CN103027901B - Capsaicin chitosan microsphere-carried enteric coated tablet and preparation method thereof - Google Patents
Capsaicin chitosan microsphere-carried enteric coated tablet and preparation method thereof Download PDFInfo
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Abstract
本发明提供一种载辣椒素壳聚糖微球（CCMS）肠溶片，包括CCMS片芯和包衣膜，其中CCMS片芯包括CCMS、黏合剂、润滑剂和崩解剂，包衣膜包括EudragitL100、增塑剂、滑石粉和95%的乙醇。辣椒素（CAP）是从辣椒中提取的一种天然产物，能促进人体内脂质代谢，减少脂肪在体内的蓄积，达到较好的减肥降血脂作用。然而CAP对胃有强烈的刺激性，将其制成壳聚糖微球可以减少CAP用量，从而减少对胃的刺激性，并采用薄膜包衣技术，将药物定位在小肠中释放，增加了患者的顺应性。另外提供一种CCMS肠溶片的制备方法，主要在制作包衣的过程进行了改进，使制备工艺简单合理。The invention provides a capsaicin-loaded chitosan microsphere (CCMS) enteric-coated tablet, including a CCMS tablet core and a coating film, wherein the CCMS tablet core includes CCMS, a binder, a lubricant and a disintegrant, and the coating film includes Eudragit L100, plasticizer, talc and 95% ethanol. Capsaicin (CAP) is a natural product extracted from peppers, which can promote lipid metabolism in the human body, reduce the accumulation of fat in the body, and achieve better weight loss and blood lipid lowering effects. However, CAP is strongly irritating to the stomach, and making it into chitosan microspheres can reduce the amount of CAP, thereby reducing the irritation to the stomach, and using film coating technology to position the drug in the small intestine for release, increasing the patient's compliance. In addition, a preparation method of the CCMS enteric-coated tablet is provided, and the process of making the coating is mainly improved, so that the preparation process is simple and reasonable.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of capsaicin chitosan microball enteric coatel tablets and preparation method thereof that carry.
Background technology
Obesity is a kind of serious chronic disease, and it is relevant with many factors such as gene, diet, environment, tradition.World Health Organization (WHO) announces, the country that the world's 65% population is lived, and the number of dying from Overweight and obesity is greater than underweight number; 2010, more than 4000,10,000 years old following child was overweight.Obesity is not only the problem that developed country faces, and it spreads to developing country, and is tending towards youth puerility.
Fat closely related with Developmental and Metabolic Disorder, be the predisposing factor of the various diseases such as atherosclerosis (AS), type Ⅱdiabetes mellitus, cardiovascular disease, tumor, non-alcohol fatty liver (NAFLD), people have progressively recognized that obesity is a kind of unsound condition.
Seriousization of whole world obesity has been the reality that can not escape, but be but phoenix feathers and unicorn horns for fat chemical slimming medicine, once public praise once preferably sibutramine, fenfluramine, amfetamine etc. all because serious side effect steps down from the stage of history, remaining orlistat has also been found some side effect in recent years, just as cause oiliness, fat-soluble avitaminosis and hepatic injury etc.And traditional Chinese medicine capable of reducing weight medicine is because active component is indefinite, mechanism of action is unclear, has hindered its further application and development.Current slimming medicine market is close to vacancy.
The inventor is through long-term a large amount of research, a kind of preparation method of carrying capsaicin chitosan microball (CCMS) is provided in the granted patent that is CN201110247678.6 at publication number, and has proposed the good effect of described microsphere aspect Weight-reducing and lipid-lowering and blood sugar lowering.Described microsphere has good sustained release performance, has realized the synergistic function of chitosan and capsaicin, has overcome that tradition prepares that medicine carrying microballoons is underproduce, envelop rate and the defect such as drug loading is not good, has good commercial Application meaning.
The fat-reducing effect of the CCMS that the present invention proposes is confirmed by pharmacodynamic experiment.But the easy moisture absorption of this microsphere powder, is difficult for preserving; In addition, although by the coated capsaicin zest that significantly reduced of successful secondary, but in slow release process, the strong impulse that CAP has stomach is not still solved well, just can both be reduced the injury of medicine to stomach if be designed to enteric coatel tablets.
But because the outstanding novelty of active drug composition, CCMS successfully to be prepared and becomes desirable enteric coatel tablets, reduce the injury of medicine to stomach, should ensure the effective effect of medicine, solve again the moistureproof problem of CCMS, and ensure the safety of integral formula, key is to find rationally suitable formula and preparation technology for brand-new active drug composition, this wherein needs the technical barrier of solution many, can not, simply with reference to the conventional preparation method of existing enteric coatel tablets, also have no now and studies have reported that.
Summary of the invention
An object of the present invention is to fill up the blank of prior art, a kind of capsaicin chitosan microball (CCMS) enteric coatel tablets that carry are provided.
Another object of the present invention is to provide the preparation method of described enteric coatel tablets.
Goal of the invention of the present invention is achieved by the following technical programs:
A kind of capsaicin chitosan microball (CCMS) enteric coatel tablets that carry are provided, and content meter by weight percentage, comprises following component:
CCMS label 96 ~ 98%;
Coating membrane 2 ~ 4%.
Described CCMS label, content meter by weight percentage, composed of the following components:
CCMS 91~95.5%；
Lubricant 0.5 ~ 2.0%;
Disintegrating agent 3 ~ 5%;
Adhesive 1 ~ 2%.
Preferably, described adhesive is hypromellose or sodium carboxymethyl cellulose, more preferably sodium carboxymethyl cellulose.
Preferably, described lubricant is magnesium stearate or sodium lauryl sulphate, more preferably magnesium stearate.
Preferably, described disintegrating agent is carboxymethylstach sodium or cross-linking sodium carboxymethyl cellulose.
The invention provides a kind of highly preferred CCMS label composition proposal, specifically content meter by weight percentage, composed of the following components:
CCMS 93.3%；
Magnesium stearate 1.0%;
Carboxymethylstach sodium 3.8%;
Sodium carboxymethyl cellulose 1.9%.
In the present invention, sodium carboxymethyl cellulose is as adhesive, compacting tablet quality is out high, solve well the phenomenon that sticks punching and sliver in enteric coatel tablets preparation process of the present invention, and compare hypromellose, sodium carboxymethyl cellulose is as the adhesive of enteric coatel tablets of the present invention, the sheet pressing out brilliant white more, there is no pit, therefore preferably carboxymethyl cellulose sodium is adhesive.Because concentration is 3%, when consumption is 1.9%, sodium carboxymethyl cellulose disintegration time is fast, so the consumption of preferably carboxymethyl cellulose sodium is 1.9%.
In the selection of lubricant, the magnesium stearate of reasonable volume or sodium lauryl sulphate can ensure the successful preparation of enteric coatel tablets of the present invention, considering sodium lauryl sulphate is anion surfactant, can not with cationic compound compatibility, and easily decompose in damp-heat air, excessive easy haemolysis, thus the present invention more preferably magnesium stearate as lubricant.Disintegrating agent of the present invention is selected carboxymethylstach sodium and cross-linking sodium carboxymethyl cellulose, can obtain good effect.The inventor scrutinizes and contrasts through a large amount of long-term experiments, sum up and find that CCMS has hygroscopicity, and cross-linking sodium carboxymethyl cellulose is while running into the crude drug of moisture absorption, can reduce the disintegration rate performance of itself, in the present invention, select carboxymethylstach sodium compared with cross-linking sodium carboxymethyl cellulose, whole structure is more excellent.
When the consumption 3.8% of carboxymethylstach sodium, can make self to absorb water fast, reach significant expansion effect, therefore the consumption of disintegrating agent is 3.8%.
Coating membrane of the present invention comprises each component of following weight percent content:
Methacrylic acid copolymer 5 ~ 6%;
Plasticizer 0.5 ~ 1.8%;
Antitackiness agent 0.5 ~ 2.4%;
Solvent 89.8 ~ 94%.
Preferably, described coating membrane comprises each component of following weight percent content:
Methacrylic acid copolymer 5.7%;
Plasticizer 1.2%;
Antitackiness agent 1.4%;
Solvent 91.7%.
Preferably, described methacrylic acid copolymer is Eudragit L100.Eudragit L100 is a kind of coating material of pH dependent form, because activity functional groups is-COOH, so do not dissolve under one's belt, and salify dissolves in the intestinal juice of pH>6, there is stable, inertia, safety and the advantage such as non-stimulated, more bring out the best in each other with the beneficial effect of enteric coatel tablets of the present invention.
Preferably, described plasticizer optimization citric acid triethyl (TEC).
Preferably, described antitackiness agent preferably talc powder.
Preferably, the ethanol that described solvent preferred volume percent concentration is 95%.
The present invention provides the preparation method of described CCMS enteric coatel tablets simultaneously, comprises the following steps:
A) prepare CCMS label;
B) prepare coating solution;
C) it is the coating pan preheating of 35 ~ 55 DEG C that CCMS label step a) being prepared is placed in inlet temperature;
D) regulating coating pan rotating speed to 10 ~ 35r/min, is 0.5 ~ 5kg/cm at spray pressure
2condition under, the coating solution that step b) is prepared sprays on CCMS label;
E) product drying step d) being sprayed and get final product.
In described step a), the preparation of enteric coatel tablets CCMS label is:
Crude drug chitosan-loaded capsaicin microsphere and other adjuvants are sieved respectively.Adhesive is mixed to soft material processed with crude drug, the mode granulation of sieving by soft material with extruding, granulate after the wet grain drying making, adds disintegrating agent and lubricant, is mixed rear tabletting.
Preferably, described label is pressed into dark arc circular piece, is conducive to coating even, and edge coating is complete.
Described step b) in, prepare coating solution and be:
Eudragit L100 is placed in 95% appropriate ethanol to swelling 12 hours, then adds plasticizer.In addition Pulvis Talci is poured in residual solvent, fully stirred evenly with refiner.Then the Pulvis Talci suspension making is slowly poured in Eudragit L100 solution, noted not sneaking into too much air, cross 40 mesh sieves.
Described step c) in, the time of preheating is 6 ~ 8min.
In described step d), in the early stage of spraying, adopt hot air drying and spraying to hocket, inlet temperature is controlled at 35 ~ 55 DEG C, after surface forms coating membrane, carries out continuous spray, the specified wt until coating membrane increases weight.
Described coating pan rotating speed is preferably 25r/min, and described spray pressure is preferably 2 ~ 3kg/cm
2, the inlet temperature of described hot air drying is preferably 40 ~ 45 DEG C.
The present invention has following beneficial effect:
(1) the present invention successfully suppresses CCMS in flakes, and prepares enteric coatel tablets based on CCMS sheet, has overcome the hygroscopicity of medicine, has effectively reduced the stimulation of CAP to stomach.
(2) CCMS is a kind of material of the very easily moisture absorption, so will guard against damp when preparation.20 century 70s are in the past main adopts sugar coating protection against the tide, and the moisture effect of sugar-coat is not as good as film-coat, coating process complexity, length consuming time; This medicine is developed for adiposis patient simultaneously, most of adiposis patients all suffer from diabetic complication, and the sucrose in sugar-coat film has brought larger harm to adiposis patient, and the present invention adopts film coating, ensure safety, with the very fit of application of enteric coatel tablets of the present invention.
Film coating is a kind of packaging technique of extensive use, and with respect to sweet tablet, thin membrane coated tablet heavily increases less.But clothing film is thinner, just higher to the requirement of coated tablet, so although film coating is a kind of packaging technique of extensive use, in concrete operations, for different ingredients.If technique is not suitable for, hardness and friability do not reach requirement, just easily cause label wearing and tearing in coating process, and in coating pan, the medicated powder of deposition and the medicated powder of sheet remained on surface, by hindering contacting of label and coating solution, have increased coating difficulty.The present invention successfully provides the film coating procedure of described enteric coatel tablets, simple to operate, and coating efficiency and effect are significantly improved.
(3) the present invention adopts and prepares CCMS enteric coatel tablets by wet granule compression tablet, has increased the mobility of CCMS, has reduced the filling difference of medicine, thereby has reduced tablet weight variation, has ensured the content of effective ingredient CAP.Its tablet forming technique reasonable, reproducible.
(4) the present invention to the accurate selection of each component be all based on active drug composition match and the whole synthesis of technical scheme is considered, enteric coatel tablets drug effect is remarkable, stable, reduced the stimulation to stomach, tablets in vitro assay method favorable reproducibility, can realize the release of medicine exactly.
(5) what the present invention prepared carries capsaicin chitosan microball (CCMS) enteric coatel tablets is a kind of medicines for adiposis patient exploitation, its active ingredient CAP is a kind of natural product extracting from Fructus Capsici, can promote people's HypercholesterolemicRats, reduce fat accumulating in vivo, there is fat-reducing and the effect for reducing blood fat of potentiation with chitosan.After preparation becomes enteric coatel tablets, not only reduce the injury of medicine to stomach, realize again moisture effect, and ensure that CAP and chitosan have the fat-reducing of potentiation and the effect of effect for reducing blood fat, bring into play well CCMS auxiliary antilipemic and anti-atherosclerotic effect, there is the advantages such as effect is extensive, good biocompatibility, degradable.Be convenient to adiposis patient and take, easy to carry, compliance is strong.
Brief description of the drawings
The different plasticizer TEC of Fig. 1, the impact of DEP on coated tablet drug release
The impact of Fig. 2 plasticizer TEC consumption on drug release
The impact on drug release of increasing weight of Fig. 3 coating
Detailed description of the invention
Further describe the present invention below in conjunction with the drawings and specific embodiments.Unless stated otherwise, the present invention adopts reagent raw material and equipment are reagent raw material and the equipment of the art routine.
embodiment 1:the optimization of CCMS label
Crude drug carries the granted patent that granted patent that the preparation of capsaicin chitosan microball can be CN201110247678.6 with reference to publication number and publication number are CN201110247679.0.
The preparation method of CCMS label: compared different label preparation method and condition by great many of experiments.Especially carried out experimentation and summary for direct powder compression and wet granule compression tablet method, the present invention adopts wet granule compression tablet method to carry out tabletting, effectively increases mobility of particle, is easy to fill, and reduces sliver phenomenon and tablet weight variation, improves tabletting environment.
Concrete preparation process was crossed 100 mesh sieves for crude drug (is carried to capsaicin chitosan microball) 80 mesh sieves, other adjuvants.Mix soft material processed with crude drug with binding agent, soft material is crossed to 24 mesh sieves in the mode of extruding granulates, the wet granular making is placed on and is dried to water content in 60 DEG C of baking ovens is 2% left and right, granulate, remove thick block, the granule being sticked together and fine powder, add magnesium stearate, carboxymethylstach sodium, mixed, use the circular punch die that diameter is 10mm to carry out tabletting.
1. determining of adhesive kind
In order to increase the compressibility of material, selecting volume by volume concentration is 5% adhesive aqueous solution soft material processed, concrete formula for the concentration of the dried CCMS soft material of 400mg granule, 1% magnesium stearate (accounting for the percentage by weight of CCMS soft material granule), adhesive be 5%.The present embodiment, taking hypromellose (HPMC), sodium carboxymethyl cellulose (CMC-Na) as adhesive representative, considers the coating in later stage, controls the hardness range 50 ~ 60N of tablet.Using hardness, disintegration and outward appearance as investigating index, the results are shown in Table shown in 1:
Determining of table 1 adhesive kind
| Adhesive | Hardness (N) | Disintegration (min) | Outward appearance |
| HPMC | 57 | 15 | Can realize, smooth surface is smooth, without glutinous punching, has a pit, a little sliver, sheet somewhat dark yellow |
| CMC-Na | 55 | 16 | Energy is realized, and smooth surface is smooth, nothing sticks punching, compare brilliant white without sliver and pit, sheet |
As shown in Table 1: can realize the object of the invention taking hypromellose (HPMC), sodium carboxymethyl cellulose (CMC-Na) as adhesive, the tablet quality that CMC-Na presses out as adhesive is high, solve the problem of glutinous punching and sliver, and compare HPMC, the sheet that CMC-Na presses out as adhesive brilliant white more, does not have pit.In view of both are to there is no larger difference the disintegration of tablet, therefore preferred CMC-Na is as formula adhesive.
2. determining of adhesive concentration
Adhesive can strengthen intergranular adhesion and compressibility, but consumption is too much, and what when soft material processed, squeeze out is strip, instead of granule, and tabletting is easy to glutinous punching, and the disintegrate of tablet is affected.Therefore the impact of the concentration that is necessary to investigate adhesive on tablet.Component design is the dried CCMS soft material of 400mg granule, 1% magnesium stearate, adhesive.The concentration of adhesive CMC-Na solution used is designed to respectively 3%, 5%, 7%, controls the hardness range 50 ~ 60N of tablet.Using hardness, disintegration and outward appearance as investigating index, the results are shown in Table shown in 2:
Determining of table 2 adhesive concentration
| Adhesive concentration | Hardness (N) | Disintegration (min) | Outward appearance |
| 3% | 58 | 14 | Smooth surface is smooth, nothing glutinous punching, sliver and pit |
| 5% | 58 | 16 | Smooth surface is smooth, nothing glutinous punching, sliver and pit |
| 7% | 56 | 16 | Smooth surface is smooth, nothing glutinous punching, sliver and pit |
As shown in Table 2: 3%, 5%, 7% adhesive is on the outward appearance of sheet without impact, and surface is all smooth, nothing glutinous punching, sliver and pit.The CMC-Na that wherein concentration is 3% just can meet tabletting outward appearance, and is better than other two concentration disintegration, therefore while adopting CMC-Na adhesive, preferably 3%.
3. determining of lubricant
Other research experiments can not repeat at this one by one, and the present embodiment provides magnesium stearate and two kinds of lubricants of sodium lauryl sulphate (SDS) at this.The CMC-Na that concrete formula is 3% for the dried CCMS soft material of 400mg granule, lubricant, concentration, the Determination of quantity of lubricant is 1%, controls the hardness range 50 ~ 60N of tablet.Using hardness, disintegration and outward appearance as investigating index, the results are shown in Table shown in 3:
Determining of table 3 lubricant
| Lubricant | Hardness (N) | Disintegration (min) | Outward appearance |
| Magnesium stearate | 54 | 14 | Smooth surface is smooth, nothing glutinous punching, sliver and pit |
| SDS | 55 | 14 | Smooth surface is smooth, nothing glutinous punching, sliver and pit |
As shown in Table 3: magnesium stearate and SDS have all improved the mobility of material well, tabletting rear surface smooth, without glutinous punching, sliver and pit phenomenon; Also no significant difference of hardness and disintegration time.Because SDS is anion surfactant, can not with cationic compound compatibility, and in damp-heat air easily decompose, consumption too much easily causes haemolysis, so finally select magnesium stearate as lubricant.Magnesium stearate is hydrophobic auxiliary, and consumption too much causes disintegration of tablet slow, through Comprehensive Experiment research, for obtaining best effect, determines that magnesium stearate optimum amount is 1%.
4. determining of disintegrating agent kind
Because tablet is that high pressure compacting forms, be therefore difficult to rapid dissolving; The disintegrate of tablet is again the first step of stripping, therefore investigate the disintegrate impact of different disintegrating agents on sheet.The CMC-Na that the concrete formula of the present embodiment is 3% for the dried CCMS soft material of 400mg CCMS granule, 1% magnesium stearate, 6% disintegrating agent (accounting for the percentage by weight of CCMS soft material granule), concentration.The disintegrating agent that participates in screening is carboxymethylstach sodium (CMS-Na) and cross-linking sodium carboxymethyl cellulose (CCNa).Control the hardness range 50 ~ 60N of tablet.Using hardness, disintegration as investigating index, the results are shown in Table shown in 4:
Determining of table 4 disintegrating agent kind
As shown in Table 4: at disintegrating agent kind apoplexy due to endogenous wind provided by the invention, the disintegrate effect of CMS-Na is more better than CCNa, the expansion rate of water absorption effect of CMS-Na is remarkable, for 300 times of original volume, and CCNa runs into the crude drug of moisture absorption and can reduce the disintegration rate of self, therefore best technical scheme is that to select CMS-Na be disintegrating agent.
5. disintegrating agent CMS-Na Determination of quantity
The effect of disintegrating agent is not only relevant, also relevant to the consumption of disintegrating agent to the system described in selection, the disintegrating agent of disintegrating agent, so the present embodiment is investigated the consumption of disintegrating agent.Concrete formula is the consumption of the dried CCMS soft material of 400mg granule, 1% magnesium stearate, design CMS-Na is respectively 4%, 6%, 8%(accounts for CCMS soft material granule percentage by weight), control the hardness range 50 ~ 60N of tablet, using hardness, disintegration as investigating index, the results are shown in Table shown in 5:
Table 5 disintegrating agent CMS-Na Determination of quantity
As shown in Table 5: when CMS-Na consumption is 4%, disintegrate effect is best, 4% consumption can make CMS-Na absorb water fast, reaches significant expansion effect.Therefore determine that the optimum amount of disintegrating agent CMS-Na is 4%, account for 3.8% of total formula.
6. the present embodiment adopts different formulas to test, and carries the formula of capsaicin microsphere label:
CCMS 91~95.5%；
Lubricant 0.5 ~ 2.0%;
Disintegrating agent 3 ~ 5%;
Adhesive 1 ~ 2%.
Summing up best formula in conjunction with 1 ~ 6 is:
CCMS：93.3%（392mg）
Magnesium stearate: 1.0%(4mg)
CMS-Na：3.8%（16mg）
CMC-Na：1.9%（8mg）。
embodiment 2:the preparation of CCMS label
The concrete preparation method of CCMS label: CCMS is crossed to 80 mesh sieves, magnesium stearate, CMS-Na, CMC-Na cross respectively 100 mesh sieves, getting 93.3%CCMS concentration is 3%CMC-Na soft material processed (the CMC-Na soft material processed of 1g CCMS powder 0.7mL, be that consumption is 1.9%), soft material reaches " gently holding agglomerating; light pressure fallen apart ", soft material is crossed to 24 mesh sieves in the mode of extruding granulates, the wet granular making is placed on and is dried to water content in 60 DEG C of baking ovens is 2% left and right, granulate, removes thick block, the granule being sticked together and fine powder.Get 95.2% dried CCMS soft material granule (400mg), add 1.0% magnesium stearate (4mg), 3.8% CMS-Na(16mg), mixed, use the circular punch die tabletting that diameter is 10mm.
embodiment 3:the preparation of CCMS label
The concrete preparation method of CCMS label: CCMS is crossed to 80 mesh sieves, magnesium stearate, CMS-Na, CMC-Na cross respectively 100 mesh sieves, getting 91%CCMS powder concentration is 3.1%CMC-Na soft material processed (the CMC-Na soft material processed of 1g CCMS powder 0.7mL, be that consumption is 2%), soft material reaches " gently holding agglomerating; light pressure fallen apart ", soft material is crossed to 24 mesh sieves in the mode of extruding granulates, the wet granular making is placed on and is dried to water content in 60 DEG C of baking ovens is 2% left and right, granulate, removes thick block, the granule being sticked together and fine powder.Get 93% dried CCMS soft material granule, add 2% magnesium stearate, 5% CMS-Na, mixed, use the circular punch die tabletting that diameter is 10mm.
embodiment 4:the preparation of CCMS label
The concrete preparation method of CCMS label: CCMS is crossed to 80 mesh sieves, magnesium stearate, CMS-Na, CMC-Na cross respectively 100 mesh sieves, getting 95.5%CCMS powder concentration is 1.5%CMC-Na soft material processed (the CMC-Na soft material processed of 1g CCMS powder 0.7mL, be that consumption is 1%), soft material reaches " gently holding agglomerating; light pressure fallen apart ", soft material is crossed to 24 mesh sieves in the mode of extruding granulates, the wet granular making is placed on and is dried to water content in 60 DEG C of baking ovens is 2% left and right, granulate, removes thick block, the granule being sticked together and fine powder.Get 96.5% dried CCMS soft material granule, add 0.5% magnesium stearate, 3% CMS-Na, mixed, use the circular punch die tabletting that diameter is 10mm.
embodiment 5:the preparation of CCMS enteric coatel tablets
1. the mensuration of enteric coatel tablets release
Get 6 of enteric coatel tablets, according to pharmacopeia drug release determination method (turning basket method) mensuration in 2010, taking 0.1mol/L hydrochloric acid 750mL as solvent, 37 DEG C ± 0.5 DEG C of temperature, rotating speed 100r/min, in the time of 2.0 h, to turn immediately basket emersion liquid level, check that every goldbeater's skin all must not have crack or Swelling.Add immediately 250mL 0.2moL/L Na
3pO
4solution (medium becomes the phosphate buffer of pH6.8, and described phosphate buffer consists of: 0.2mol/L tertiary sodium phosphate: 0.1mol/L hydrochloric acid=1:3), rotating speed is constant, 0.75,1.0,1.5,2.0, after 5.0,9.0,13.0 h, sample 5mL, after every sub-sampling, supplement the dissolution medium of equivalent, then use the filtering with microporous membrane of 0.45 μ m, under selected chromatographic condition, measure peak area, calculate cumulative release percentage rate.
2. coating method
The CCMS enteric label that embodiment 2 ~ 4 is pressed is wiped fine powder, be placed in respectively preheating (35 ~ 45 DEG C of inlet temperature in coating pan in batches, 6 ~ 8min), rotating speed is too not fast, then coating pan rotating speed is slowly increased, be sprayed at the sheet wicking surface of rotation with the coating solution preparing, retention tab bed tempertaure, when beginning in order to prevent the infiltration of moisture and label wearing and tearing, adopt hot air drying and spraying to hocket, form slightly significantly and carry out again continuous spray operation after clothing film until surface, the weight of specifying until clothing film increases weight to.After having sprayed, continue to be dried ten minutes with hot blast, be then cooled to room temperature.The enteric coatel tablets of wrapping clothing are placed on to dry 3h in the baking oven of 40 DEG C, obtain enteric coatel tablets finished product.The CCMS enteric label that embodiment 2 ~ 4 is pressed all can successfully prepare enteric coatel tablets.
3. the configuration of coating solution
Eudragit L100 is placed on to appropriate 95%(volume by volume concentration) in ethanol swelling 12 hours, then add plasticizer.In addition Pulvis Talci is poured in residual solvent, fully stirred evenly with refiner, make Pulvis Talci suspension; Pulvis Talci suspension is slowly poured in Eudragit L100 solution, noted not sneaking into too much air, cross 40 mesh sieves.
4. art for coating optimization
4.1. the selection of inlet temperature
Other conditions of fixing coating, coating effect when the present embodiment provides investigation inlet temperature to be 30 ~ 35 DEG C, 40 ~ 45 DEG C, 50 ~ 55 DEG C describes.Experimental result shows, when inlet temperature is 30 ~ 35 DEG C, film property is better, but easily sticks together between sheet; 40 ~ 45 DEG C time, good film-forming property, solvent can volatilize in time, is difficult for adhesion between sheet; 50 ~ 55 DEG C time, temperature is higher, and coating is inhomogeneous, produces spraying and be dried in hydrojet process, and it is just dry on sheet that coating solution does not also reach, and reduced coating quality.Therefore determine at 40 ~ 45 DEG C of best control temperature and carry out coating.
4.2. the selection of coating pan rotating speed
The rotating speed of coating pan is very large on the impact of coating quality, and rotating speed is large, can increase the rate of drying of clothing film, but the label that also can wear and tear; The little drying effect that can affect clothing film of rotating speed, sticks together sheet.So suitable rotating speed is the successful key condition of coating of the present invention.10r/min, 25 r/min are chosen in experiment, tri-levels of 35 r/min are carried out the investigation of coating rotating speed.The spraying of result 10r/min rotating speed coating solution is inhomogeneous, easily sticks together, and clothing film became uneven, affects the release of medicine; 25r/min rotary speed is moderate, and solvent can volatilize in time, and film property is better; 35r/min rotating speed is very fast, and label is easy to wear.Therefore selecting 25r/min is that optimum speed carries out coating.
4.3. the selection of atomisation pressure
Atomisation pressure directly affects the state of spray droplet, and atomisation pressure is little, and drop is just large, causes spraying inhomogeneous, also difficult dry; Atomisation pressure is large, there will be spraying dry.The present embodiment is chosen 0 ~ 1kg/cm
2, 2 ~ 3kg/cm
2, 4 ~ 5kg/cm
2three levels are investigated explanation, and result shows, at 0 ~ 1kg/cm
2under condition, spray effect is bad, and spray droplet is large, and in pot, humidity is larger, and clothing film is dry not in time, easily sticks together; At 2 ~ 3kg/cm
2under condition, spray effect is good, and film property might as well; At 4 ~ 5kg/cm
2under condition, though film property is good, occur spraying dry-out phenomenon, spray time extends, and efficiency is not high.Therefore select 2 ~ 3kg/cm
2pressure spray.
4.4. determining of art for coating
The CCMS pressing is wiped to fine powder and be placed on (35 ~ 45 DEG C of the inlet temperature of preheating in coating pan, 6 ~ 8min), rotating speed is too not fast, then coating pan rotating speed is slowly adjusted to 25r/min, be sprayed at the sheet wicking surface of rotation with the coating solution preparing, inlet temperature is controlled between 40 ~ 45 DEG C, and spray press control is at 2 ~ 3kg/cm
2, after having sprayed, be placed on dry 3h in the baking oven of 40 DEG C, to obtain final product.
5. the optimization of coating fluid prescription
5.1. the investigation of amount of talc
pulvis Talci can effectively prevent adhesion phenomenon in coating process, but consumption too much easily precipitates, and stops up spray gun.Three levels of experimental design: account for 10%, 25%, 40% of polymer.10% Pulvis Talci anti-adhesion effectiveness is poor as a result; 40% Pulvis Talci easily deposits, and stops up spray gun, causes spraying difficulty; 25% Pulvis Talci coating is smooth, and anti-adhesion effectiveness is good, is also difficult for stopping up spray gun.Therefore choose 25% and carry out coating for talcous optimum amount.
5.2. the investigation of plasticizer kind
Plasticizer refers to for increasing the plastic material of macromolecular material.Plasticizer is general has good mildness with polymer, in the time that it is inserted between polymer molecular chain, weakens the Van der Waals force of polymer molecule interchain, increases the mobility of polymer molecular chain, the degree of crystallinity of reduction strand.Thereby the plasticity of coating material is increased, and coating membrane is smooth evenly.Enteric coatel tablets prepared by embodiment 2 are chosen in experiment, and using TEC, dibutyl sebacate (DEP) as plasticizer, consumption is 20% of Eudragit L100, and the release conditions of coated tablet in enteric liquid investigated in coating weightening finish 4%, and result as shown in Figure 1.
From accompanying drawing 1, TEC and DEP are not very large as plasticizer on the release impact of enteric coatel tablets medicine, because the former is easy to get and low price, are plasticizer therefore selected.
5.3. the investigation of plasticising dosage
Other materials in fixing coating solution, enteric coatel tablets prepared by embodiment 2 are chosen in the present embodiment experiment, taking TEC as plasticizer, coating weightening finish 4%, investigate the impact of plasticizer TEC consumption on enteric coatel tablets drug release, the level of design is to account for 10%, 20%, 30% of Eudragit L100, and result as shown in Figure 2.
From release profiles, the TEC release of first 1 hour 10% is relatively very fast, and later stage release does not have two other level complete, may be because plasticizer is few, and clothing film pliability is inadequate, and coating membrane is inhomogeneous, causes chitosan swelling.In 30% TEC coating process, having the glutinous sheet of part, while doing drug release, have a slice to occur screening phenomenon, may be to cause because coating fluid prescription ratio is improper.In coating solution, add 20% TEC coating smooth, clothing film is smooth evenly, and release curve meets administration regulation.Therefore the consumption of TEC is decided to be 20% of Eudragit L100 in coating solution.
5.4. the investigation of coating weightening finish
Show to cover the clothing film of different-thickness at label, the degree that corroded by gastric acid is also different, and larger on the release impact of medicine, and experiment is chosen 2%, 3%, 5% 3 level of weightening finish and tested, and result as shown in Figure 3.
Coating increases weight 2% time, and label edge coating is imperfect, swelling in hydrochloric acid solution, and swelling chitosan has hindered the release of CAP, causes release ability to weaken; Coating increases weight 5% time, can find out that drug release is slow, and release is incomplete from release curve, does not reach administration requirement; Coating increases weight 3% time, and release curve is more reasonable, and film property is better.Therefore coating weightening finish location 3%.
embodiment 6:the assay of CCMS enteric coatel tablets
Get 10 of enteric coatel tablets prepared by embodiment 2, remove enteric coating, grind to form fine powder, take 0.42g, be dissolved in 100mL volumetric flask and be diluted to scale with methanol, violent jolting, fully shakes even, centrifugal (8000r/min, 15min), filter, the accurate 1mL subsequent filtrate of drawing, to 10mL volumetric flask, is diluted to scale with simulated intestinal fluid, after the filtering with microporous membrane of 0.45 μ m, under selected chromatographic condition, measure content, the results are shown in Table 6.
The assay result of three batches of enteric coatel tablets of table 6
| Lot number | The content (mg/ sheet) of CAP |
| 1207014 | 5.4 |
| 1207015 | 5.4 |
| 1207016 | 5.4 |
embodiment 7:detect
Get the CCMS enteric coatel tablets that label that embodiment 2 prepares prepared under 5 technique in conjunction with the embodiments and detect, the zest of CAP obviously reduces, and has increased patient's compliance.In 0.1mol/L hydrochloric acid, 2 hours all there is not crack or Swelling in underwear film, stable in gastric acid.In the phosphate buffer of pH6.8, the burst size of CAP is all greater than 70% of labelled amount.Solved patient's compliance issues so adopt the method to prepare CCMS enteric coatel tablets, successfully controlled CAP and discharge in intestinal, the stripping of CCMS enteric coatel tablets simultaneously meets state-promulgated pharmacopoeia regulation.
Claims (3)
1. carry capsaicin chitosan microball enteric coatel tablets, it is characterized in that, by weight, comprise following component:
Carry capsaicin chitosan microball label 96～98%;
Coating membrane 2～4%;
Described year capsaicin chitosan microball label, by weight, composed of the following components:
By weight, the coating solution that described coating membrane uses comprises following component:
Methacrylic acid copolymer 5 ~ 6%;
Plasticizer 0.5 ~ 1.8%;
Antitackiness agent 0.5 ~ 2.4%;
Solvent 89.8 ~ 94%;
Described methacrylic acid copolymer is Eudragit L100, and described plasticizer is triethyl citrate or dibutyl sebacate, and described antitackiness agent is Pulvis Talci, and described solvent is 95% ethanol.
2. the preparation method of as claimed in claim 1 year capsaicin chitosan microball enteric coatel tablets, is characterized in that, comprises the following steps:
A) enteric coatel tablets carry the preparation of capsaicin chitosan microball label;
B) prepare coating solution;
C) carry capsaicin chitosan microball label to be placed in inlet temperature be the coating pan preheating of 35～55 DEG C described;
D) regulating coating pan rotating speed to 10～35r/min, is 0.5～5kg/cm at spray pressure
2condition under, coating solution is sprayed to and is carried on capsaicin chitosan microball label;
E) be drying to obtain.
3. carry as claimed in claim 2 the preparation method of capsaicin chitosan microball enteric coatel tablets, it is characterized in that, steps d) in, in the early stage of spraying, adopt hot air drying and spraying to hocket, inlet temperature is controlled at 35～55 DEG C, after label surface filming, carry out continuous spray, the specified wt until coating membrane increases weight.
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| GB9711962D0 (en) * | 1997-06-10 | 1997-08-06 | Reckitt & Colmann Prod Ltd | Therapeutically active compositions |
| CN1288730A (en) * | 1999-09-07 | 2001-03-28 | 麦克内尔-Ppc股份有限公司 | Slight-purgitive composition |
| JP4647933B2 (en) * | 2003-04-23 | 2011-03-09 | 森永製菓株式会社 | Composition having intestinal regulating action |
| CN102293752B (en) * | 2011-08-26 | 2013-01-23 | 广东药学院 | Preparation method of chitosan-carried capsaicin microsphere as well as microsphere and application of microsphere in weight reduction and sugar reduction |
| CN102389398A (en) * | 2011-08-26 | 2012-03-28 | 广东药学院 | Chitosan-loaded capsaicin microspheres, preparation method thereof, and application thereof |
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