CN105748410A - Preparation technique for improving dissolution rate and stability of insoluble drug - Google Patents
Preparation technique for improving dissolution rate and stability of insoluble drug Download PDFInfo
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- CN105748410A CN105748410A CN201410773959.9A CN201410773959A CN105748410A CN 105748410 A CN105748410 A CN 105748410A CN 201410773959 A CN201410773959 A CN 201410773959A CN 105748410 A CN105748410 A CN 105748410A
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Abstract
The invention relates to a preparation technique for improving the dissolution rate and stability of an insoluble drug; the technique includes the step of preparing a complex from a liposome containing an insoluble active ingredient and is characterized in that in the complex preparing process, microcrystalline cellulose is added in a stirring manner. A preparing method of a topiroxostat solid preparation comprises the following steps: (1) a step of preparing a topiroxostat liposome; (2) a step of preparing a complex from the topiroxostat liposome; and (3) a step of preparing the topiroxostat complex preparation. The technique is characterized in that in the topiroxostat complex preparing process, microcrystalline cellulose is slowly added in a stirring manner.
Description
Technical field
The present invention relates to the method that microcrystalline Cellulose absorption liposomal preparation contains drug composite.The invention still further relates to the method this complex being carried out coating and then adjusting dissolution rate.
Background technology
A lot of medicines are due to poorly water-soluble, it is difficult to by gastrointestinal absorption, thus causing that oral administration biaavailability is low.It is reported, the new chemical entities of about 40% is slightly water-soluble or water-insoluble materials, and the medicine up to 50% brings difficulty because of high hydrophobicity to preparation.Therefore how to solve the relatively low problem of insoluble drug dissolution rate is all a galenic pharmacy difficult problem urgently to be resolved hurrily all the time.
Current existing technology mainly has two categories below: one is liquid preparation, such as microemulsion technology, cyclodextrin inclusion technique, liposome technology etc., such technology well improves the dissolution rate of insoluble drug to a certain extent, but due to such preparation place for a long time stablize poor, for instance Emulsion there will be breakdown of emulsion to a certain extent.It is solid preparation on the other hand; such as micronization technology, nanocrystalline technology, solid dispersions technique etc.; such technical thought is to reduce diameter of aspirin particle from then on to improve dissolution rate; the problem that such technology would ordinarily be encountered Medicine small molecule recrystallization; although solving the dissolution rate problem of medicine, but in stability, it need further reinforcement.Good stability is the key of preparation, and it not only can extend the effect duration reduction cost of medicine, it is often more important that adds the safety of patient medication.
The present inventor is found surprisingly that in process of the test, microcrystalline Cellulose can effectively wrap load liposome, and the complex that this bag carries attached liposome can significantly change the dissolution rate of insoluble drug, more infusive is that this complex has good stability, and this technology has very strong versatility and is suitable for most of insoluble drug.
Summary of the invention
Low in order to solve insoluble drug dissolution rate, and the shortcoming of preparation stability difference.The present inventor obtains a kind of preparation technique that can be obviously improved insoluble drug dissolution rate and have good stability through a series of test, the drug composite obtained by this technology has good mobility and compressibility, it is possible to other auxiliary material combinations and then prepare the solid preparation such as tablet or capsule.
First the liposome containing insoluble drug is prepared.The preparation method of liposome can be film dispersion method or the method such as alcohol injection or pro-liposome method, and the preparation method of liposome of the present invention does not have special requirement, it is possible to form stable liposome.
Film dispersion method: weigh appropriate phospholipid, cholesterol, is dissolved in appropriate dehydrated alcohol, 45 DEG C of waters bath with thermostatic control, and decompression rotary evaporation removes ethanol, adds appropriate insoluble drug solution, and swelling 60min vibrate 60min, standing 20min,.Ultrasonic method: by film dispersion method prepare liposome, 80W ultrasonic 10min, 30s once, interval 30s,.Lyophilization: take appropriate phospholipid, cholesterol, evenly spread in insoluble drug solution, ultrasonic, add frozen-dried supporting agent, lyophilization.Ultrasonic-nanometer machine method (new-method): take appropriate phospholipid, cholesterol, join in appropriate insoluble drug solution, bath formula is ultrasonic, crosses nanometer granulation,.
Then being placed in isosmotic solution by liposome, isosmotic solution is 0.85%～0.9%NaCl solution and 5% glucose solution, it is preferable that 0.9%NaCl solution.The concentration of liposome is 2%～40% preferably 10%.Being slowly added to microcrystalline Cellulose when stirring, the rotating speed of stirring is 20rpm～200rpm, it is preferable that 100rpm.The consumption of microcrystalline cellulose is 10mg/ml～200mg/ml, preferred 100mg/ml.Microcrystalline Cellulose can select the models such as PH101, PH102, PH301, PH302, it is preferable that PH101, PH102, more preferably PH102.Continue stirring 5～40min, static 10～60min.It is then centrifuged for collecting microcrystalline Cellulose, microcrystalline Cellulose is placed in 50 DEG C of baking ovens and overnight dries.Finally the microcrystalline Cellulose including liposome crossed 60 mesh sieves or press lightly on dispersion.Namely complex is obtained.
This complex can significantly improve insoluble drug dissolution rate, the complex of preparation respectively compared with liposome and solid dispersion stability significantly improve.This complex can carry out Cotton seeds simultaneously, agree according to needing adjust the rate of release of medicine and then reach the purpose of controlled release.
In the process prepare preparation due to this complex has good stability and compressibility can mix with other adjuvant after direct compression, it is also possible to mix filling capsule with suitable adjuvant.
The complex of the active component of the present invention, can combine by one or several therein with binding agent, disintegrating agent, excipient, stop-off gent, antioxidant, coloring agent, correctives and lubricant etc., prepares the solid dosage forms such as tablet or capsule.Additionally this complex can also be filled in conjunction with carrying out tabletting or capsule after dry granulation by one or several therein with binding agent, disintegrating agent, excipient, stop-off gent, coloring agent, antioxidant, correctives and lubricant etc..It addition, the tablet prepared by said method also can film coating or sugar coating or add the film-coat of the coloring agent bag different colours such as different ferrum oxides or bag has slow control-release function.
Detailed description of the invention
Further illustrate, by following instance, the complex prepared by this technology and can be prepared as the solid preparation such as tablet or capsule, the dissolution rate making insoluble drug is significantly improved and said preparation has and has good stability, it is not limited to following instance.
The preparation of embodiment 1 Topiroxostat complex
1) Topiroxostat liposome
Preparation method: weigh soybean lecithin 1.0g, cholesterol 0.823g in 85ml redistilled water, bathes the ultrasonic 33min of formula.(temperature controls at about 4 DEG C), adds Topiroxostat, mixing, with 725bar pressure by nanometer granulation, circulates 3 times.Adjusting pH value to 8.0, add trehalose 1.5g, filtering with microporous membrane, be sub-packed in cillin bottle, by lyophilisation condition lyophilization, obtain Topiroxostat liposome, after dispersion, envelop rate is (38.3 ± 0.06) %.
The evaluation of Liposomal formulation is mainly the envelop rate of medicine, size and distribution and stability, and wherein envelop rate is the key factor investigating liposome quality.Owing to the mean molecule quantity of liposome is about 10-30 ten thousand dalton, and the molecular weight of Topiroxostat is only small, utilize SephadexG-25 post for this, it is possible to the medicine wrapped in liposome and free drug are separated, measure the medicament contg not wrapping in liposome, obtain envelop rate (En%).
/ C is always × 100% for En%=(total-C of C dissociates)
C dissociate=does not wrap into the amount of the Topiroxostat in liposome
C is total=preparation in the amount of total Topiroxostat
2) preparation of drug composite
Take liposome 500ml (concentration is 30%).It is slowly added to microcrystalline Cellulose Ph102100g when stirring (100rpm), continues stirring 20min, be then centrifuged for collecting microcrystalline Cellulose, microcrystalline Cellulose be placed in 50 DEG C of baking ovens and overnight dry.Finally the microcrystalline Cellulose including liposome is crossed 60 mesh sieves.Namely complex is obtained.
The preparation of embodiment 2 Topiroxostat complex tablet
The prescription of tablet is as follows
Preparation method:
Topiroxostat complex, lactose are crossed 100 mesh sieves, carboxymethyl starch sodium, mix homogeneously.Then with magnesium stearate mixed pressuring plate.
The preparation of embodiment 3 Topiroxostat complex capsule
Capsule prescription:
The preparation of Topiroxostat tablet capsule:
Topiroxostat complex, lactose are crossed 100 mesh sieves, carboxymethyl starch sodium, mix homogeneously, adds binding agent and granulate.Then filling capsule is mixed with magnesium stearate.
Embodiment 4: the preparation of Topiroxostat complex tablet
Preparation method:
Topiroxostat complex, microcrystalline Cellulose are crossed 100 mesh sieves, carboxymethyl starch sodium, mix homogeneously.Then with magnesium stearate mixed pressuring plate.
Embodiment 5: Topiroxostat composite sheet or capsule dissolved corrosion are investigated
Described in above example 2-4, preparing given the test agent, investigate the stability of preparation simultaneously, stability conditions is as follows: place 6 months, and placement condition is 25 DEG C ± 2 DEG C/60%RH ± 5%RH.With reference to the dissolution method of FDA, the dissolution testing conditions of capsule is as follows: basket method, 100rpm, dissolution medium: phosphate (pH6.8), dissolution medium volume: 900ml, sample time: to 45 minutes.The dissolution test method of tablet is as follows: paddle method, 100rpm, dissolution medium: phosphate (pH6.8), dissolution medium volume: 900ml, sample time: to 45 minutes.
According to gained dissolution data, draw stripping curve figure respectively, compared.Result is as follows:
Result above is meansigma methods, n=6
Stripping curve figure is as shown in Figure 1, Figure 2, Figure 3 shows.
From above dissolution results it can be seen that prescription Topiroxostat there is good dissolved corrosion, and, after 6 months, its dissolved corrosion is substantially free of change, illustrates that said preparation has good stability.
Accompanying drawing explanation
Fig. 1, embodiment 2 preparation stripping curve compares
Fig. 2, embodiment 3 preparation stripping curve comparison diagram 3, embodiment 4 preparation stripping curve compares.
Claims (9)
1. improving a preparation technique for insoluble drug dissolution rate and stability thereof, this technology comprises the step that the liposome containing slightly solubility active component is made complex, it is characterised in that: in the preparation process of complex, stirring adds microcrystalline Cellulose.
2. preparation technique as claimed in claim 1, described liposome is made the step of complex and is: be placed in isosmotic solution by liposome, is slowly added to microcrystalline Cellulose, continuously stirred 5～40min when stirring, stands 10～60min；Collect microcrystalline Cellulose, dry, obtain complex.
3. preparation technique as claimed in claim 2, described isosmotic solution is 0.85%～0.9%NaCl solution and/or 5% glucose solution, it is preferable that 0.9%NaCl solution；The concentration of liposome is 2%～40%, it is preferable that 10%；The rotating speed of stirring is 20rpm～200rpm, preferred 100rpm；The consumption of microcrystalline cellulose is 10mg/ml～200mg/ml, preferred 100mg/ml；Microcrystalline Cellulose can select the models such as PH101, PH102, PH301, PH302, it is preferable that PH101, PH102, more preferably PH102.
4. preparation technique as claimed in claim 1, described complex can need to carry out Cotton seeds according to preparation.
5. the arbitrary preparation technique as described in claim 1-4, described complex can with binding agent, disintegrating agent, excipient, stop-off gent, antioxidant, coloring agent, correctives and/or lubricant or in conjunction with, after dry granulation, making solid preparation.
6. a preparation method for his solid preparation of Toby department, comprises the following steps:
1. the preparation process of his liposome of Toby department；
2. his liposome of Toby department makes the step of complex；
3. the preparation process of his complex preparation of Toby department；
It is characterized in that: in the preparation process of his complex of Toby department, be slowly stirred addition microcrystalline Cellulose.
7. preparation method as claimed in claim 6, his liposome of described Toby department makes the step of complex: be placed in isosmotic solution by his liposome of Toby department, it is slowly added to microcrystalline Cellulose, continuously stirred 5～40min when stirring, stands 10～60min；Collect microcrystalline Cellulose, dry, obtain complex.
8. preparation method as claimed in claim 7, his liposome of described Toby department makes the step of complex: be that 20%～40% his liposome of Toby department is placed in isosmotic solution by concentration, it is slowly added to microcrystalline Cellulose when stirring (100rpm), continuously stirred 20min, stands 30min；Collect microcrystalline Cellulose, dry, obtain complex.
9. preparation method as claimed in claim 6, the preparation process of his complex preparation of described Toby department is: is mixed homogeneously with corresponding adjuvant by his complex of Toby department, makes the solid preparation such as tablet, capsule.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107375212A (en) * | 2017-08-24 | 2017-11-24 | 青岛正大海尔制药有限公司 | A kind of Topiroxostat Liposomal formulation and preparation method thereof |
| CN108498459A (en) * | 2017-02-23 | 2018-09-07 | 北京阜康仁生物制药科技有限公司 | A kind of pharmaceutical composition and preparation method thereof including hydrobromic acid Vortioxetine |
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| CN101023941A (en) * | 2007-03-26 | 2007-08-29 | 黄成安 | Docetaxel injecta and preparing method |
| CN101623269A (en) * | 2009-08-04 | 2010-01-13 | 南京大渊美容保健有限公司 | Oral sustained release granules |
| CN103142480A (en) * | 2011-12-07 | 2013-06-12 | 郑州锦宏瑞达医药科技有限公司 | Febuxostat nanoliposome and purpose |
| CN104042577A (en) * | 2014-06-13 | 2014-09-17 | 安徽省逸欣铭医药科技有限公司 | Stable topiroxostat tablet and preparation method thereof |
| CN104814937A (en) * | 2015-04-22 | 2015-08-05 | 青岛正大海尔制药有限公司 | Topiroxostat tablet |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101023941A (en) * | 2007-03-26 | 2007-08-29 | 黄成安 | Docetaxel injecta and preparing method |
| CN101623269A (en) * | 2009-08-04 | 2010-01-13 | 南京大渊美容保健有限公司 | Oral sustained release granules |
| CN103142480A (en) * | 2011-12-07 | 2013-06-12 | 郑州锦宏瑞达医药科技有限公司 | Febuxostat nanoliposome and purpose |
| CN104042577A (en) * | 2014-06-13 | 2014-09-17 | 安徽省逸欣铭医药科技有限公司 | Stable topiroxostat tablet and preparation method thereof |
| CN104814937A (en) * | 2015-04-22 | 2015-08-05 | 青岛正大海尔制药有限公司 | Topiroxostat tablet |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108498459A (en) * | 2017-02-23 | 2018-09-07 | 北京阜康仁生物制药科技有限公司 | A kind of pharmaceutical composition and preparation method thereof including hydrobromic acid Vortioxetine |
| CN107375212A (en) * | 2017-08-24 | 2017-11-24 | 青岛正大海尔制药有限公司 | A kind of Topiroxostat Liposomal formulation and preparation method thereof |
| CN107375212B (en) * | 2017-08-24 | 2021-02-26 | 正大制药（青岛）有限公司 | Topiroxostat liposome preparation and preparation method thereof |
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