CN101422441B - Nimesulide sustained-release tablet and preparation method thereof - Google Patents
Nimesulide sustained-release tablet and preparation method thereof Download PDFInfo
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- CN101422441B CN101422441B CN2008101810301A CN200810181030A CN101422441B CN 101422441 B CN101422441 B CN 101422441B CN 2008101810301 A CN2008101810301 A CN 2008101810301A CN 200810181030 A CN200810181030 A CN 200810181030A CN 101422441 B CN101422441 B CN 101422441B
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Abstract
The invention provides a Nimesulide sustained-release tablet and a preparation method thereof. The Nimesulide sustained-release tablet is prepared by Nimesulide, skeleton sustained-release material, a bond and a lubricant. The invention is characterized in that the skeleton sustained-release material is a mixture of compressible starch and hydroxypropyl methylcellulose with the weight ratio of 1 : 1; moreover, the weight ratio of the Nimesulide: the compressible starch : the hydroxypropyl methylcellulose is 2 : 1 : 1; wherein, the preferable viscidity range of the hydroxypropyl methylcellulose is 20 to 4000 mpa.s. The Nimesulide sustained-release tablet can be slowly released to maintain more stable blood medicine concentration and longer action time; the Nimesulide sustained-release tablet taken before sleeping can appear peaking effect in the morning, achieve the best clinic treatment target and have better medicament economy advantage.
Description
Technical field
The present invention relates to a kind of Nimesulide sustained-release tablet, adopt the combination of suitable pharmaceutic adjuvant and nimesulide, make the pharmaceutical preparation that release reaches slow release.
Background technology
Nimesulide, latin name: Nimesulide, anti-inflammatory and analgesic effect is extensive, can alleviate various pain such as toothache, menstrual pain, postoperative pain rapidly, and can effectively improve relevant symptoms such as osteoarthritis or rheumatoid arthritis, pelvic inflammatory disease, otitis, laryngitis, be the high selectivity of a new generation, potent, the non-steroidal anti-inflammatory and analgesic medicine of safety.2-3 hours half-life.The commercially available prod specification is every (or every) 100mg at present, every day 2 times, a 100mg.For this medicine, the patient needs sometimes that a kind of can to take number of times few, and the slow release formulation that can steadily discharge.Symptoms such as the deadlock in morning that causes for osteoarthritis or rheumatoid arthritis etc., pain, be taken at bed time and use this product conventional formulation, early morning, the drug level peak missed, can not bring into play best drug effect, thereby cause the waste of medical resource, also increased the weight of patient's financial burden simultaneously.
Disclose a kind of Nimesulide sustained release medicinal composition in the Chinese patent application 200510050842.9, wherein the skeleton slow-release material is to be made of methoxyl content 19%-24% hypromellose, methoxyl content 28%-30% hypromellose and ethyl cellulose.This Nimesulide sustained-release preparation is obtained slow releasing effect, but also needs further to improve on stability and slow release effect.
Summary of the invention
The invention provides Nimesulide sustained-release tablet of a kind of stability and slow release better effects and if preparation method thereof.For achieving the above object, technical solution of the present invention is as follows:
The invention provides a kind of Nimesulide sustained-release tablet, make by nimesulide, skeleton slow-release material, binding agent and lubricant, it is characterized in that: wherein said skeleton slow-release material is the mixture of amylum pregelatinisatum and hypromellose weight ratio 1:1, and by weight, nimesulide: amylum pregelatinisatum: hypromellose is 2:1:1.
Wherein, above-mentioned described Nimesulide sustained-release tablet, described hypromellose are preferably range of viscosities 20～4000 milli pascal second hypromelloses.
Further, preferred wherein said range of viscosities 20～4000 milli pascal second hypromelloses, preferably adaptive with high viscosity scope 4000～12000 milli pascal second hypromellose ECDCs than the mixture that forms by low viscosity scope 20～400 milli pascal second hypromelloses, wherein said proportioning is not particularly limited, and satisfies formed hypromellose range of viscosities and gets final product at 20～4000 milli pascal seconds.
Above-mentioned described Nimesulide sustained-release tablet, wherein said binding agent is not particularly limited, and can be binding agent conventional on the medicament, as preferably, can select ethyl cellulose or polyvinylpyrrolidone for use.
Above-mentioned described Nimesulide sustained-release tablet, wherein said lubricant is not particularly limited, and can be lubricant conventional on the medicament, as preferably, can select magnesium stearate for use.
Further, as the present invention's one preferred embodiment, wherein said Nimesulide sustained-release tablet, make 1000 by following supplementary material: nimesulide 200g, amylum pregelatinisatum 100g, hypromellose 100g, binding agent 120～160ml, magnesium stearate 3～7g, wherein said binding agent are the alcoholic solution of 1%～5% ethyl cellulose or the alcoholic solution of 3%～10% polyvinylpyrrolidone.
More preferably, Nimesulide sustained-release tablet of the present invention, make 1000 by following supplementary material: nimesulide 200g, amylum pregelatinisatum 100g, hypromellose 100g, binding agent 140ml, magnesium stearate 5g, wherein said binding agent are the alcoholic solution of 1%～5% ethyl cellulose or the alcoholic solution of 3%～10% polyvinylpyrrolidone.
As another purpose of the present invention, a kind of method for preparing described Nimesulide sustained-release tablet is provided, wherein, nimesulide 200g, amylum pregelatinisatum 100g, hypromellose 100g, 2.5% ethyl cellulose, 95% alcoholic solution 140ml, magnesium stearate 5g, make 1000 through following method: with nimesulide and hypromellose, the amylum pregelatinisatum mix homogeneously is made soft material with the powder of 2.5% ethyl cellulose, 95% alcoholic solution after with above-mentioned mix homogeneously, crosses 16 mesh sieves and granulates, in 55～60 ℃ of aeration-dryings, control water content＜3% behind 14 mesh sieve granulate, adds the magnesium stearate mixing, tabletting, the control tablet hardness is between 6.5～7.5kg.
Nimesulide sustained-release tablet of the present invention has good slow release effect and stability, obviously is better than the Nimesulide sustained-release preparation of prior art.The present invention adopts the hydrophilic gel skeleton as the slow release means, and slow-release material is the safe pharmaceutic adjuvant of using always, and method for making is simple and direct, and the technology favorable reproducibility can reach special slow release effect.The clinical purpose of slow releasing preparation is to be taken at bed time can occur the peak effect in the morning with this product, keeps clinical efficacy then one day, symptoms such as the deadlock in morning that effective relief from osteoarthritis or rheumatoid arthritis etc. cause, pain.Result from this test, the peak time of Nimesulide sustained-release tablet peak concentration is between 4～8h, take medicine later on for late 10, reach peak concentration second day early morning, the blood drug level of 12h is at 2.707 ± 1.080 μ g/ml, and ordinary preparation reaches the peak about 3 hours, early obey 100mg, the blood drug level of 12h is at 1.215 ± 1.088 μ g/ml, and obey 100mg evening, and the blood drug level of 12h (second day morning) is at 1.083 ± 0.876ng/ml.Therefore Nimesulide sustained-release tablet of the present invention more can solve symptoms such as deadlock in morning, pain effectively, reaches the optimal clinical therapeutic purposes, and the patient can abide by the doctor's advice minimizing and take number of times, and haemoconcentration is steady, and compliance is good.
Hypromellose has the effect that improves drug dissolution, this mainly is the result that HPMC has suspending and surface activity effect, has reduced the surface tension between this solution and solid drugs, has increased degree of wetting, thereby helping the stripping of medicine, is a kind of common drug adjuvant.The slow releasing tablet adjuvant removes the hydrophilic gel matrix material hypromellose, and still multiselect is used in combination with multiple filler, and as lactose and amylum pregelatinisatum, the present invention only uses amylum pregelatinisatum, and technological process is simple and direct, helps controlling cost.Medicament of the present invention does not have too much numerous and diverse supplementary product kind, and selected cost of supplementary product is relatively cheap, and manufacturing cost is cheap relatively.Technical solution of the present invention has realized combining of process optimization and cost optimization.Preparation technology is easy to be stable, and method for making of the present invention is convenient, and the control tablet hardness is between 6.5～7.5kg, and is very convenient in the production working control.Particularly, the present invention finds that surprisingly hypromellose and amylum pregelatinisatum are pressed the skeleton slow-release material of the mixture of special ratios formation as Nimesulide sustained-release tablet, obtain beyond thought preparation effect.
Medicament of the present invention can slowly discharge to be kept comparatively stable blood concentration and longer action time, be taken at bed time and occur the peak effect in the morning with this product, kept clinical efficacy then one day, reduce the patient and take number of times, because this product user is long-term chronic often, reduce and take the compliance that number of times can increase patient's medication, have pharmacoeconomics advantage preferably, the present invention program's effect shows that also this on the one hand.
24 healthy volunteers by the body weight pairing, to intersect single oral dose Nimesulide sustained-release tablet (getting the preparation finished product of the embodiment of the invention 1) and reference medicine nimesulide sheet (Guangdong JIANLIBAO pharmaceutcal corporation, Ltd) medicine cleaning phase at random be 3 days.Measure the concentration of nimesulide in the blood plasma with the HPLC method.The result shows that compare with the nimesulide sheet, the bioavailability of Nimesulide sustained-release tablet meets the slow releasing preparation relevant requirements in 80%～125% scope.
Release rate and absorbance with each corresponding on the absorption curve in the release curve of nimesulide in the Nimesulide sustained-release tablet and body time point return, linear regression equation.The result shows r〉r
0.001 (5)=0.935 (one-sided test) meets the Chinese Pharmacopoeia regulation, can determine that the inside and outside has dependency, can adopt the quality of release in vitro degree control this product.
Description of drawings
The release in vitro of the sample of Fig. 1 embodiment of the invention 1 preparation line chart of writing music
Wherein, abscissa unit is hour that vertical coordinate unit is a cumulative release percent.
The specific embodiment
Embodiment 1
1000 Nimesulide sustained-release tablets, every contains nimesulide 200mg.
Nimesulide 200g,
Hypromellose 60RT50 100g,
Amylum pregelatinisatum 100g,
Magnesium stearate 5g,
2.5% ethyl cellulose, 95% alcoholic solution 140ml.
Method for making: progressively increase method with mix homogeneously such as nimesulide and hypromellose, amylum pregelatinisatums by equivalent, make soft material with the powder of 2.5% ethyl cellulose, 95% alcoholic solution 140ml after with above-mentioned mix homogeneously, crossing 16 mesh sieves granulates, in 55～60 ℃ of aeration-dryings, control water content＜3% is behind 14 mesh sieve granulate, the magnesium stearate that adds recipe quantity, mixing, tabletting, the control tablet hardness is between 6.5～7.5kg.
Embodiment 2
1000 Nimesulide sustained-release tablets, every contains nimesulide 200mg.
Nimesulide 200g,
High viscosity hypromellose 90g,
Low viscosity hypromellose 10g,
Amylum pregelatinisatum 100g,
Magnesium stearate 5g,
2.5% ethyl cellulose, 95% alcoholic solution 140ml.
Method for making: high viscosity hypromellose and low viscosity hypromellose are mixedly configured into viscosity 4000 milli pascal second hypromelloses, progressively increase method with mix homogeneously such as nimesulide and hypromellose, amylum pregelatinisatums by equivalent, make soft material with the powder of 2.5% ethyl cellulose, 95% alcoholic solution 140ml after with above-mentioned mix homogeneously, crossing 16 mesh sieves granulates, in 55～60 ℃ of aeration-dryings, control water content＜3%, behind 14 mesh sieve granulate, the magnesium stearate that adds recipe quantity, mixing, tabletting, the control tablet hardness is between 6.5～7.5kg.
Embodiment 3
1000 Nimesulide sustained-release tablets, every contains nimesulide 200mg.
Nimesulide 200g,
High viscosity hypromellose 65g,
Low viscosity hypromellose 35g,
Amylum pregelatinisatum 100g,
Magnesium stearate 5g,
4.5% polyvinylpyrrolidone, 95% alcoholic solution 120ml.
Method for making wherein is mixedly configured into range of viscosities 2000 milli pascal second hypromelloses with high viscosity hypromellose and low viscosity hypromellose with embodiment 2.
Embodiment 4
1000 Nimesulide sustained-release tablets, every contains nimesulide 200mg.
Nimesulide 200g,
High viscosity hypromellose 15g,
Low viscosity hypromellose 85g,
Amylum pregelatinisatum 100g,
Magnesium stearate 5g,
4.5% polyvinylpyrrolidone, 95% alcoholic solution 120ml.
Method for making wherein is mixedly configured into range of viscosities 400 milli pascal second hypromelloses with high viscosity hypromellose and low viscosity hypromellose with embodiment 2.
Embodiment 5 presses the Chinese Pharmacopoeia method and measures the release in vitro degree:
Assay method: get this product, according to drug release determination method (first method under two appendix XD of Chinese Pharmacopoeia version in 2005 item), adopt dissolution determination first subtraction unit, (get Tris 12.1g with TRIS buffer, add water 900ml and make dissolving, regulate pH value to 9.0 ± 0.1 with dilute hydrochloric acid, thin up is to 1000ml, promptly) 1000ml is solvent, rotating speed is that per minute 100 changes, operation in accordance with the law, through 1,2,4,6,8,12,16,20, in the time of 24 hours, get solution 10ml, filter, get subsequent filtrate as need testing solution, and in time in process container, replenish above-mentioned buffer 10ml; Accurate in addition title is fixed an amount of through 105 ℃ of nimesulide reference substances that are dried to constant weight, adds above-mentioned buffer and makes dissolving in right amount and quantitatively be diluted to the solution that contains 0.2mg among every 1ml approximately, product solution in contrast.Precision measures reference substance solution and each 5ml of need testing solution puts respectively in the 50ml measuring bottle, be diluted to scale with the 0.05mol/L sodium hydroxide solution, shake up, according to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2005 item), measure trap at 393nm wavelength place, calculate each time point burst size by external standard method.
The prepared Nimesulide sustained-release tablet of the present invention is pressed the inspection of Chinese Pharmacopoeia method, discharges 10%-35%, discharges 50%-75%, discharged greater than 80%, and had good slow release effect in 12 hours in 6 hours in 2 hours.For example making sample with embodiment 1 is example, and measurement result sees Table 1.
Table 1 is the sample determination result who makes by embodiment 1.
Table 1 embodiment 1 Nimesulide sustained-release tablet drug release determination result
By last table data, the embodiment of the invention 1 Nimesulide sustained-release tablet, release in 2 hours is no less than 19.14%, is not more than 24.26%, 6 hour and discharges to be no less than 60.74%, is not more than 63.46%, 12 hour and discharges to be no less than 90.07%, is not more than 95.48%.Its release in vitro line of writing music is seen Fig. 1.
Embodiment 6: the contrast experiment
According to application number is that 200510050842.9 disclosed methods make sample (lot number: 060202), (make with sample of the present invention by embodiment 1 method, lot number: 051201) carried out the comparative study of related substance, content, release and stable aspect, experimental result shows, Nimesulide sustained-release tablet of the present invention and contrast Nimesulide sustained-release preparation related substance, content, release and stable aspect reach requirement, the every better effects if of preparation of the present invention improves Nimesulide sustained-release effect and tablet stability more.The results are shown in following table 2-4.
Table 2 related substance, content, release contrast and experiment
Result of the test shows that 060202 batch sample its related substances increases to some extent than 051201 batch, and drug release rate also than comparatively fast, can not reach best slow release effect.
Table 3 accelerated test (40 ℃, RH75%) result
Table 4 long-term stable experiment (25 ± 2 ℃, RH60 ± 10%) result
The present invention is described according to preferred embodiment.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (1)
1. Nimesulide sustained-release tablet, make 1000 by nimesulide 200g, amylum pregelatinisatum 100g, hypromellose 60RT50100g, 2.5% ethyl cellulose, 95% alcoholic solution 140ml, magnesium stearate 5g through following method: with nimesulide and hypromellose, amylum pregelatinisatum mix homogeneously, make soft material with the powder of 2.5% ethyl cellulose, 95% alcoholic solution after with above-mentioned mix homogeneously, crossing 16 mesh sieves granulates, in 55～60 ℃ of aeration-dryings, control water content＜3%, behind 14 mesh sieve granulate, add the magnesium stearate mixing, tabletting.
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| CN105434385B (en) * | 2014-08-29 | 2018-12-11 | 武汉光谷人福生物医药有限公司 | Mei Suoshuli sustained release tablets and preparation method thereof |
| CN105435239B (en) * | 2014-08-29 | 2019-04-26 | 武汉光谷人福生物医药有限公司 | Mei Suoshuli Film coated tablets and preparation method thereof |
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Address after: 570216 Haikou South Road, Hainan, No. 168 Haikou Free Trade Zone No. Patentee after: Kang pharmaceutical Limited by Share Ltd Address before: 570216 Haikou South Road, Hainan, No. 168 Haikou Free Trade Zone No. Patentee before: Hainan Honz Pharmaceutical Co., Ltd. |