehydrated alcohol, add the carbamazepine of 0.0115mol (2.72g), be heated to 65 DEG C, until carbamazepine dissolves completely, be cooled to 55 DEG C, be beneficial to the precipitation of carbamazepine-nicotinamide eutectic, temperature is further down to 20 DEG C, promotes the further precipitation of crystallization, adopts buchner funnel sucking filtration to separate, ethyl acetate solution rinses, and is placed in air drying and get final product.And adopting powder X-ray diffraction, differential scanning calorimetry is identified eutectic.
(2) prepare eutectic solid dispersion
Get 2.5g carbamazepine-nicotinamide eutectic and 2.5g polymer carrier copolyvidone VA64 mix homogeneously, get appropriate physical mixture, join in the machine barrel of hot-melt extruded machine, under the rotating speed lower than 300 turn/min, the mean residence time of material in machine barrel is 2～4min.The temperature setting of single screw rod or twin screw hot-melt extruded machine heating and melting section is set to 100～160 DEG C.Hot-melt extruded machine is sheared physical mixture to disperse, and melt extrudes.Fused mass drying at room temperature is cooling, pulverizes and sieves and obtains the eutectic solid dispersion of the present embodiment.
Powder X-ray diffraction (Fig. 3) and fourier transform infrared spectroscopy result show that eutectic is dispersed in carrier material with amorphous or molecular state.High performance liquid chromatography testing result shows that medicament contg is without significant change.In Vitro Dissolution experimental result shows that the medicine accumulative total stripping percentage rate accumulative total stripping percentage rate of this eutectic solid dispersion significantly improves (Fig. 4).
Embodiment 7 carbamazepine eutectic solid dispersion
Be prepared from by following component:
Carbamazepine (insoluble drug, Wuhan Yuancheng Technology Development Co., Ltd.) 2.72g
Nicotiamide (eutectic part, Shanghai brilliant pure reagent Co., Ltd) 1.29g
Copolyvidone VA64 (polymer carrier, German BASF AG) 6.02g
The preparation method of the carbamazepine eutectic solid dispersion of embodiment 3 is hot-melt extruded method, comprises the following steps:
Take respectively 0.0115mol (2.72g) carbamazepine, 0.0115mol (1.29g) nicotiamide and 6.02g copolyvidone VA64 are placed in mortar mix homogeneously.The heating and melting zone temperatures of hot-melt extruded machine is set as to 100-160 DEG C.Physical mixture is joined in the machine barrel of hot-melt extruded machine, screw speed is set as 50-100 turn/min, the time of staying of material in machine barrel is 2～3min.Hot-melt extruded machine is sheared physical mixture to disperse, and melt extrudes.Fused mass drying at room temperature is cooling, pulverizes 80 mesh sieves and obtain the eutectic solid dispersion of the present embodiment.
Powder X-ray diffraction result shows that medicine is dispersed in carrier material with amorphous or molecular state.High performance liquid chromatography testing result shows that medicament contg is without significant change.In Vitro Dissolution experimental result shows that the medicine accumulative total stripping percentage rate acquisition of this eutectic solid dispersion significantly improves.
Embodiment 4 carbamazepine eutectic solid dispersion
Be prepared from by following component:
Carbamazepine (insoluble drug, Wuhan Yuancheng Technology Development Co., Ltd.) 2.72g
Nicotiamide (eutectic part, Shanghai brilliant pure reagent Co., Ltd) 1.29g
Soluplus (polymer carrier, German BASF AG) 16.04g
The preparation method of the carbamazepine eutectic solid dispersion of embodiment 4 is hot-melt extruded method, comprises the following steps:
Take respectively 0.0115mol (2.72g) carbamazepine, 0.0115mol (1.29g) nicotiamide and 16.04gsoluplus are placed in mortar mix homogeneously.The heating and melting zone temperatures of hot-melt extruded machine is set as to 100-160 DEG C.Physical mixture is joined in the machine barrel of hot-melt extruded machine.Screw speed is set as 50-100 turn/min, the time of staying of material in machine barrel is 2～3min.Hot-melt extruded machine is sheared physical mixture to disperse, and melt extrudes.Fused mass drying at room temperature is cooling, pulverizes 80 mesh sieves and obtain the eutectic solid dispersion of the present embodiment.
Powder X-ray diffraction result (Fig. 5) shows that medicine is dispersed in carrier material with amorphous or molecular state.High performance liquid chromatography testing result shows that medicament contg is without significant change.In Vitro Dissolution experimental result shows that the medicine accumulative total stripping percentage rate acquisition of this eutectic solid dispersion significantly improves (Fig. 6).
Claims (9)
1. a carbamazepine eutectic solid dispersion, it is characterized in that, carbamazepine, eutectic part and polymer carrier are prepared from, the mol ratio of described carbamazepine and eutectic part is 1～2: 1, and the quality percentage composition that polymer carrier accounts for described solid dispersion is 10%～90%.
2. carbamazepine eutectic solid dispersion according to claim 1, it is characterized in that, described carbamazepine has the bioactive substance compared with low aqueous solubility, there is hydrogen bond receptor and donor groups, can form eutectic by solvent method, heating and melting method, mechanical milling method or liquid feeding polishing with specific eutectic part.
3. carbamazepine eutectic solid dispersion according to claim 1, it is characterized in that, described eutectic part can form eutectic with carbamazepine, after melting, be dispersed in polymer carrier with amorphous or molecular state, the fusing point of eutectic regulating drug, thereby expand temperature and the carrier material range of choice for solid dispersion of fusion method and hot-melt extruded legal system, improve the heat stability of medicine.
4. carbamazepine eutectic solid dispersion according to claim 1, it is characterized in that, described eutectic part is selected from pharmaceutically acceptable nicotiamide, glycolic, adipic acid, salicylic acid, citric acid, succinic acid and can forms eutectic and eutectic melting point below or above one or more in the eutectic part of carbamazepine with carbamazepine.
5. carbamazepine eutectic solid dispersion according to claim 1, it is characterized in that, described polymer carrier is selected from one or more in polyethylene glycols, poly(ethylene oxide)polymers class, polyvidone class, copolyvidone class, hypromellose class, hyprolose class, poloxamer class, novel adjuvant soluplus water-soluble high-molecular material.
6. a method of preparing carbamazepine eutectic solid dispersion described in claim 1-5 any one, is characterized in that, described method is eutectic-fusion method, comprises the following steps:
(1) by after carbamazepine and eutectic part mix homogeneously, by solvent method, heating and melting method, mechanical milling method, or eutectic is prepared in liquid feeding grinding;
(2) by the eutectic of step (1) and polymer carrier mix homogeneously, be heated to 50-300 DEG C, melting 3-10min, dry cooling, solidify, pulverize and sieve and get final product.
7. a method of preparing carbamazepine eutectic solid dispersion described in claim 1-5 any one, is characterized in that, described method is eutectic-hot-melt extruded method, comprises the following steps:
(1) by after carbamazepine and eutectic part mix homogeneously, by solvent method, heating and melting method, mechanical milling method, or eutectic is prepared in liquid feeding grinding;
(2) by the eutectic of step (1) and polymer carrier mix homogeneously, join in hot-melt extruded machine machine barrel, barrel section temperature setting is set to 50-300 DEG C, screw speed is lower than 300 turn/min, material melt extrudes stop 2～4min in machine barrel after, dry cooling, solidify, pulverize and sieve and get final product.
8. prepare the method for the carbamazepine eutectic solid dispersion described in claim 1-5 any one for one kind, it is characterized in that, described method is fusion method: by carbamazepine, eutectic part and polymer carrier mix homogeneously, be heated to 50-300 DEG C, melting 3-10min, dry cooling, solidify, pulverize and sieve and get final product.
9. prepare the method for the carbamazepine eutectic solid dispersion described in claim 1-6 any one for one kind, it is characterized in that, described method is hot-melt extruded method: by carbamazepine, eutectic part and polymer carrier mix homogeneously, join in hot-melt extruded machine machine barrel, barrel section temperature setting is set to 50-300 DEG C, and screw speed is lower than 300 turn/min, material melt extrudes stop 2～4min in machine barrel after, dry cooling, solidify, pulverize and sieve and get final product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109464398A (en) * | 2018-11-30 | 2019-03-15 | 浙江工业大学 | A kind of preparation method of the carbamazepine solid dispersions of high drug load |
| CN110683990A (en) * | 2019-09-02 | 2020-01-14 | 华南理工大学 | Method for preparing pure carbamazepine-malonic acid eutectic through solution crystallization |
| CN112608273A (en) * | 2020-12-25 | 2021-04-06 | 武汉工程大学 | Two solvates of flunixin and carbamazepine eutectic and preparation method thereof |
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2013
- 2013-03-15 CN CN201310082826.2A patent/CN104042561A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109464398A (en) * | 2018-11-30 | 2019-03-15 | 浙江工业大学 | A kind of preparation method of the carbamazepine solid dispersions of high drug load |
| CN109464398B (en) * | 2018-11-30 | 2021-04-06 | 浙江工业大学 | Preparation method of carbamazepine solid dispersion with high drug loading capacity |
| CN110683990A (en) * | 2019-09-02 | 2020-01-14 | 华南理工大学 | Method for preparing pure carbamazepine-malonic acid eutectic through solution crystallization |
| CN112608273A (en) * | 2020-12-25 | 2021-04-06 | 武汉工程大学 | Two solvates of flunixin and carbamazepine eutectic and preparation method thereof |
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Application publication date: 20140917 |