CN103948550A - Cisapride dispersible tablet and preparation method thereof - Google Patents
Cisapride dispersible tablet and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a cisapride dispersible tablet and a preparation method thereof. As the cisapride is low in bioavailability via oral administration and the difference between the pharmacy individuals is relatively large, the invention provides the cisapride dispersible tablet which comprises cisapride, hydroxypropyl-beta-cyclodextrin, a filling agent, a disintegrating agent, a binding agent and a lubricant. The cisapride is extremely easily dissolved in water after being included by the hydroxypropyl-beta-cyclodextrin (HP-beta-CD), so that the drug stability is improved, the release of the drug in vivo is promoted, the absorption is increased, the bioavailability is improved and the difference between the pharmacy individuals is reduced.
Description
Invention field
The present invention relates to chemical pharmacy field, be specifically related to a kind of cisapride dispersible tablet and preparation method thereof.
Background of invention
Because modern society rhythm of life is accelerated, the factors such as dietary structure change, the gastric motility crowd that lowly falls ill is increasing, and gastric motility lowly often causes the diseases such as functional dyspepsia, gastroesophageal reflux, and people are greatly affected quality of life.China's gastropathy sickness rate is approximately according to statistics
number of the infected is about 300,000,000 people left and right, occupies first of the world.It is reported, gastrointestinal tract medication occupies the larger market share always, and world's gastrointestinal tract medicine annual sales amount is about 13,000,000,000 dollars, is the third-largest drug market.According to domestic Epidemiological study, find, in gastrointestinal special outpatient clinic patient, what relate to gastric motility problem accounts for 50%, and chronic gastritis sickness rate increases with the growth at age, and 50 years old above crowd can be up to
since Xi'an Yang Sen introduces domestic market by third generation medicine for stomach dynamic-cisapride in 1993, medicine for stomach dynamic hospital market is fast-developing, has now become the important clinical application of domestic gastroenteropathy.
Cisapride, English name Cisapride.A gastrointestinal tract dynamia medicine, can strengthen and coordinate gastrointestinal motility, prevents food entrapment and anti-stream, and its mechanism of action is mainly the release that optionally promotes place's acetylcholine after myenteron plexus nervorum joint (in time and quantitatively), thereby strengthens the motion of gastrointestinal; But do not affect submucosal nervous plexus, therefore do not change the secretion of mucosa.
Dispersible tablet is a kind of novel form being born in recent years, and records in British Pharmacopoeia and Chinese Pharmacopoeia.Dispersible tablet is put into water disintegrate rapidly, disperses to form the suspension of equal Uniform, has taking convenience, the feature that bioavailability is high, and the preparation method of dispersible tablet, working condition and production technology are simple; Its instructions of taking is more flexible, can as ordinary tablet, swallow, and also can be distributed to wet suit and use.
The oral organism-absorbing availability of cisapride in human body is not high, and scope is generally 10-50% widely, has very large individual difference, comprises interindividual variation and individual interior difference.The dissolubility of cisapride depends on pH, and cisapride dissolubility in sour environment is very little, but solvable in gastrointestinal neutral environment.The permeability of cisapride is very low and be also to rely on pH environment, and in gastrointestinal tract, when environment pH is increased to neutrality from acidity, the permeability of cisapride reduces.Due to the biopharmaceutics character of cisapride complexity, the dosage form with less individual variation and raising bioavailability of research and development cisapride is challenging.
HP-β-CD (Η Ρ-β-CD) is amorphous, very easily water-soluble.It has a hydrophobic pocket to carry out enclose to medicine, aspect pharmaceutical preparation, has a wide range of applications.Be mainly manifested in the stability that it is widely used in the solubilising of insoluble drug and improves medicine, can also promote medicine release in vivo, increase and absorb, improve bioavailability, have certain effect covering aspect adverse drug abnormal smells from the patient also tool.
Summary of the invention
In order to increase the stability of medicine, further improve bioavailability, the reduction toxic and side effects of medicine and the individual difference of medication of cisapride, the invention provides a kind of dispersible tablet of cisapride, it contains cisapride, hydroxypropyl cyclodextrin and filler, disintegrating agent, binding agent, lubricant.Described filler is selected from one or more in amylum pregelatinisatum, dextrin, lactose, microcrystalline Cellulose and mannitol, and especially, described filler is amylum pregelatinisatum, microcrystalline Cellulose and manna.
The dissolubility of cisapride in water is lower, after HP-β-CD hydrophobic pocket enclose, has improved dissolubility and the stability of medicine, has promoted medicine release in vivo, increases and absorbs, and improves bioavailability.
The object of the present invention is to provide a kind of cisapride dispersible tablet that can improve bioavailability and preparation method thereof, and through repetition test, each component screening is arrived to weight ratio of the present invention, be surprised to find that the dispersible tablet steady quality obtaining, stripping is fast, in body, distribute rapidly, bioavailability is high.
On the one hand, the invention provides a kind of cisapride dispersible tablet, it is comprised of cisapride, HP-β-CD, filler, binding agent, lubricant and disintegrating agent, wherein said cisapride and HP-β-CD weight ratio are 1:1-4, and cisapride and HP-β-CD formation clathrate; Described filler is amylum pregelatinisatum, microcrystalline Cellulose and mannitol; Described binding agent is selected from 2% polyvinylpyrrolidone aqueous solution; Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci and Stepanol MG; Described disintegrating agent is selected from one or more in microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.
Some embodiments therein, dispersible tablet of the present invention, wherein said cisapride, filler, disintegrating agent, binding agent and lubricant according to the proportioning of weight portion are:
10 parts of cisaprides
Filler 100-300 part
Disintegrating agent 10-60 part
Binding agent 200-800 part
Lubricant 0.1-15 part.
In other embodiments, described dispersible tablet, wherein said cisapride, filler, disintegrating agent, binding agent and lubricant according to the proportioning of weight portion are:
10 parts of cisaprides
300 parts of filleies
30 parts of disintegrating agents
600 parts of binding agents
2 parts of lubricants.
Some embodiments therein, dispersible tablet of the present invention, wherein said lubricant is Pulvis Talci, described disintegrating agent is low-substituted hydroxypropyl cellulose.
Some embodiments therein, dispersible tablet of the present invention, the weight ratio of wherein said cisapride and hydroxypropyl cyclodextrin is 1:4.
On the other hand, the present invention relates to a kind of preparation method of cisapride dispersible tablet, it comprises following steps: first with hydroxypropyl-cyclodextrin and cisapride, form clathrate, wherein the weight ratio of cisapride and HP-β-CD is 1:1-4, again by gained clathrate, mannitol, starch and microcrystalline Cellulose, mix equal Uniform, add 2% polyvinylpyrrolidone aqueous solution and make soft material, with 18 mesh sieve granulations; Granule is at 40-70 ℃ of dry 5-6 hour; Granule adds low-substituted hydroxypropyl cellulose and Pulvis Talci to mix after drying, 20 mesh sieve granulate, last tabletting.
Some embodiments therein, preparation method of the present invention, the preparation process of wherein said clathrate is: get HP-β-CD and be dissolved in right amount in appropriate water and make saturated aqueous solution, cisapride is crossed 120 mesh sieves, be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of cisapride is slowly added in the saturated aqueous solution of HP-β-CD, all add continuation under rear room temperature and stir 2-4 hour, 40-50 ℃ of rotary evaporation removed most ethanol, pack tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, temperature is-50 ℃, when in freeze drying box, condenser temperature reaches-50 ℃, put into sample, evacuation, pressure is no more than 20 Ρ a, sublimation drying 24h, obtain clathrate.
The present invention has specifically described cisapride dispersible tablet and preparation technology thereof by embodiment 1-3.The present invention is not limited only to the embodiment of this part, and the change of the replacement of the adjuvant of any identical function, identical or close adjuvant weight is apparent for a person skilled in the art, and is included among the present invention.
The present invention is also by the bioavailability study of embodiment 4 cisapride dispersible tablets, utilize cisapride ordinary tablet of the prior art as reference reagent, using healthy Beagle dog as animal subject, and result of the test shows that the cisapride ordinary tablet bioavailability that cisapride dispersible tablet provided by the invention provides compared with prior art obviously improves.And the cisapride ordinary tablet that cisapride dispersible tablet provided by the invention provides compared with prior art is smaller at interindividual variation, and there is statistical significance (P<0.05).
In a word, cisapride dispersible tablet provided by the invention compared with prior art has advantages of as follows:
1) improved bioavailability.The cisapride ordinary tablet that cisapride dispersible tablet provided by the invention provides with prior art is compared, ln (AUC
0-∞), lnC
maxbetween medicament, difference has statistical significance (P<0.05), cisapride dispersible tablet of the present invention is 115.92 scholars 18.68% to the relative bioavailability of cisapride ordinary tablet, this illustrates that cisapride dispersible tablet of the present invention compares with cisapride ordinary tablet, and bioavailability obviously improves.
2) reduced the interindividual variation of medication.Cisapride is very easily water-soluble after HP-β-CD (Η Ρ-β-CD) enclose, and improve the stability of medicine, reduced the dependency of cisapride biological metabolism to pH, therefore reduced the interindividual variation of medication, and confirmed this conclusion by embodiment 4.
The specific embodiment
Below in conjunction with embodiment, further explain the present invention, but embodiment does not limit in any form to the present invention.
Embodiment 1
Cisapride 10g
HP-β-CD 40g
Mannitol 150g
Amylum pregelatinisatum 75g
Microcrystalline Cellulose 75g
Low-substituted hydroxypropyl cellulose 30g
2% polyvinylpyrrolidone aqueous solution 600g
Pulvis Talci 2g
Make 1000.
Preparation technology:
Getting recipe quantity HP-β-CD is dissolved in right amount in appropriate water and makes saturated aqueous solution, cisapride is crossed 120 mesh sieves, be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of cisapride is slowly added in the saturated aqueous solution of hydroxypropyl cyclodextrin, all add under rear room temperature and continue to stir 3 hours, 45 ℃ of rotary evaporations are removed most ethanol.Pack tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, and temperature is-50 ℃, when condenser temperature reaches-50 ℃ in freeze drying box, puts into sample, evacuation, and pressure is no more than 20Pa, and sublimation drying 24h, obtains clathrate.
Microcrystalline Cellulose is crossed 100 mesh sieves, and cisapride hydroxypropyl-cyclodextrin clathrate, mannitol, starch and microcrystalline Cellulose are mixed to equal Uniform, adds 2% polyvinylpyrrolidone aqueous solution and makes soft material, with 18 mesh sieve granulations;
Granule is dried 5 hours at 45 ℃; Granule adds low-substituted hydroxypropyl cellulose and Pulvis Talci to mix after drying, 20 mesh sieve granulate, last tabletting.
Embodiment 2
Cisapride 10g
HP-β-CD 10g
Mannitol 150g
Amylum pregelatinisatum 75g
Microcrystalline Cellulose 75g
Low-substituted hydroxypropyl cellulose 30g
2% polyvinylpyrrolidone aqueous solution 600g
Magnesium stearate 2g
Stepanol MG 3g
Make 1000.
Preparation technology:
Getting recipe quantity HP-β-CD is dissolved in right amount in appropriate water and makes saturated aqueous solution, cisapride is crossed 120 mesh sieves, be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of cisapride is slowly added in the saturated aqueous solution of HP-β-CD, all add under rear room temperature and continue to stir 4 hours, 45 ℃ of rotary evaporations are removed most ethanol.Pack tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, and temperature is-50 ℃, when condenser temperature reaches-50 ℃ in freeze drying box, puts into sample, evacuation, and pressure is no more than 20Pa, and sublimation drying 24h, obtains clathrate;
Microcrystalline Cellulose is crossed 100 mesh sieves, and cisapride hydroxypropyl-cyclodextrin clathrate, mannitol, starch and microcrystalline Cellulose are mixed to equal Uniform, adds 2% polyvinylpyrrolidone aqueous solution and makes soft material, with 18 mesh sieve granulations;
Granule is dried 4 hours at 70 ℃; Granule adds low-substituted hydroxypropyl cellulose and magnesium stearate, Stepanol MG to mix after drying, 20 mesh sieve granulate, last tabletting.
Embodiment 3
Cisapride 10g
HP-β-CD 40g
Mannitol 150g
Amylum pregelatinisatum 75g
Microcrystalline Cellulose 75g
Cross-linking sodium carboxymethyl cellulose 30g
2% polyvinylpyrrolidone aqueous solution 600g
Magnesium stearate 2g
Make 1000.
Preparation technology:
Getting recipe quantity HP-β-CD is dissolved in right amount in appropriate water and makes saturated aqueous solution, cisapride is crossed 120 mesh sieves, be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of cisapride is slowly added in the saturated aqueous solution of hydroxypropyl cyclodextrin, all add under rear room temperature and continue to stir 2 hours, 40 ℃ of rotary evaporations are removed most ethanol.Pack tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, and temperature is-50 ℃, when condenser temperature reaches-50 ℃ in freeze drying box, puts into sample, evacuation, and pressure is no more than 20Pa, and sublimation drying 24h, obtains clathrate;
Microcrystalline Cellulose is crossed 100 mesh sieves, and cisapride hydroxypropyl-beta-cyclodextrin inclusion, mannitol, starch and microcrystalline Cellulose are mixed to equal Uniform, adds 2% polyvinylpyrrolidone aqueous solution and makes soft material, with 18 mesh sieve granulations;
Granule is dried 6 hours at 40 ℃; Granule adds cross-linking sodium carboxymethyl cellulose and magnesium stearate to mix after drying, 20 mesh sieve granulate, last tabletting.
Biological test
Embodiment 4 cisapride dispersible tablet Study on relative bioavailability
1 materials and methods
1.1 medicines and reagent
Test preparation: cisapride dispersible tablet I, according to the embodiment of the present invention 1 preparation, specification 10mg/ sheet; Reference preparation: commercially available cisapride ordinary tablet II, specification 10mg/ sheet, Zhejiang Jingxin Pharmaceutical Co., Ltd.
1.2 instruments and high performance liquid chromatography (HPLC) condition
SPD-10Avp UV-detector, LC-10ADvp infusion pump, is Japanese Shimadzu company and produces; N2000 chromatographic data workbench software, Zhejiang University's intelligence reaches Information Technology Co. Ltd and produces; AT-130 post case, AUTOSCIENCE company produces; High speed micro centrifuge, Beijing Medical Centrifugal Machine Factory; BT25S electronic balance, Sartorius produces.Chromatographic condition: HigginsC
18post, 250mmX4.6mm, I.D.5 μ m, column temperature is; 35 ℃, mobile phase: organic facies (methanol: acetonitrile 400:275): (acetic acid: water=1:60): 70:30, flow velocity 1.0ml/min. detects wavelength 225nm, sensitivity 0.005AUFS to water.
1.3 sample process
The accurate serum 0.2ml that draws is placed in 2ml tool plug centrifuge tube, and precision adds nimesulide (interior mark) solution (22 μ g/ml) 20 μ l, vortex 1min.Precision adds acetonitrile 0.6ml, vortex 2min, and 16000r/min high speed centrifugation 10min, gets supernatant 20 μ 1 sample introductions.
The foundation of 1.4 serum standard curves
Get blank test tube and add respectively not commensurability standard solution, with nitrogen, dry up, then add the blank serum of 0.2ml, make its concentration be respectively 0.0388,0.097,0.194,0.485,0.97,1.94,3.8 μ g/ml, by " sample process " lower operation, record the peak area of cisapride and internal standard substance.With cisapride peak area (Ai) and the ratio (Ai/As) of internal standard substance peak area (As), concentration (X, μ g/ml) is carried out to linear regression.
1.5 precision and determination of recovery rates
Basic, normal, high by (0.097 with blank serum preparation, 0.485,1.94 μ g/ml) the cisapride standard series of 3 variable concentrations, each concentration is carried out 5 sample analyses, by " sample process " lower operation, calculate in a few days, the coefficient of variation in the daytime, extraction recovery, the preci-sion and accuracy of evaluation methodology.
1.6 animal subjects are selected
12 male dogs of healthy Beagle, body weight 10 ± 1kg; 6 monthly ages of age.Complete physical examination is all normal, comprising auscultation of lung, liver palpation of spleen, electrocardiogram, heart rate, blood pressure, hepatic and renal function, routine blood test, routine urinalysis etc.
1.7 EXPERIMENTAL DESIGN
12 healthy Beagle dogs are divided into 2 groups at random, adopt the random trial design of single dose binary cycle, and twice intertrial interval phase is 1 week; Each cycle dosage is 5mg; Start fasting 12h the first 1 day evening in test day, starts test the 2nd day 7: 30 morning.Single dose gives on an empty stomach cisapride and is subject to test preparation or reference preparation.Before administration and after administration 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24h venous blood collection 3ml.Blood sample is through centrifuging and taking serum, put in-20 ℃ of refrigerators, preserve to be measured.Take medicine behind pond and freely intake, unified feed after 4h.The tested dog adverse events of tight observation.Tested dog avoids aggravating activities after taking medicine.
1.8 date processing and statistical method
According to surveyed cisapride blood drug level-time data, adopt DAS2.0 pharmacokinetics program, calculate main pharmacokinetic parameter (Cmax, the Tmax measured value of cisapride test preparation and reference preparation, AUCmax adopts trapezoidal method to calculate), Tmax adopts rank test, Cmax and AUCmax go respectively to adopt t check after ln logarithm, and carry out (
) Confidence interval analysis, and evaluate the bioavailability of cisapride dispersible tablet I to cisapride ordinary tablet II.
2 results
2.1 pharmacokinetic parameter
According to surveyed cisapride serum-concentration-time data, utilize DAS2.0 pharmacokinetics program to calculate main pharmacokinetic parameters Tmax, Cmax, AUC
0-∞with relative bioavailability F(%) (in Table 1).
The pharmacokinetic parameter of table 1 cisapride dispersible tablet I and cisapride ordinary tablet II
| Parameter | Cisapride dispersible tablet I | Cisapride ordinary tablet |
| AUC 0-∞（μg/ml） | 116.56±6.98 | 95.33±10.23 |
| ln?AUC 0-∞ | 4.64±0.07 | 4.35±0.16 |
| Cmax（mg/ml） | 25.58±3.65 | 17.10±4.34 |
| lnCmax | 3.17±0.13 | 2.78±0.26 |
| Tmax（h） | 2.28±0.44 | 2.73±0.64 |
| F（%） | 115.92 scholars 18.68% | ? |
Tmax is through rank test difference not statistically significant (P>0.05); Cisapride dispersible tablet Tmax, Cmax, AUC
0-∞numerical value is through to number conversion, and the results of analysis of variance shows, cisapride dispersible tablet I compares with cisapride ordinary tablet II, ln (AUC
0-∞), lnC
maxbetween medicament, difference has statistical significance (P<0.05), cisapride dispersible tablet I is 115.92 scholars 18.68% to the relative bioavailability of cisapride ordinary tablet II, this explanation cisapride dispersible tablet I compares with cisapride ordinary tablet II, and bioavailability obviously improves.
Owing to having described the present invention according to above embodiment, any to be equal to replacement be all apparent for a person skilled in the art, and be included among the present invention.
Claims (7)
1. a cisapride dispersible tablet, it is comprised of cisapride, HP-β-CD, filler, binding agent, lubricant and disintegrating agent, wherein said cisapride and HP-β-CD weight ratio are 1:1-4, and cisapride and HP-β-CD formation clathrate; Described filler is amylum pregelatinisatum, microcrystalline Cellulose and mannitol; Described binding agent is selected from 2% polyvinylpyrrolidone aqueous solution; Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci and Stepanol MG; Described disintegrating agent is selected from one or more in microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.
2. dispersible tablet according to claim 1, wherein said cisapride, filler, disintegrating agent, binding agent and lubricant according to the proportioning of weight portion are:
10 parts of cisaprides
Filler 100-300 part
Disintegrating agent 10-60 part
Binding agent 200-800 part
Lubricant 0.1-15 part.
3. dispersible tablet according to claim 2, wherein said cisapride, filler, disintegrating agent, binding agent and lubricant according to the proportioning of weight portion are:
10 parts of cisaprides
300 parts of filleies
30 parts of disintegrating agents
600 parts of binding agents
2 parts of lubricants.
4. according to the arbitrary described dispersible tablet of claim 1-3, wherein said lubricant is Pulvis Talci, and described disintegrating agent is low-substituted hydroxypropyl cellulose.
5. dispersible tablet according to claim 1, the weight ratio of wherein said cisapride and hydroxypropyl cyclodextrin is 1:4.
6. the preparation method of a claim 1-5 any one cisapride dispersible tablet, it comprises following steps: first with hydroxypropyl-cyclodextrin and cisapride, form clathrate, wherein the weight ratio of cisapride and HP-β-CD is 1:1-4, again by gained clathrate, mannitol, starch and microcrystalline Cellulose, mix equal Uniform, add 2% polyvinylpyrrolidone aqueous solution and make soft material, with 18 mesh sieve granulations; Granule is at 40-70 ℃ of dry 5-6 hour; Granule adds low-substituted hydroxypropyl cellulose and Pulvis Talci to mix after drying, 20 mesh sieve granulate, last tabletting.
7. preparation method according to claim 6, the preparation process of wherein said clathrate is: get HP-β-CD and be dissolved in right amount in appropriate water and make saturated aqueous solution, cisapride is crossed 120 mesh sieves, be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of cisapride is slowly added in the saturated aqueous solution of HP-β-CD, all add continuation under rear room temperature and stir 2-4 hour, 40-50 ℃ of rotary evaporation removed most ethanol, pack tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, temperature is-50 ℃, when in freeze drying box, condenser temperature reaches-50 ℃, put into sample, evacuation, pressure is no more than 20 Ρ a, sublimation drying 24h, obtain clathrate.
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| CN107684548A (en) * | 2017-09-19 | 2018-02-13 | 鲁南制药集团股份有限公司 | A kind of mosapride citrate preparation and preparation method thereof |
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Application publication date: 20140730 |