CN105434385A - Meisuoshuli sustained release tablet and preparation method thereof - Google Patents
Meisuoshuli sustained release tablet and preparation method thereof Download PDFInfo
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- CN105434385A CN105434385A CN201410438651.9A CN201410438651A CN105434385A CN 105434385 A CN105434385 A CN 105434385A CN 201410438651 A CN201410438651 A CN 201410438651A CN 105434385 A CN105434385 A CN 105434385A
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Abstract
The invention provides a Meisuoshuli sustained release tablet and a preparation method thereof. The Meisuoshuli sustained release tablet comprises Meisuoshuli and pharmaceutically acceptable auxiliary materials. The Meisuoshuli sustained release tablet can realize 24h sustained release, and also has the advantages of stable quality, high bioavailability and good medication compliance.
Description
Technical field
The invention belongs to pharmaceutical technology sectors, particularly, relate to Mei Suoshuli slow releasing tablet and preparation method thereof.
Background technology
Mei Suoshuli is the pioneering 1.1 class chemicalses in the whole world by Military Medical Science Institute and people's good fortune Pharmaceutical Group R & D Cooperation, Mei Suoshuli is a kind of NSAID (non-steroidal anti-inflammatory drug) (being called for short NSAID), main mechanism is for suppressing cyclooxygenase (COX-2) active, thus suppress arachidonic acid finally to generate prostacyclin (PG II), prostaglandin (PGE1, and thromboxane A2 (TXA2) PGE2), namely reduce the synthesis of the inflammatory mediator such as prostaglandin, thromboxane, thus there is the effects such as well antipyretic, analgesia, antiinflammatory, detumescence.
Mei Suoshuli is insoluble drug, can be prepared into conventional tablet, but due to taken three times a day not too convenient, and easily there is situation about missing, have impact on overall curative effect.Conventional tablet oral administration biaavailability is slightly low simultaneously need repeatedly take medicine, and too increases the body burden of patient.
At present, the correlational study about Mei Suoshuli preparation still needs deeply.
Summary of the invention
The present invention is intended to solve one of technical problem in correlation technique at least to a certain extent.For this reason, one object of the present invention is to propose a kind of steady quality, bioavailability is high, compliance is good long-acting Mei Suoshuli slow releasing tablet.
The present invention completes based on the following discovery of inventor:
Mei Suoshuli is insoluble drug, and because its dissolubility in water is little, medicine enters in body and is difficult to be absorbed completely by human body, and common oral preparation needs the curative effect repeatedly taking medicine to reach expection.And sustained-release preparation has the advantage reducing medication accumulated dose and times for spraying, the compliance that reduction toxic and side effects, raising patient take medicine, thus, slow releasing tablet is for raising patient compliance, reduce poisonous side effect of medicine, improve bioavailability in body, there is very important clinical meaning.
Based on above-mentioned discovery, the present inventor utilizes the technology such as superfine grinding, solid dispersion, cyclodextrin inclusion compound, adopt the form of sustained-release matrix tablets, achieve the preparation of insoluble drug Mei Suoshuli slow releasing tablet, and improve the dissolubility of Mei Suoshuli in water, improve medicine absorption in vivo, improve oral administration biaavailability, select for patient provides a new clinical application.
In one aspect of the invention, the invention provides a kind of Mei Suoshuli slow releasing tablet.According to embodiments of the invention, this Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli; And pharmaceutically acceptable adjuvant.Inventor finds, Mei Suoshuli slow releasing tablet of the present invention, can realize 24 hours slow release, and steady quality, bioavailability is high, compliance good.
According to embodiments of the invention, described pharmaceutically acceptable adjuvant is be selected from least one in skeleton slow-release material, filler, lubricant, solubilizing agent and disintegrating agent.
According to embodiments of the invention, described solubilizing agent is at least one in hydroxypropylβ-cyclodextrin or PLURONICS F87, preferred hydroxypropylβ-cyclodextrin.Thereby, it is possible to effectively improve the result of extraction of Mei Suoshuli, and then improve the bioavailability of Mei Suoshuli.
According to embodiments of the invention, described filler is be selected from least one in lactose, mannitol, starch, microcrystalline Cellulose, preferably microcrystalline cellulose.Thereby, it is possible to improve the compressibility of medicine, reduce the dose deviations of main component, promote disintegrate and stripping.Especially, inventor finds, when selecting microcrystalline Cellulose to be filler, DO compressibility is not good, and disintegrate meets the requirements, and dissolution is high, and can improve the hardness of slow releasing tablet and unilateral fineness.
According to embodiments of the invention, described skeleton slow-release material is for being selected from hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K100M, at least one in hydroxypropyl methylcellulose E50, hydroxypropyl methylcellulose E4M, preferred HPMC K4M.Thereby, it is possible to extend the half-life of Mei Suoshuli slow releasing tablet, drug release is steady in vivo, effectively realizes 24 hours Stable Releases.
According to embodiments of the invention, described disintegrating agent is be selected from least one in carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, preferred carboxymethyl starch sodium.Thus, be conducive to the stripping improving Mei Suoshuli, improve the bioavailability of Mei Suoshuli.
According to embodiments of the invention, described lubricant is be selected from least one in magnesium stearate, micropowder silica gel, fumaric acid sodium, sodium lauryl sulphate, preferred magnesium stearate.Thus, the unilateral fineness of Mei Suoshuli slow releasing tablet is good, and outward appearance meets the requirements.
According to embodiments of the invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: described Mei Suoshuli 25 ~ 125 weight portion; Described skeleton slow-release material 80 ~ 127.5 weight portion; Described filler 5 ~ 75 weight portion; Described lubricant 1.5 ~ 2.5 weight portion; Described solubilizing agent 15 ~ 20 weight portion; And described disintegrating agent 3 ~ 9 weight portion.Thus, the steady quality of Mei Suoshuli slow releasing tablet, result of extraction is better, and steadily, the bioavailability of Mei Suoshuli is higher in drug disposition release.And inventor finds through screening, the Mei Suoshuli slow releasing tablet with this ratio shows the pharmaceutical properties being better than other ratios.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose K4M100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 20 weight portion, microcrystalline Cellulose 38.5 weight portion, hydroxypropyl methylcellulose K4M80 weight portion, carboxymethyl starch sodium 9 weight portion and magnesium stearate 1.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 17.5 weight portion, microcrystalline Cellulose 5 weight portion, hydroxypropyl methylcellulose K4M120 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose K15M100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 18 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose K100M100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose E50100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 25 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 75 weight portion, hydroxypropyl methylcellulose K4M127.5 weight portion, carboxymethyl starch sodium 5 weight portion and magnesium stearate 2.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 50 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 65 weight portion, hydroxypropyl methylcellulose K4M110 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 75 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 50 weight portion, hydroxypropyl methylcellulose K4M100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 125 weight portion, hydroxypropyl beta cyclodextrin 20 weight portion, microcrystalline Cellulose 7.5 weight portion, hydroxypropyl methylcellulose K4M90 weight portion, carboxymethyl starch sodium 5 weight portion and magnesium stearate 2.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 16 weight portion, lactose 25 weight portion, hydroxypropyl methylcellulose K15M100 weight portion, polyvinylpolypyrrolidone 7.5 weight portion and micropowder silica gel 2.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, mannitol 25 weight portion, hydroxypropyl methylcellulose K100M100 weight portion, low-substituted hydroxypropyl cellulose 7.5 weight portion and sodium lauryl sulphate 1.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, starch 25 weight portion, hydroxypropyl methylcellulose E50100 weight portion, cross-linking sodium carboxymethyl cellulose 7.5 weight portion and fumaric acid sodium 2.5 weight portion.
According to a concrete example of the present invention, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises: Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose E4M100 weight portion, carboxymethyl starch sodium 3 weight portion and magnesium stearate 2 weight portion.
In another aspect of this invention, the invention provides a kind of method preparing foregoing Mei Suoshuli slow releasing tablet.According to embodiments of the invention, the method comprises: by Mei Suoshuli and the mixing of pharmaceutically acceptable adjuvant, and obtained mixture is carried out tabletting, to obtain Mei Suoshuli slow releasing tablet.Utilize the method for the present invention, fast and effeciently can prepare foregoing Mei Suoshuli slow releasing tablet, and it is fast simple, convenient, the suitability for industrialized production be applicable to, simultaneously, the Mei Suoshuli slow releasing tablet steady quality prepared, bioavailability is high, compliance good, and effective acting time is longer.
According to embodiments of the invention, described by Mei Suoshuli and the mixing of pharmaceutically acceptable adjuvant, and obtained mixture is carried out tabletting comprise further:
(1) described Mei Suoshuli is dissolved in acetone, and hydroxypropyl beta cyclodextrin aqueous solution is mixed mutually with Mei Suoshuli acetone soln, volatilize solvent, to obtain crystalline powder.
According to embodiments of the invention, can Mei Suoshuli be dissolved in acetone, obtain Mei Suoshuli acetone soln, hydroxypropyl beta cyclodextrin is dissolved in purified water and obtains hydroxypropyl beta cyclodextrin aqueous solution, then, stir while Mei Suoshuli acetone soln is slowly added in hydroxypropyl beta cyclodextrin aqueous solution, after obtained solution is volatilized solvent, obtain crystalline powder.
(2) described crystalline powder is carried out superfine grinding, and mix with skeleton slow-release material, filler.
According to embodiments of the invention, the mode of crystalline powder being carried out to superfine grinding is not particularly limited, and those skilled in the art can select flexibly according to practical situation.In some embodiments of the invention, can be pulverized by ball mill or comminution by gas stream carries out superfine grinding to crystalline powder.
(3) mixture obtained in step (2) is granulated, and obtained granule is carried out drying;
According to embodiments of the invention; can be granulated by following step: the mixture obtained in step (2) is added in wet granulator; mix 15 minutes; pure water granulation 90s is carried out under mixing speed 3r/s, cutting speed 10r/s condition, and by described obtained particle drying 90 minutes at 60 DEG C.
(4) dried granule is mixed with lubricant and disintegrating agent, and obtained mixture is carried out tabletting.
According to embodiments of the invention, the method preparing Mei Suoshuli slow releasing tablet may further include: the label film coating that (5) obtain tabletting.
According to embodiments of the invention, based on the gross mass of described label, according to mass percent, coating weight gain is 2%-3%.
According to embodiments of the invention, the label film coating described in step (5), coating powder material selection white stomach dissolved film coating pre-mix dose Opadry 81W68907.The compound method of coating solution: coating powder purified water disperseed, is formulated into 15% solid content, stirs 60 minutes.The technological parameter of coating is: atomizing pressure 0.2MP (MPa), thimble pressure 0.2MP, coating pan rotating speed 15r/s, feed liquor speed 3r/min, inlet temperature 75 DEG C, air intake frequency 1100Hz, temperature of charge 35 ~ 45 DEG C, and coating weight gain 2% ~ 3% terminates.
According to embodiments of the invention, the hardness of described Mei Suoshuli slow releasing tablet is 5-8N (newton).Thus, the dissolution of Mei Suoshuli slow releasing tablet is better.
According to embodiments of the invention, beneficial effect of the present invention is:
1, according to embodiments of the invention, the technology based on solid dispersion improves the dissolubility of Mei Suoshuli in water, utilizes the mechanism of skeleton slow release to prepare Mei Suoshuli slow releasing tablet simultaneously.The Mei Suoshuli slow releasing tablet prepared with the present invention and the ordinary preparation result in animal body in pharmacokinetic shows, its prolonged half-life in vivo of Mei Suoshuli slow releasing tablet of the present invention 2 ~ 5 times, its in vivo release curve display drug release is steady, can realize the Stable Release of 24 hours.
2, according to embodiments of the invention, combined by solid dispersion technology with skeleton slow release method, solve the low problem of Mei Suoshuli oral administration biaavailability on the one hand, making slow releasing tablet decreases medicining times on the one hand, improves the compliance of patient medication.The present invention is different from and Mei Suoshuli raw material is directly made slow releasing tablet, but the dissolubility of Mei Suoshuli is first improved by solid dispersions technique, be made into slow releasing tablet again, not only reach the object of slow releasing, also improve medicine bioavailability in vivo.
Accompanying drawing explanation
Fig. 1 shows according to one embodiment of present invention and comparative example 1, prepares the dissolution determination comparing result figure dissolution of gained Mei Suoshuli slow releasing tablet;
Fig. 2 shows according to one embodiment of present invention and comparative example 2, prepares the dissolution determination comparing result figure of gained Mei Suoshuli slow releasing tablet;
Fig. 3 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli slow releasing tablet;
Fig. 4 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli slow releasing tablet;
Fig. 5 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli slow releasing tablet;
Fig. 6 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli slow releasing tablet;
Fig. 7 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli slow releasing tablet;
Fig. 8 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli slow releasing tablet;
Fig. 9 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli slow releasing tablet;
Figure 10 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli slow releasing tablet; And
Figure 11 shows according to one embodiment of present invention, the pharmacokinetic studies result of Mei Suoshuli slow releasing tablet and ordinary tablet.
Detailed description of the invention
Embodiments of the invention are described below in detail.Embodiment described below is exemplary, only for explaining the present invention, and can not be interpreted as limitation of the present invention.Mei Suoshuli crude drug in embodiment is the original medicine of 1.1 class chemistry, is the self-control of people's good fortune Pharmaceutical Group.Unreceipted concrete technology or condition in embodiment, according to the technology described by the document in this area or condition or carry out according to product description.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Following examples feed intake according to 1000 tablet recipe amounts, and specification is 100mg.Following examples are just described, and do not limit invention scope.
Embodiment 1:
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Microcrystalline Cellulose | 25g |
| Hydroxypropyl methylcellulose K4M | 100g |
| Carboxymethyl starch sodium | 7.5g |
| Magnesium stearate | 2.5g |
The present invention adopts the technology of solid dispersion, by wet granulation technology, then the label film coating that will press, prepare Mei Suoshuli slow releasing tablet, preparation method is as follows:
1. above-mentioned recipe quantity Mei Suoshuli is dissolved in 50ml acetone and obtains A liquid, the hydroxypropyl beta cyclodextrin of recipe quantity is dissolved in 40ml purified water and obtains B liquid;
2. stir while A liquid is slowly added in B liquid, solution is volatilized rear collection powder;
3. mix homogeneously after powder superfine grinding with the microcrystalline Cellulose of recipe quantity and hydroxypropyl methylcellulose K4M;
4. the mixed-powder in is 3. added in wet granulator, mix 15 minutes, mixed powder is carried out pure water granulation 90s under mixing speed 3r/s, cutting speed 10r/s condition, obtained granule at 60 DEG C dry 90 minutes;
5. dried granule adds magnesium stearate and the carboxymethyl starch sodium of recipe quantity, tabletting after mix homogeneously, and sheet Hardness Control is at 5 ~ 8N;
6. the label film coating will pressed.The compound method of coating solution: coating powder purified water disperseed, is formulated into 15% solid content, stirs 60 minutes.The technological parameter of coating is: atomizing pressure 0.2MP (MPa), thimble pressure 0.2MP, coating pan rotating speed 15r/s, feed liquor speed 3r/min, inlet temperature 75 DEG C, air intake frequency 1100Hz, temperature of charge 35 ~ 45 DEG C, and coating weight gain 2% ~ 3% terminates.
Dissolution experiments:
With Chinese Pharmacopoeia version in 2010 two annex XC second subtraction units, measure the dissolution of the Mei Suoshuli slow releasing tablet prepared according to Chinese Pharmacopoeia version in 2010 two annex XD first methods.With the buffer salt 1000ml of pH6.8 for solvent, rotating speed 50 turns, sampling in 1,4,8,12,16,20,24 hour, measures the dissolution of Mei Suoshuli slow releasing tablet, the results are shown in Figure 1.
Comparative example 1
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Microcrystalline Cellulose | 25g |
| Hydroxypropyl methylcellulose K4M | 100g |
| Carboxymethyl starch sodium | 7.5g |
| Magnesium stearate | 2.5g |
Comparative example does not adopt the technology of solid dispersion, and it is by wet granulation technology, then the label film coating that will press, and prepare Mei Suoshuli slow releasing tablet, preparation method is as follows:
1. mix homogeneously after the superfine grinding of above-mentioned recipe quantity Mei Suoshuli raw material with microcrystalline Cellulose and hydroxypropyl methylcellulose K4M;
2. the powder of above-mentioned mix homogeneously is added in wet granulator, mix 15 minutes, then, under mixing speed 3r/s, cutting speed 10r/s, pure water granulation 90s, obtained granule at 60 DEG C dry 90 minutes;
3. dried granule adds carboxymethyl starch sodium and the magnesium stearate of recipe quantity, tabletting after mix homogeneously, and sheet Hardness Control is at 5 ~ 8N;
4. the label film coating will pressed.The compound method of coating solution: coating powder purified water disperseed, is formulated into 15% solid content, stirs 60 minutes.The technological parameter of coating is: atomizing pressure 0.2MP (MPa), thimble pressure 0.2MP, coating pan rotating speed 15r/s, feed liquor speed 3r/min, inlet temperature 75 DEG C, air intake frequency 1100Hz, temperature of charge 35 ~ 45 DEG C, and coating weight gain 2% ~ 3% terminates.
Dissolution experiments: assay method is with embodiment 1, and measurement result is shown in Fig. 1.
The embodiment of the present invention 1 have employed the technology of solid dispersion to prepare Mei Suoshuli slow releasing tablet, and comparative example 1 does not adopt the technology of solid dispersion to prepare Mei Suoshuli slow releasing tablet.By embodiments of the invention 1 and comparative example 1 gained Mei Suoshuli slow releasing tablet respectively, the dissolution determination result of the two is contrasted, result shows, by preparing the technology of solid dispersion, the overall dissolution of Mei Suoshuli in slow releasing tablet can be significantly improved, therefore preferably adopt the technical method of solid dispersion as the preparation method of Mei Suoshuli slow releasing tablet.
Comparative example 2
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| PLURONICS F87 | 15g |
| Microcrystalline Cellulose | 25g |
| Hydroxypropyl methylcellulose K4M | 100g |
| Carboxymethyl starch sodium | 7.5g |
| Magnesium stearate | 2.5g |
Compared with embodiment 1 of the present invention, in the prescription of comparative example 2, do not adopt solubilizing agent hydroxypropyl beta cyclodextrin, but adopt PLURONICS F87.
Comparative example 2 also adopts the technology of solid dispersion, by wet granulation technology, then the label film coating that will press, prepare Mei Suoshuli slow releasing tablet, preparation method is with embodiment 1.
Dissolution experiments: assay method is with embodiment 1, and measurement result is shown in Fig. 2.
By embodiments of the invention 1 and comparative example 2 gained Mei Suoshuli slow releasing tablet respectively, the dissolution determination result of the two is contrasted, result shows, by adopting solubilizing agent hydroxypropyl beta cyclodextrin, can significantly improve the dissolution of Mei Suoshuli in slow releasing tablet.Whether take hydroxypropyl beta cyclodextrin enclose, will directly have influence on the final concentration of drug release, therefore in prescription, take hydroxypropyl beta cyclodextrin enclose effectively can improve the dissolution of Mei Suoshuli.
Embodiment 2
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 20g |
| Microcrystalline Cellulose | 38.5g |
| Hydroxypropyl methylcellulose K4M | 80g |
| Carboxymethyl starch sodium | 9g |
| Magnesium stearate | 1.5g |
Preparation method is with embodiment 1.
Dissolution experiments: assay method, with embodiment 1, measures dissolution results and sees Fig. 3.
Embodiment 3
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 17.5g |
| Microcrystalline Cellulose | 5g |
| Hydroxypropyl methylcellulose K4M | 120g |
| Carboxymethyl starch sodium | 7.5g |
| Magnesium stearate | 2g |
Preparation method is with embodiment 1.
Dissolution experiments: assay method is with embodiment 1, and measurement result is shown in Fig. 4.
Embodiment 4
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Microcrystalline Cellulose | 25g |
| Hydroxypropyl methylcellulose K15M | 100g |
| Carboxymethyl starch sodium | 7.5g |
| Magnesium stearate | 2.5g |
Preparation method is with embodiment 1.
Dissolution experiments: assay method is with embodiment 1, and measurement result is shown in Fig. 5.
Embodiment 5
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 18g |
| Microcrystalline Cellulose | 25g |
| Hydroxypropyl methylcellulose K100M | 100g |
| Carboxymethyl starch sodium | 7.5g |
| Magnesium stearate | 2g |
Preparation method is with embodiment 1.
Dissolution experiments: assay method is with embodiment 1, and measurement result is shown in Fig. 6.
Embodiment 6
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Microcrystalline Cellulose | 25g |
| Hydroxypropyl methylcellulose E50 | 100g |
| Carboxymethyl starch sodium | 7.5g |
| Magnesium stearate | 2.5g |
Preparation method is with embodiment 1.
Dissolution experiments: assay method is with embodiment 1, and measurement result is shown in Fig. 7.
Embodiment 7
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 25g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Microcrystalline Cellulose | 75g |
| Hydroxypropyl methylcellulose K4M | 127.5g |
| Carboxymethyl starch sodium | 5g |
| Magnesium stearate | 2.5g |
Preparation method is with embodiment 1.
Dissolution experiments: assay method is with embodiment 1, and measurement result is shown in Fig. 8.
Embodiment 8
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 50g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Microcrystalline Cellulose | 65g |
| Hydroxypropyl methylcellulose K4M | 110g |
| Carboxymethyl starch sodium | 7.5g |
| Magnesium stearate | 2.5g |
Preparation method is with embodiment 1.
Dissolution experiments: assay method is with embodiment 1, and measurement result is shown in Fig. 9.
Embodiment 9
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 75g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Microcrystalline Cellulose | 50g |
| Hydroxypropyl methylcellulose K4M | 100g |
| Carboxymethyl starch sodium | 7.5g |
| Magnesium stearate | 2.5g |
Preparation method is with embodiment 1.
Embodiment 10
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 125g |
| Hydroxypropyl beta cyclodextrin | 20g |
| Microcrystalline Cellulose | 7.5g |
| Hydroxypropyl methylcellulose K4M | 90g |
| Carboxymethyl starch sodium | 5g |
| Magnesium stearate | 2.5g |
Preparation method is with embodiment 1.
Embodiment 11:
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 16g |
| Lactose | 25g |
| Hydroxypropyl methylcellulose K15M | 100g |
| Polyvinylpolypyrrolidone | 7.5g |
| Micropowder silica gel | 2.5g |
Preparation method is with embodiment 1.
Embodiment 12:
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Mannitol | 25g |
| Hydroxypropyl methylcellulose K100M | 100g |
| Low-substituted hydroxypropyl cellulose | 7.5g |
| Sodium lauryl sulphate | 1.5g |
Preparation method is with embodiment 1.
Embodiment 13:
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Starch | 25g |
| Hydroxypropyl methylcellulose E50 | 100g |
| Cross-linking sodium carboxymethyl cellulose | 7.5g |
| Fumaric acid sodium | 2.5g |
Preparation method is with embodiment 1.
Embodiment 14:
Prescription:
| Prescription | Recipe quantity |
| Mei Suoshuli | 100g |
| Hydroxypropyl beta cyclodextrin | 15g |
| Microcrystalline Cellulose | 25g |
| Hydroxypropyl methylcellulose E4M | 100g |
| Carboxymethyl starch sodium | 3g |
| Magnesium stearate | 2g |
Preparation method is with embodiment 1.
Dissolution experiments: assay method is with embodiment 1, and measurement result is shown in Figure 10.
Can be found out by the result of Fig. 1-Figure 10, the different impact on drug release of the selection of skeleton slow-release material is very large, and by the comparison of dissolved corrosion, preferred hydroxypropyl methylcellulose K4M is skeleton slow-release material.Dissolution degree
Embodiment 15: the medicine stability test of Mei Suoshuli slow releasing tablet of the present invention
1, influence factor's experiment in 10 days: the Mei Suoshuli slow releasing tablet of the 100mg specification prepared in embodiment 1 is uncovered in culture dish, respectively at high temperature (60 DEG C), high humidity (RH92.5%, 25 DEG C), place 10 days under high light (4500lx ± 500lx) condition, in sampling in the 0th, 5,10 day, observe the projects such as formulation aesthetics, content, dissolution, related substance, weight-loss ratio, and compare, shown in 10 days following Table As of influence factor's experimental result with the inspection data investigating front sample.
Wherein, impurity 1 is compound shown in the formula I disclosed in Chinese invention patent application CN103553984A, and its structural formula is as follows:
Formula I
Table A
10 days influence factor's result of the tests of upper table 1 show, Mei Suoshuli slow releasing tablet is stable under high temperature and illumination condition, and under super-humid conditions, slow releasing tablet has the phenomenon of the moisture absorption, dissolution decreases, and therefore should consider moistureproof problem when finished product packing, stores under hermetically drying condition.
2, stability test: accelerate test in 6 months:
Inventor has carried out the research of packaging material to Mei Suoshuli slow releasing tablet, selects packaging material to be PVC bubble-cap+two-sided composite aluminium film bag.By packaged Mei Suoshuli slow releasing tablet temperature be 40 DEG C ± 2 DEG C, relative humidity be 75% ± 5% experimental condition under place 6 months, carry out the investigation accelerating 6 months, respectively at the 1st, 2,3, sampling in June, carried out the detection of each inspection target of stability test, detailed results sees the following form B.
Table B:
Shown by the acceleration stability experiment data of 6 months of table B, Mei Suoshuli slow releasing tablet of the present invention is not significant change in leading indicator, shows that Mei Suoshuli sustained release tablet products quality of the present invention is reliable and stable.PVC bubble-cap adds the packaged form of two-sided composite aluminium film bag, can meet product demand.
Embodiment 16: the prescription screening of Mei Suoshuli slow releasing tablet of the present invention is studied
Carry out prescription screening research for Mei Suoshuli 100mg sheet, Mei Suoshuli sustained-release tablet recipe screening table, in Table C, the selection result is in Table D.
Table C:
| Principal agent and adjuvant | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 |
| Mei Suoshuli | 100 | 100 | 100 | 100 | 100 | 100 |
| Hydroxypropylβ-cyclodextrin | / | / | 15 | 25 | 20 | 15 |
| Microcrystalline Cellulose | 47.5 | 65 | 27.5 | 55 | 17.5 | 25 |
| Hydroxypropyl methylcellulose | 100 | 80 | 100 | 60 | 100 | 100 |
| Carboxymethyl starch sodium | / | 2.5 | 5 | 7.5 | 10 | 7.5 |
| Magnesium stearate | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
Table D
| Project | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 |
| Dissolution | 63％ | 66％ | 85％ | 81％ | 87％ | 90％ |
| Peak time | 7 hours | 6.3 hour | 10 hours | 4.7 hour | 7.5 hour | 8.1 hour |
| Rate of release | Moderate | Moderate | Slower | Comparatively fast | Moderate | Moderate |
Prescription screening with Dissolution of Sustained Release Tablet release profiles for according to passing judgment on, can draw from the dissolution of above 6 prescriptions, peak time, rate of release measurement result, whether take hydroxypropyl beta cyclodextrin enclose, to directly have influence on the final concentration of drug release, therefore take hydroxypropyl beta cyclodextrin enclose effectively can improve the dissolubility of Mei Suoshuli.The consumption of hydroxypropyl methylcellulose will directly have influence on slow releasing tablet rate of release in media as well in addition, therefore can obtain specific release behavior by regulating the consumption of hydroxypropyl methylcellulose as required, the weight proportion of Mei Suoshuli and hydroxypropyl methylcellulose meets prescription demand at 1:1.Microcrystalline Cellulose is as filler, and on concrete release behavior regulates, role is less.On the whole, the composition of prescription 6 is than preferably, can meet the demand to Mei Suoshuli slow releasing tablet.And weight proportion release behavior when 1:1 of principal agent Mei Suoshuli and skeleton slow-release material hydroxypropyl methylcellulose is the most desirable, when carrying out enclose process with hydroxypropyl beta cyclodextrin to Mei Suoshuli, stripping is more excellent.
Embodiment 17
With the Mei Suoshuli slow releasing tablet prepared in embodiment 1 for object of study, compared for Mei Suoshuli slow releasing tablet and Mei Suoshuli sheet (for general thin coated tablet) the pharmacokinetics behavior in Beagle dog body, the pharmacokinetic studies of Mei Suoshuli slow releasing tablet and Mei Suoshuli sheet the results are shown in Figure 11.
Wherein: prescription and the method for making of Mei Suoshuli sheet are as follows:
Prescription:
Preparation method is as follows:
(1) get the raw materials ready: after principal agent and lactose co-grinding, cross 80 mesh sieves, for subsequent use;
(2) preparation of binding agent: take appropriate 30 POVIDONE K 30 BP/USP
30(PVPK
30) in beaker, add Purified Water q. s, stir to clarify, obtain certain density PVPK30 aqueous solution I, for subsequent use;
(3) mix: other adjuvants taking recipe quantity, after mix homogeneously, obtain II;
(4) soft material processed and granulation: added in mixture II by the binding agent I of recipe quantity, make soft material, crosses 18 order stainless steel sifts and granulates;
(5) dry: dry at 60 DEG C ± 5 DEG C;
(6) granulate: cross 18 order stainless steel sift granulate, obtain dry granule;
(7) always mix: the disintegrating agent (additional) adding recipe quantity in dry granule, after mix homogeneously, then adds magnesium stearate, mix homogeneously;
(8) tabletting: the content of dispersion measuring above-mentioned pellet product, according to the theoretical sheet weight of its cubage, tabletting time slice heavily controls in heavy ± 5% scope of theoretical sheet, and Hardness Control is at 5 ~ 7kg;
(9) coating: join in purified water by coating powder, is mixed with the Coating Solution that content is 20%, after stirring 45 minutes, carries out coating with screw type stirring paddle, i.e. obtained Mei Suoshuli sheet.
As can be seen from the result of Figure 11, the AUC of Mei Suoshuli slow releasing tablet
0-∞larger than Mei Suoshuli ordinary tablet, and the half-life obviously extend, reach the object of initial design slow releasing tablet, provide steadily effective blood drug level, avoid or reduce the appearance of blood medicine peak valley phenomenon, be conducive to the safety improving drug use, reduce medicining times, improve the compliance of patient.
In the description of this description, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this description or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.
Claims (10)
1. Yi Zhong Mei Suoshuli slow releasing tablet, is characterized in that, comprising:
Mei Suoshuli; And
Pharmaceutically acceptable adjuvant.
2. Mei Suoshuli slow releasing tablet according to claim 1, is characterized in that, described pharmaceutically acceptable adjuvant is be selected from least one in skeleton slow-release material, filler, lubricant, solubilizing agent and disintegrating agent,
Wherein,
Described solubilizing agent is at least one in hydroxypropylβ-cyclodextrin, PLURONICS F87, preferred hydroxypropylβ-cyclodextrin;
Described filler is be selected from least one in lactose, mannitol, starch, microcrystalline Cellulose, preferably microcrystalline cellulose;
Described skeleton slow-release material for being selected from hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K100M, at least one in hydroxypropyl methylcellulose E50, hydroxypropyl methylcellulose E4M, preferred HPMC K4M;
Described disintegrating agent is be selected from least one in carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, preferred carboxymethyl starch sodium;
Described lubricant is be selected from least one in magnesium stearate, micropowder silica gel, fumaric acid sodium, sodium lauryl sulphate, preferred magnesium stearate.
3. Mei Suoshuli slow releasing tablet according to claim 2, is characterized in that, according to parts by weight, described Mei Suoshuli slow releasing tablet comprises:
Described Mei Suoshuli 25 ~ 125 weight portion;
Described skeleton slow-release material 80 ~ 127.5 weight portion;
Described filler 5 ~ 75 weight portion;
Described lubricant 1.5 ~ 2.5 weight portion;
Described solubilizing agent 15 ~ 20 weight portion; And
Described disintegrating agent 3 ~ 9 weight portion.
4. Mei Suoshuli slow releasing tablet according to claim 3, is characterized in that, described Mei Suoshuli slow releasing tablet comprises one of following:
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose K4M100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion;
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 20 weight portion, microcrystalline Cellulose 38.5 weight portion, hydroxypropyl methylcellulose K4M80 weight portion, carboxymethyl starch sodium 9 weight portion and magnesium stearate 1.5 weight portion;
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 17.5 weight portion, microcrystalline Cellulose 5 weight portion, hydroxypropyl methylcellulose K4M120 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2 weight portion;
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose K15M100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion;
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 18 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose K100M100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2 weight portion;
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose E50100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion;
Mei Suoshuli 25 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 75 weight portion, hydroxypropyl methylcellulose K4M127.5 weight portion, carboxymethyl starch sodium 5 weight portion and magnesium stearate 2.5 weight portion;
Mei Suoshuli 50 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 65 weight portion, hydroxypropyl methylcellulose K4M110 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion;
Mei Suoshuli 75 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 50 weight portion, hydroxypropyl methylcellulose K4M100 weight portion, carboxymethyl starch sodium 7.5 weight portion and magnesium stearate 2.5 weight portion;
Mei Suoshuli 125 weight portion, hydroxypropyl beta cyclodextrin 20 weight portion, microcrystalline Cellulose 7.5 weight portion, hydroxypropyl methylcellulose K4M90 weight portion, carboxymethyl starch sodium 5 weight portion and magnesium stearate 2.5 weight portion;
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 16 weight portion, lactose 25 weight portion, hydroxypropyl methylcellulose K15M100 weight portion, polyvinylpolypyrrolidone 7.5 weight portion and micropowder silica gel 2.5 weight portion;
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, mannitol 25 weight portion, hydroxypropyl methylcellulose K100M100 weight portion, low-substituted hydroxypropyl cellulose 7.5 weight portion and sodium lauryl sulphate 1.5 weight portion;
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, starch 25 weight portion, hydroxypropyl methylcellulose E50100 weight portion, cross-linking sodium carboxymethyl cellulose 7.5 weight portion and fumaric acid sodium 2.5 weight portion;
Mei Suoshuli 100 weight portion, hydroxypropyl beta cyclodextrin 15 weight portion, microcrystalline Cellulose 25 weight portion, hydroxypropyl methylcellulose E4M100 weight portion, carboxymethyl starch sodium 3 weight portion and magnesium stearate 2 weight portion.
5. prepare a method for the Mei Suoshuli slow releasing tablet according to any one of claim 1-4, it is characterized in that, comprising:
By Mei Suoshuli and the mixing of pharmaceutically acceptable adjuvant, and obtained mixture is carried out tabletting, to obtain Mei Suoshuli slow releasing tablet.
6. method according to claim 5, is characterized in that, comprising:
(1) described Mei Suoshuli is dissolved in acetone, and hydroxypropyl beta cyclodextrin aqueous solution is mixed mutually with Mei Suoshuli acetone soln, volatilize solvent, to obtain crystalline powder;
(2) described crystalline powder is carried out superfine grinding, and mix with skeleton slow-release material, filler;
(3) mixture obtained in step (2) is granulated, and obtained granule is carried out drying;
(4) dried granule is mixed with lubricant and disintegrating agent, and obtained mixture is carried out tabletting;
Optionally, comprise further:
(5) by label film coating that described step (4) tabletting obtains.
7. method according to claim 6, is characterized in that, described step (3) comprises further:
The mixture obtained in described step (2) is added in wet granulator, mixes 15 minutes, under mixing speed 3r/s, cutting speed 10r/s condition, carry out pure water granulation 90s, and by described obtained particle drying 90 minutes at 60 DEG C.
8. method according to claim 6, is characterized in that, described step (5) comprises further:
Coating powder purified water is disperseed, preparation obtains the coating solution of 15% solid content, then described coating solution is utilized, in atomizing pressure 0.2MP, thimble pressure 0.2MP, coating pan rotating speed 15r/s, feed liquor speed 3r/min, inlet temperature 75 DEG C, air intake frequency 1100Hz, under temperature of charge 35 ~ 45 DEG C of conditions, film coating is carried out to described label, obtain described Mei Suoshuli slow releasing tablet.
9. method according to claim 8, is characterized in that, based on the gross mass of described label, according to mass percent, coating weight gain is 2%-3%.
10. method according to claim 5, is characterized in that, the hardness of described Mei Suoshuli slow releasing tablet is 5-8N.
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| CN1511828A (en) * | 2002-12-31 | 2004-07-14 | �й������ž�����ҽѧ��ѧԺ����ҽ | Sufonic aniline derivatives and their medicinal use |
| CN101422441A (en) * | 2008-11-21 | 2009-05-06 | 海南康芝药业股份有限公司 | Nimesulide sustained-release tablet and preparation method thereof |
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| CN1511828A (en) * | 2002-12-31 | 2004-07-14 | �й������ž�����ҽѧ��ѧԺ����ҽ | Sufonic aniline derivatives and their medicinal use |
| EP1586557A1 (en) * | 2002-12-31 | 2005-10-19 | Institute of Radiation Medicine, Academy of Military Medical Sciences Pla | 4-nitro-2- (4 -methoxy)-phenoxy -methanesulfonanilide derivates and their pharmaceutical use |
| CN101422441A (en) * | 2008-11-21 | 2009-05-06 | 海南康芝药业股份有限公司 | Nimesulide sustained-release tablet and preparation method thereof |
| CN103553984A (en) * | 2013-03-14 | 2014-02-05 | 人福医药集团股份公司 | 2-(4'-methoxy phenoxy)-4-nitro methanesulfonanilide crystal form and preparation method thereof |
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