CN102357091B - A kind of Chlocibutamine slow release medicinal composition - Google Patents
A kind of Chlocibutamine slow release medicinal composition Download PDFInfo
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- CN102357091B CN102357091B CN201110260696.8A CN201110260696A CN102357091B CN 102357091 B CN102357091 B CN 102357091B CN 201110260696 A CN201110260696 A CN 201110260696A CN 102357091 B CN102357091 B CN 102357091B
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- chlocibutamine
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- lactose
- acrylic resin
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Abstract
The present invention relates to a kind of Chlocibutamine slow release medicinal composition for the treatment of epileptics and preparation method thereof, it is characterized in that containing chlocibutamine and No. II, acrylic resin.The present composition can discharge chlocibutamine slowly, and the fluctuation of blood drug level peak valley is little, can avoid exceeding the toxic and side effects of therapeutic plasma concentrations scope.Can remain on again within Valid concentration, to maintain curative effect, reduce medicining times.
Description
Technical field
The present invention relates to a kind of Chlocibutamine slow release medicinal composition for the treatment of epileptics and preparation method thereof.
Background technology
Chlocibutamine is a kind of aromatic radical acrylamide derivative, be the simple name of 3,4-dichloro Chinnamyl-sec-butylamine, its chemical name is: (1S, 1R)-(E)-3-(3,4-Dichlorobenzene base)-N-(1-methyl-propyl)-2-acrylamide.This compound belongs to a kind of Cinnamamide Deriv A Tives.
Chlocibutamine has stronger antiepileptic action, and because the half-life is shorter, the chlocibutamine ordinary tablet having implemented clinical research is 100mg/ sheet, within 1st, takes three times.Ordinary preparation not only takes inconvenience, and blood drug level rises and falls very large, has peak valley phenomenon, falls after rise fast after causing blood drug level to raise.During blood drug level height, may have side effects even poisoning, when blood drug level is low, below treatment concentration, so that may can not manifest curative effect.
There is no open source literature and the marketed drugs of chlocibutamine Co ntrolled release preparation at present.
For reducing administration number of times, reducing the fluctuation of blood drug level, improving the compliance of patient, inventor developed Chlocibutamine slow release medicinal composition.
Summary of the invention
The object of the present invention is to provide a kind of sustained release pharmaceutical composition of chlocibutamine, to reduce blood drug level " peak valley " phenomenon.
The technical problem to be solved in the present invention is a kind of chlocibutamine slow releasing composition of development, and to reduce the fluctuation of blood drug level after patient consumes, after medication, sustained release drugs, to reach the object of long-acting, reduces times for spraying in a long time.
Experiment finds: in numerous matrix type slow-release materials, in matrix sustained release tablet, framework material is selected has significant impact with the rate of release of consumption on slow releasing preparation.The present inventor has screened suitable adjuvant by experiment, adopts preparation technique to reach the object of controlled release drug.
No. II, acrylic resin starts when PH is greater than 6 to dissolve, therefore can avoid the dissolving in gastric juice used as the skeleton of slow releasing tablet.Methylcellulose, carboxymethyl cellulose and carboxylic third methylcellulose belong to hydrophilic back bone material, i.e. solubilized in gastric juice.The present invention passes through the reasonable compatibility of No. II, acrylic resin and other adjuvants, reaches the object controlling chlocibutamine release.
Technical scheme of the present invention is:
A kind of chlocibutamine slow releasing composition, is characterized in that containing chlocibutamine and No. II, acrylic resin.
The preferred technical scheme of the present composition is, also containing one or both in methylcellulose of methylcellulose, carboxymethyl cellulose or carboxylic third.
The preferred technical scheme of the present composition is that chlocibutamine accounts for 20% ~ 60% of prescription total amount, and what No. II, acrylic resin accounted for prescription total amount accounts for 16% ~ 36% of prescription total amount.
The preferred technical scheme of the present composition is that chlocibutamine accounts for 30% ~ 60% of prescription total amount.
The preferred technical scheme of the present composition is, what one or both in methylcellulose of contained methylcellulose, carboxymethyl cellulose or carboxylic third accounted for prescription total amount accounts for prescription 10% ~ 20%.
The preferred technical scheme of the present composition is, in the compositions of unit dose, being good containing chlocibutamine 150mg ~ 300mg.Within 1st, take 1 ~ 2 time, once take 1 ~ 2.
The preparation method of the present composition is:
First step pre-treatment: pulverized by supplementary material, crosses 100 mesh sieves, for subsequent use.
The preparation of second step binding agent: take appropriate polyvidone (K30) and be dissolved in 50% ethanol, is mixed with 10% polyvidone (K30) 50% alcoholic solution, for subsequent use.
3rd step is granulated: take the chlocibutamine of recipe quantity, No. II, acrylic resin and other adjuvants, mix homogeneously.Add binding agent soft material, 18 mesh sieves are granulated.
4th step is dry: wet granular is dry in baking oven.
5th step granulate mixing: 16 mesh sieve granulate, magnesium stearate, micropowder silica gel, be always mixed even.
6th step tabletting or encapsulated.
Slow releasing preparation of the present invention adopts common preparation technique preparation.
Beneficial effect of the present invention: the present composition compares with ordinary preparation, the present composition can discharge slowly, thus enters slowly in body, and the fluctuation of blood drug level peak valley is little, can avoid exceeding the toxic and side effects of therapeutic plasma concentrations scope.Can remain on again within Valid concentration, to maintain curative effect.Poisonous side effect of medicine is lower, and therapeutical effect is lasting, and times for spraying reduces.
Embodiment 1 chlocibutamine 150g, acrylic resin II 180g, methylcellulose 100g, lactose 60g, polyvidone (K30) 6.0g, magnesium stearate 2.0g, micropowder silica gel 1.0g, make 1000.
Preparation process:
First step pre-treatment: pulverized by supplementary material, crosses 100 mesh sieves, for subsequent use.
The preparation of second step binding agent: the polyvidone (K30) taking recipe quantity is dissolved in 50% ethanol, is mixed with 10% polyvidone (K30) 50% alcoholic solution, for subsequent use.
3rd step is granulated: take the chlocibutamine of recipe quantity, No. II, acrylic resin, methylcellulose, lactose, mix homogeneously.Add binding agent soft material, 18 mesh sieves are granulated.
4th step is dry: wet granular is dry in baking oven.
5th step granulate mixing: 16 mesh sieve granulate, magnesium stearate, micropowder silica gel, be always mixed even.
6th step tabletting.
Embodiment 2 chlocibutamine 200g, acrylic resin II 55g, carboxymethyl cellulose 35g, lactose 40g, polyvidone (K30) 3.5g, magnesium stearate 0.8g, micropowder silica gel 0.7g, prepare 1000 by the preparation method of embodiment 1.
Embodiment 3 chlocibutamine 200g, acrylic resin II 150g, carboxylic third methylcellulose 75g, lactose 65g, polyvidone (K30) 6.0g, magnesium stearate 2.0g, micropowder silica gel 1.0g, make 1000 by the preparation method of embodiment 1.
Embodiment 4 chlocibutamine 150g, acrylic resin II 180g, carboxymethyl cellulose 50g, carboxylic third methylcellulose 50g, lactose 60g, polyvidone (K30) 6.0g, magnesium stearate 2.0g, micropowder silica gel 1.0g, make 1000 by the preparation method of embodiment 1.
Embodiment 5 chlocibutamine 200g, acrylic resin II 100g, methylcellulose 60g, lactose 100g, polyvidone (K30) 6.0g, makes 1000 by the preparation method of embodiment 1.
Embodiment 6 chlocibutamine 150g, acrylic resin II 160g, methylcellulose 50g, carboxylic third methylcellulose 30g, lactose 80g, polyvidone (K30) 6.0g, magnesium stearate 2.0g, micropowder silica gel 1.0g, make 1000 by the preparation method of embodiment 1.
Reference examples 1: the preparation of ordinary tablet
Prescription: chlocibutamine 200g, lactose 100g, microcrystalline Cellulose 100g, carboxymethyl starch sodium 16g, polyvidone (K30) 6.0g, magnesium stearate 2.0g, micropowder silica gel 1.0g, make 1000 by the method for preparing tablet thereof that pharmaceutical industry is common.
Vitro release test (according to 2010 editions Chinese Pharmacopoeias, two annex KIXD sustained-release and controlled releases and the operation of delayed release formulation guideline)
Under analogue body digested road condition, control temperature is 37 DEG C ± 0.5 DEG C, adds sodium lauryl sulphate 0.5%, and rotating speed is 100r/min, and medium is 900ml distilled water, in 0.5,1,2,3,4,5,6,7,8,12,16 hours sampling 5ml, supplement the synthermal distilled water of same volume simultaneously.The sample taken out microporous filter membrane (0.8 μm) filters, and dilutes one times, get 20 μ l with distilled water, injection liquid chromatography respectively, according to Syrups by HPLC (Chinese Pharmacopoeia 2010 editions two annex VD), record each chromatographic peak area, calculate stripping percentage rate by external standard method.
Chromatographic condition is as follows: be filler with octadecylsilane chemically bonded silica, (ammonium acetate 1.4g is got with acetate buffer solution, the 980ml that adds water makes dissolving, add glacial acetic acid and be about 2.6ml, regulate PH4.2 ± 0.1, moisturizing is to 1000ml)-methanol is mobile phase, flow velocity is 1ml per minute, determined wavelength 276nm.
Table 1 each embodiment release situation
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| 1 hour release percentage rate % | 25 | 23 | 27 | 30 | 27 | 24 |
| 3 hours release percentage rate % | 45 | 45 | 43 | 48 | 44 | 40 |
| 5 hours release percentage rate % | 60 | 58 | 55 | 60 | 55 | 54 |
| 8 hours release percentage rate % | 70 | 69 | 70 | 71 | 69 | 65 |
| 10 hours release percentage rate % | 79 | 80 | 78 | 80 | 80 | 76 |
| 12 hours release percentage rate % | 89 | 88 | 86 | 87 | 86 | 84 |
| 16 hours release percentage rate % | 99 | 97 | 96 | 97 | 96 | 94 |
According to table 1 data, can find out that chlocibutamine slow releasing composition tablets in vitro of the present invention is slow, the drug release profiles of 16 hours meets Higuchi equation, and the cumulative release amount of 16 hours can reach more than 85%.
Present composition pharmacokinetic
Plasma sample process:
Experiment: 6 healthy experimental dog, are divided into three groups at random.Overnight fasting, can't help water.Take reference examples 1 product 1 (dosage 200mg) for first group, take embodiment 2 product 1 (dosage 200mg) for second group, the third party takes embodiment 5 product 1 (dosage 200mg).
The sampling time of reference examples 1 is 5,10,30,60,90,120,180,300,480,720 minutes.The sampling time of embodiment 2 and embodiment 5 is respectively 0.5,1.0,2.0,3.0,4.0,5.0,6.0,7.0,8.0,10.0,12.0,14.0,16.0,24.0 hour.
The processing method of blood sample:
Adopt venous samples can 1.5ml at every turn, centrifugal, get blood plasma and be stored in-20 DEG C of refrigerators, for subsequent use as plasma sample.
Sample pretreatment
Accurately measure plasma sample 0.5ml, add mark storing solution (100 μ g/ml) 25 μ l in chlocibutamine reference substance, with extractant ethyl acetate 3ml, after concussion 2min, centrifugal (3000r/min) 5min, drawing upper organic phase moves in another 5ml test tube, and remaining aqueous phase adds the cruel re-extract of 3ml acetic acid second 1 time again, merges organic facies.Test tube is placed in 35 DEG C of water-baths, nitrogen slowly dries up.With the 0.5ml dissolved residue that flows, get 15 μ l sample introductions after mixing and measure, peak area inner mark method ration is analyzed.
Standard curve, the range of linearity, Monitoring lower-cut
Get 5ml centrifuge tube some, add the blank dog plasma of people respectively, each pipe adds the chlocibutamine reference substance storing solution of people's doubling dilution more successively, be made into final concentration and be respectively 0.01,0.05,0.1,0.25,0.5,1,2,4, the reference substance blood plasma of 8 μ g/ml series concentration, each Guan Jun adds mark storing solution (100 μ g/ml) 25 μ l in chlocibutamine reference substance, analyzes as stated above.With the ratio of chlocibutamine chromatographic peak and interior mark peak area for vertical coordinate, reference substance concentration is as abscissa preparation standard curve.
Chromatographic condition is as follows: be filler with octadecylsilane chemically bonded silica, (ammonium acetate 1.4g is got with acetate buffer solution, the 980ml that adds water makes dissolving, add glacial acetic acid and be about 2.6ml, regulate PH4.2 ± 0.1, moisturizing is to 1000ml)-methanol is mobile phase, flow velocity is 1ml per minute, determined wavelength 276nm.
Table 2 reference examples 1 compositions takes rear blood drug level situation
| Time, minute | 10 | 30 | 60 | 90 | 120 | 180 | 300 | 480 | 720 |
| Concentration, ug/ml | 1 | 2.2 | 3.4 | 4.3 | 5.6 | 7.5 | 4.8 | 2.6 | 2.0 |
As can be seen from Table 2, the tablet of reference examples 1 is after taking, and within 180 minutes, (3 hours) left and right blood drug level reaches maximum.
Table 3 embodiment 2, embodiment 5 compositions take rear blood drug level situation
| Embodiment 2 | Embodiment 5 | |
| 1.0 hours blood drug level, ug/ml | 0.31 | 0.26 |
| 2.0 hours blood drug level, ug/ml | 0.54 | 0.49 |
| 3.0 hours blood drug level, ug/ml | 0.74 | 0.72 |
| 4.0 hours blood drug level, ug/ml | 0.91 | 0.89 |
| 5.0 hours blood drug level, ug/ml | 1.23 | 1.2 |
| 6.0 hours blood drug level, ug/ml | 1.46 | 1.4 |
| 7.0 hours blood drug level, ug/ml | 1.69 | 1.66 |
| 8.0 hours blood drug level, ug/ml | 1.99 | 2.01 |
| 10.0 hours blood drug level, ug/ml | 1.91 | 1.93 |
| 12.0 hours blood drug level, ug/ml | 1.84 | 1.9 |
| 14.0 hours blood drug level, ug/ml | 1.54 | 1.61 |
| 16.0 hours blood drug level, ug/ml | 1.13 | 1.21 |
| 24.0 hours blood drug level, ug/ml | 0.29 | 0.32 |
As can be seen from Table 3, the compositions of embodiment 2, embodiment 5 is slow releasing in vivo after taking, the last taking 6 to 12 hours, remains on higher value.Compare with reference examples 1 ordinary tablet, pharmaceutical composition of the present invention has obvious slow release characteristic in vivo, and bulk concentration change is mild, does not have violent peak to occur.
Claims (6)
1.
a kind of chlocibutamine slow releasing tablet pharmaceutical composition, it is characterized in that, by chlocibutamine 150g, acrylic resin II 180g, methylcellulose 100g, lactose 60g, PVP K30 6.0g, magnesium stearate 2.0g, micropowder silica gel 1.0g makes 1000.
2.
a kind of chlocibutamine sustained-release tablet composition, it is characterized in that, by chlocibutamine 200g, acrylic resin II 55g, carboxymethyl cellulose 35g, lactose 40g, PVP K30 3.5g, magnesium stearate 0.8g, micropowder silica gel 0.7g makes 1000.
3.
a kind of chlocibutamine sustained-release tablet composition, it is characterized in that, by chlocibutamine 200g, acrylic resin II 150g, carboxylic third methylcellulose 75g, lactose 65g, PVP K30 6.0g, magnesium stearate 2.0g, micropowder silica gel 1.0g makes 1000.
4.
a kind of chlocibutamine sustained-release tablet composition, is characterized in that, by chlocibutamine 150g, and acrylic resin II 180g, carboxymethyl cellulose 50g, carboxylic third methylcellulose 50g, lactose 60g, PVP K30 6.0g, magnesium stearate 2.0g, micropowder silica gel 1.0g makes 1000.
5.
a kind of chlocibutamine sustained-release tablet composition, it is characterized in that, by chlocibutamine 150g, acrylic resin II 160g, methylcellulose 50g, carboxylic third methylcellulose 30g, lactose 80g, PVP K30 6.0g, magnesium stearate 2.0g, micropowder silica gel 1.0g makes 1000.
6.
described in claim 1,2,3,4 or 5, the preparation method of compositions, is characterized in that,
first step pre-treatment: pulverized by supplementary material, crosses 100 mesh sieves, for subsequent use;
the preparation of second step binding agent: take appropriate PVP K30 and be dissolved in 50% ~ 60% ethanol, be mixed with PVP K30 alcoholic solution, for subsequent use;
3rd step is granulated: take the chlocibutamine of recipe quantity, EudragitⅡ, lactose and other adjuvants, mix homogeneously; Add binding agent soft material, 18 mesh sieves are granulated;
4th step is dry: wet granular is dry in baking oven;
5th step granulate mixing: 16 mesh sieve granulate, magnesium stearate, micropowder silica gel, be always mixed even;
6th step tabletting.
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| CN1513439A (en) * | 2003-06-05 | 2004-07-21 | 南京长澳医药科技有限公司 | Slow release medicine of pseudo-ephedrine hydrochloride |
| CN1476831A (en) * | 2003-07-18 | 2004-02-25 | 袁雪莲 | Biphenyl double-ester solid slowly-releasing composite |
| CN101085072A (en) * | 2007-06-21 | 2007-12-12 | 复旦大学 | Sustained-release tablet containing folium crataegi total flavone |
| CN101229141A (en) * | 2008-02-29 | 2008-07-30 | 常州制药厂有限公司 | Aspirin sustained release tablet and preparing method thereof |
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