CN1864681A - Preparation method of composite rifampicin micro-tablet capsule - Google Patents
Preparation method of composite rifampicin micro-tablet capsule Download PDFInfo
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- CN1864681A CN1864681A CN 200610092086 CN200610092086A CN1864681A CN 1864681 A CN1864681 A CN 1864681A CN 200610092086 CN200610092086 CN 200610092086 CN 200610092086 A CN200610092086 A CN 200610092086A CN 1864681 A CN1864681 A CN 1864681A
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Abstract
The preparation process of compound rifampicin micro tablet capsule features that during compounding rifampicin, isoniazide, pyrazinamide and ethambutol hydrochloride, at least one of the medicine components is first formed into micro tablet before encapsulating. During the preparation process, the micro tablet is coated to avoid the excess contact between rifampicin and other medicine components inside the compound capsule and to raised the stability of the compound rifampicin preparation further.
Description
Technical field
The application is actually a kind of continuous application that has patented and authorized, the patent of invention title that the inventor has obtained the authorization is " a kind of medicine-releasing system of compound rifampicin preparation ", its number of patent application is 03101211.6, its granted patent certificate number is 208518, the application gos deep into the preparation method of neoteric a kind of compound rifampicin preparation on the basis of patent 03101211.6 according to the further of research.
Technical background
The World Health Organization (WHO) is the generation that prevents drug-resistant tuberculosis, has recommended 12 kinds of standardization prescriptions combination of fixed dosage compound (FDC) preparation to the whole world in calendar year 2001 number one (79 the 1st phase of volume) bulletin.WHO emphasizes when making the FDC preparation when recommending FDC standard preparation prescription very much, must ensure that the rifampicin bioavailability is not suffered a loss in the product quality of FDC preparation and the FDC preparation.Do not suffer Study on Damage various countries pharmacy worker by the end of so far for the product quality of FDC preparation and the bioavailability of guarantee rifampicin, do not pause always yet.Up to now, about the result of study of this respect can reduce following some:
1, the degraded of rifampicin is the function of environmental PH and temperature, and therefore, the environment diarrhea good fortune of gastric acid is shown no increases in output and given birth to degraded in vivo, and under the isoniazid and the situation of depositing, the degraded of rifampicin will speed up.According to this result of study, prompting make rifampicin avoid sour environment when FDC makes before absorption as far as possible, and meets with isoniazid in sour environment, for example, and with the notion of rifampicin in upper part of small intestine release.
2, under FDC preparation solid environment, rifampicin contacts with isoniazid, and not only rifampicin produces degraded, and isoniazid also produces degraded, and pyrazinamide, ebutol, humidity, temperature play catalytic action to this degraded.Therefore, prompting should avoid rifampicin to contact closely with isoniazid in the solid environment of FDC preparation, and damp proof to the FDC preparation, keep away temperature.
3, there is the above-mentioned degradation problem that is difficult to overcome in the mill owing to contain the tuberculosis FDC preparation of rifampicin, in the process that the FDC preparation is made and stored and transported, is easy to cause the decline of FDC formulation products quality.Therefore, should carry out strict control to the product quality of FDC preparation, its emphasis is except dissolution, release control and the content detection of each component, and the catabolite of particularly importantly tackling each drug component detects control.Yet, by the end of also do not have so far easy and effectively analytical technology can be to tuberculosis FDC preparation in the catabolite of Rimactazid, pyrazinamide, ebutol effectively detect the FDC preparation of 3 medicines and 4 medicines especially.
At present many pharmaceutical preparation patents problem of being devoted to solve is that the bioavailability that prevents rifampicin in the FDC preparation does not suffer a loss, patent WO02/087547 A1 for example, WO2004/041284 etc.These patents all disclose some effective methods of dealing with problems, yet, also there is certain defective simultaneously.The application gos deep into the preparation method of neoteric a kind of compound rifampicin preparation on the basis of patent 03101211.6 according to the further of research.Perhaps, improvement of the present invention is small at patent 03101211.6, still, has remarkable meaning in the suitability for industrialized production of real product.Yet,, can produce unavoidable defective too owing to improve in some places.The state that the progress of science invariably accompanies advantage and defective and deposits can not and be deposited and ignores progressive advantage because of defectiveness, is also encouraging researcher to go constantly to develop advantage simultaneously and is overcoming one's shortcomings.
Summary of the invention
Patent of invention " a kind of medicine-releasing system of compound rifampicin preparation " is actually invention a kind of compound rifampicin preparation is provided, it is a kind of medicine-releasing system of compound rifampicin preparation that this preparation can be interpreted as, because this preparation has related to by four kind of one line antituberculotics rifampicin, isoniazid, pyrazinamide, ebutol is prepared into four kinds of medicament pellets, and their preparation method, and by the drug dose of these the four kinds standard prescriptions of announcing according to World Health Organization (WHO) respectively, combination rule rifampicin micropill and other three kinds of micropills are filled in the capsule shells arranged, form a kind of medicine-releasing system of special compound rifampicin preparation, this system is afterwards by " two release " preparation of China national committee of pharmacopeia called after rifampicin compound preparation, be characterized in that some medicament pellet is to discharge under one's belt, some medicament pellet is to discharge at upper part of small intestine.By this two medicine-releasing systems that discharge, can protect the stability of rifampicin and isoniazid in the compound rifampicin preparation effectively, improve the quality of product and ensure that the bioavailability of rifampicin does not suffer a loss.
In 03101211.6 patent of invention, the inventor externally announces is based on the composing method of the medicine-releasing system of micropill technology and the preparation method of 4 kinds of medicament pellets.The characteristics of this preparation method are exactly respectively various medicines to be made into micropill, and then micropill is packed in the capsule.This way has effectively solved rifampicin and isoniazid contacting in preparation, has avoided because the degradation problem that contact produces between medicine.
Yet,, better manufacture method is provided for the pharmacy researcher along with the fast development of pharmaceutical machine.Core technology of the present invention is exactly that at first rifampicin to be made microplate (be small tablet, be called for short microplate), perhaps these 4 kinds of medicines are all made the folk prescription microplate, perhaps part is made the folk prescription microplate and is partly made up and make the compound recipe microplate, and the standard drug compatibility prescription of the tuberculosis fixed dosage compound formulation that proposes in strict accordance with WHO, carry out compatibility of drugs, to meet the microplate of said medicine of ratio and the former powder of said medicine, or granule, or micropill uses the multistation capsule filling machine to be packed into successively in the capsule, and final formation has the microplate capsule formulation of microplate as the such characteristics of capsule filling.The main feature of this compound rifampicin preparation is: in capsule filling, having a kind of drug component at least is that form with microplate is packed into capsule, and the rifampicin component does not form the compound capsule implant with the other medicines component, for example, carry out capsule after 3 kinds of medicine materials of rifampicin raw material and other are directly mixed and fill, carry out the capsule filling after perhaps rifampicin and other 3 kinds of medicines being made the microplate of compound recipe or granule or micropill.
In preparation technology, can comprise that microplate, granule, micropill even former powder etc. carry out the difference coating of gastric solubleness material or enteric material (mainly referring to the enteric material in upper part of small intestine release) to the implant in the capsule.The purpose of doing like this is to play on the one hand each ingredient is implemented to isolate, avoid in preparation owing to medicine directly contacts the drug degradation that produces, on the other hand, also can be as patent 03101211.6 form two delivery systems that discharge in vivo the drug release process, avoid medicine degraded in vivo, thereby ensure that bioavailability of medicament does not suffer a loss.
Adopt said method that following combination filling mode can be arranged:
(1) the rifampicin component is prepared into microplate, and the formed microplate of rifampicin component is implemented enteric coating.Other isoniazid, pyrazinamide, these three kinds of compositions of ebutol are prepared into microplate respectively and carry out gastric solubleness material coating.Use the multistation capsule filling machine to carry out capsule according to standard prescription then and fill the compound rifampicin preparation that also can form 2 medicines or 3 medicines or 4 medicines.
This mode can also be carried out multiple extension combination, for example, rifampicin is prepared into the enteric microplate, and other composition is prepared into granule, micropill even former powder, carries out capsule with the rifampicin microplate then and fills; Again for example, the rifampicin composition is prepared into enteric coated particles or enteric coated micropill, and other composition is prepared into microplate, perhaps wherein a kind of or two kinds of compositions are prepared into microplate, and other composition is prepared into granule, micropill even directly uses former powder, and then implements capsule and fill.In a word, also can list some compound modes, still, combination howsoever, this filling mode should possess two kinds of features: it 1 is that the rifampicin component is to implement enteric coating, and other component is to implement gastric solubleness coating or not coating, filled capsules then; It 2 is that to have a kind of component in capsule at least be to adopt the microplate filling forms.
(2) the isoniazid composition is prepared into microplate, and the formed microplate of isoniazid composition is implemented enteric coating.Other rifampicin, pyrazinamide, these three kinds of compositions of ebutol are prepared into microplate respectively and carry out gastric solubleness material coating.Use the multistation capsule filling machine to carry out capsule according to standard prescription then and fill the compound rifampicin preparation that also can form 2 medicines or 3 medicines or 4 medicines.
This mode can also be carried out multiple extension combination, for example, isoniazid is prepared into microplate, and other composition is prepared into granule, micropill even former powder, carries out capsule with the isoniazid microplate then and fills; Again for example, the isoniazid composition is prepared into enteric coated particles or enteric coated micropill, and other composition is prepared into microplate, perhaps wherein a kind of or two kinds of compositions are prepared into microplate, and other composition is prepared into granule, micropill even directly uses former powder, and then implements capsule and fill.In a word, also can list some compound modes, still, combination howsoever, this filling mode also should possess two kinds of features: it 1 is that the isoniazid component is to implement enteric coating, and other component is to implement gastric solubleness coating or not coating, filled capsules then; It 2 is that to have a kind of component in capsule at least be to adopt the microplate filling forms.
(3) in the preparation of above-mentioned (1) and (2) combination and respectively rifampicin and isoniazid component are carried out on the basis of individual processing, pyrazinamide, ebutol can be mixed in proportion, make the compound recipe microplate of these two kinds of compositions then, use this compound recipe microplate and rifampicin and isoniazid component to carry out complex capsule and fill.Also the independent enteric coating of rifampicin component can be handled, isoniazid, pyrazinamide, ebutol are carried out mixing by the proportion compatibility of WHO standard prescription, make the compound recipe microplate of these three kinds of compositions then.The independent enteric coating of rifampicin component can also be handled, isoniazid, pyrazinamide are carried out mixing by the proportion compatibility of WHO standard prescription, make the compound recipe microplate of these two kinds of compositions then.The advantage of above-mentioned these 3 kinds of preparation methods is that the capsule that can use 3 station capsule filling machines to implement 4 medicine components is filled or the capsule that uses 2 station capsule filling machines to implement 4 medicine components and 3 medicine components is filled.
Above-mentioned preparation method also can expand to handles the independent enteric coating of rifampicin component, isoniazid, pyrazinamide, ebutol is carried out being prepared into 2 medicines or 3 recurrence due to taking drug side's granules or compound recipe micropill by the proportion compatibility that WHO standard is write out a prescription carry out capsule filling etc. with the rifampicin component then.
The reason that other 3 kinds of components outside the rifampicin are prepared into compound recipe microplate, granule, micropill is that these 3 kinds of medicines all belong to the good chemical substance of water solublity, if there is not the intervention of rifampicin, after its mixing, stability to each drug component can not brought tangible negative effect, but, but can bring and simplify the advantage that capsule is filled.This filling mode should possess two kinds of features: it 1 is that the rifampicin component is the folk prescription form, and other components are compound recipe forms; It 2 is that to have a kind of component in capsule at least be to adopt the microplate filling forms.
Why adopt microplate capsule filling forms, it is in setting up the catabolite detection method of each drug component that the advantage of this method is compared with patent 03101211.6, need pick drug component, microplate pick picking with respect to micropill, want simple many, can optimize the operating process of the examination and test of products like this, this suitability for industrialized production for product is very important.Based on such advantage obviously as seen, in above-mentioned (1), (2), (3) two kinds of combination filling modes, all being prepared into microplate respectively with 4 kinds of drug components is best combination filling mode.Next is that rifampicin or isoniazid are prepared into microplate respectively, other component can adopt the mode of micropill, granule or former powder, but, adopt this mode, its advantage that is convenient to pick will be given a discount, yet, if the catabolite that adopts more advanced detection method to solve each medicine in the compound recipe component detects, then on the basis that the rifampicin component is implemented to handle respectively, other component adopts the compound recipe processing mode, to fill for simplifying capsule, reduce equipment investment, and then be very favorable reducing production cost of products to greatest extent.
For enteric-coating material, get final product as the coating material of introducing in the patent 03101211.6, it mainly puts when being to implement enteric coating, because requiring the drug component of coating object is that upper part of small intestine at human body discharges, therefore, coating material is best between pH5.0～pH5.5 to the sensitive spot of pH.For the gastric solubleness coating material, also as the description in the patent 03101211.6, can certainly select other gastric solubleness coating material for use, but only otherwise destroy that to be begun rapid release under one's belt by the drug component of coating be basic principle.It is pointed out that using the main purpose of gastric solubleness coating material is in preparation drug component to be isolated, and therefore, conventionally also will use the gastric solubleness coating material that the way that medicine wraps up is referred to as " bag sealing coat ".
The diameter dimension of microplate is extremely important, if oversize, the capsule filling encounters difficulties, if undersized, then wastes the capsule content space.Because, standard drug compatibility prescription according to WHO, tuberculosis patient every day to take dose bigger, for example, body weight is strengthened the rifampicin that the phase daily requirement is taken 600mg, the isoniazid of 300mg in the adult patients of 60kg, the pyrazinamide of 1600mg and the ebutol of 1100mg, 4 medicines total amount altogether is up to 3600mg.If it is bad that the size of microplate is grasped, will cause the waste of capsule content volume, finally causing needs to use more capsule quantity, and not only the patient takes inconvenience, and product cost is increased.Therefore, Zui Jia microplate diameter should like this, be No. 00, No. 0,1, No. 2 capsule corresponding to employed capsule shells between 6.0mm～7.8mm, 5.5mm～7.0mm, 4.5mm～6.0mm, 4mm～5.7mm.If diameter is littler, for the tuberculosis compound rifampicin preparation,, be nonsensical because dose is bigger.Certainly, the diameter of the required preparation of microplate has relation with the specification that will load, owing to contain 2～4 kinds of principal agent compositions in this product, and also the component content of each principal agent differs greatly, the microplate that therefore should be prepared into suitable diameter as required reinstalls in the corresponding capsule, can not extremely remove the size according to the above-mentioned microplate of cover of doctrine, still, first and last, the size of all microplates should be controlled between 4mm～7.8mm, can not be excessive, especially can not be too small, minimum is not less than 3mm yet.
The profile of micropill is also extremely important, and the external form of general tablet mostly adopts outside round convex shape, helps the patient like this and swallows.For being packed into capsular microplate, adopt outside round convex shape obviously to be unfavorable for saving the capsule content space, therefore, need to adopt the planar wafer profile.For the ease of molding, it is favourable that the disk periphery has the inclination corner angle, but the inclination corner angle are unsuitable excessive.The thickness of tablet does not have fixed requirement, and is still, unsuitable blocked up yet.
For the microplate of rifampicin component, the hardness of microplate is extremely important, and hardness is excessive, is unfavorable for the release of rifampicin, and hardness is too small, easily fragment.Though it is different and different that hardness requires with the adjuvant that is adopted,, for most of convas tablet adjuvants, when hardness surpasses 8kg/cm
2The time, rifampicin is difficult for discharging from sheet, when hardness less than 3kg/cm
2The time, tablet is easy fragment in the process of coating and capsule filling.
For rifampicin or isoniazid component, it is prepared into the enteric microplate of one pack system after, should before the capsule filling, detect its release conditions, the method for its detection and discharge limit require as follows:
Can adopt second method in the drug release rate detection method of two regulations of Chinese Pharmacopoeia (version in 2005).Apparatus adopts changes 37 ℃ of basket method, temperature, and Revolution Per Minute 50 changes.2 hours planted agents are less than 10% of labelled amount for rifampicin or the isoniazid burst size in acid; 45 minutes planted agents are greater than 75% of labelled amount for rifampicin or the isoniazid burst size in buffer solution, and the best should be greater than more than 85%.
For the microplate of implementing enteric coating, in order to implement the enteric material coating better, can on microplate, at first carry out water-soluble material bag contagion gown, the water solublity coating material can be that pharmaceutic adjuvant allows the material that uses, for example PVP etc.The reason of carrying out water solublity contagion gown parcel is the initial stage of carrying out enteric coating at microplate, have a spot of drug powder and break away from microplate, in the coating environment, form the fine powder that flies upward, these fine powders are blended in the coating solution that is sprayed by shower nozzle easily, and finally be mixed in the enteric coat layer, so just cause the release of medicine overdose when carrying out gastric solubleness liquid drug release determination, this is unallowed in quality control.Certainly, if through overtesting, the microplate fine drug powder breaks away from seldom, and then sealing coat has just no longer needed.
Adopt the preparation method of above-mentioned compound rifampicin preparation to compare with patent 03101211.6 described method, if the component of medicine all adopts the one pack system microplate to carry out capsule and fills, the advantage that not only can keep patent 03101211.6, the pellet capsule product that can also overcome patent 03101211.6 is carrying out catabolite loaded down with trivial details to the micropill letter sorting when detecting.
If the microplate to other component employing compound recipe form except the rifampicin component carries out the mode that capsule is filled with the rifampicin component then, can simplify capsule and fill, but need cooperation can detect the detection method of compound recipe component.
The release that a not enough point that adopts the present invention and patent 03101211.6 to compare is the rifampicin microplate slightly is worse than the form of rifampicin micropill.
In sum, said method is compared with the complex rifampin preparation method that patent 03101211.6 is described, and merits and demerits has both.Yet under current pharmaceutical technology environment with keen competition, the preparation method of compound rifampicin preparation described in the invention will still have good allure in the advantage that is had aspect reduction production equipment cost, the simplification detecting operation to manufacturing enterprise.
The specific embodiment
The present invention has been described in detail in detail above, and the release behaviour in vitro that discloses microplate more in conjunction with the embodiments is described in further detail the present invention, and obviously, embodiment is only for explanation restriction absolutely not.
The preparation and the release behaviour in vitro of embodiment 1 isoniazid enteric microplate:
1, the preparation of isoniazid enteric microplate
The plain tablet recipe isoniazid of isoniazid 25g, starch 5g, 5% polyvidone (K30) solution is an amount of, and magnesium stearate 0.12g makes 1000 altogether.
Method for making takes by weighing isoniazid and starch respectively by recipe quantity, and mixing behind 100 mesh sieves is granulated with 5% polyvidone (K30) solution excessively, puts 60 ℃ of dryings in the baking oven, sieves, and granulate adds the magnesium stearate mixing, and tabletting, sheet diameter are 4mm.
The preparation of enteric coating solution: get hydroxypropyl methylphthalic acid ester 5g, add acetone liquid (3/7) 100ml dissolving back and add diethyl phthalate 0.5g, dissolving evenly promptly.
The preparation of enteric microplate: the plain sheet that will prepare is put in the coating pan, the rolling coating pan, limit spray enteric coating liquid, the limit blowing hot-air, wrap to the sheet weightening finish to about 10%, take out and put 60 ℃ of dryings of baking oven 1 hour.Take out, 2 hours burst size should be less than 10% in the 0.1mol/L hydrochloric acid solution for the release of checking this product, and 0.5 hour burst size should be greater than 70% in phosphate buffer (pH6.8).
2, the release behaviour in vitro of isoniazid enteric microplate
(1) experiment purpose: measure the burst size of isoniazid enteric microplate in 0.1mol/L hydrochloric acid, water, pH6.8 phosphate buffer, pH5.0 phosphate buffer.
(2) experimental basis: Chinese Pharmacopoeia two appendix of version in 2005 " drug release determination method " item is the method 2 of second method down.Get this product, according to dissolution method first subtraction unit, be solvent with 0.1mol/L hydrochloric acid, water, pH5.0 phosphate buffer, pH6.8 phosphate buffer 900ml respectively, 50 rev/mins of rotating speeds, operation in accordance with the law, respectively at getting solution 10ml in 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, filter, replenish solvent simultaneously, get subsequent filtrate 3ml and place the 5ml measuring bottle to be diluted to scale with corresponding solvent with volume, shake up, as sample solution; Other gets the contrast solution that isoniazid is mixed with in right amount 16ug/ml according to product.Between 200～350nm wavelength, scan its maximum absorption wavelength and survey its trap according to spectrophotography, calculate burst size in the maximum absorption wave strong point.
(3) experimental result is shown in the following table data:
The preparation and the release behaviour in vitro of embodiment 2 rifampicin enteric microplates
1, the preparation of rifampicin enteric microplate
The plain tablet recipe rifampicin of rifampicin 50g, microcrystalline Cellulose 15g, vitamin C 1g, carboxymethyl starch sodium 1g, magnesium stearate 0.25g makes 1000 altogether.
Method for making is got by above-mentioned prescription and is claimed each former, adjuvant, and mixing behind 80 mesh sieves is granulated excessively, granulate, and tabletting, sheet diameter are 5.5mm.
The preparation of film coating solution: get hydroxypropyl emthylcellulose 3g, Macrogol 4000 3g, the dissolve with ethanol solution with 70% are evenly promptly.
Film-coated preparation: the plain sheet that will prepare is put in the coating pan, the rolling coating pan, the limit film coating solution that gushs, the limit blowing hot-air, wrap to the sheet weightening finish to about 3%, take out and put 50 ℃ of dryings of baking oven 1 hour.
The preparation of enteric coating solution: get hydroxypropyl methylphthalic acid ester 5g, add acetone liquid (3/7) 100ml dissolving back and add diethyl phthalate 0.5g, dissolving evenly promptly.
The preparation of enteric microplate: the Film coated tablets for preparing is put in the coating pan, the rolling coating pan, limit spray enteric coating liquid, the limit blowing hot-air, wrap to the sheet weightening finish to about 10%, take out and put 60 ℃ of dryings of baking oven 1 hour.Take out, 2 hours burst size should be less than 10% in the 0.1mol/L hydrochloric acid solution for the release of checking this product, and 0.5 hour burst size should be greater than 70% in phosphate buffer (pH6.8).
2, the release behaviour in vitro of rifampicin enteric microplate
(1) experiment purpose: measure the stripping curve of enteric rifampicin microplate in the hydrochloric acid solution of 0.1mol/L, water, pH5.0, pH5.6, pH6.8 phosphate buffer.
(2) experimental basis: Chinese Pharmacopoeia two appendix of version in 2005 " drug release determination method " item is the method 2 of second method down.Get this product, according to dissolution method first subtraction unit, be solvent with 0.1mol/L hydrochloric acid, water, pH5.0, pH5.6, pH6.8 buffer 900ml respectively, 50 rev/mins of rotating speeds, operation in accordance with the law, respectively at getting solution 10ml in 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, filter, replenish solvent simultaneously, get subsequent filtrate 4ml and place the 10ml measuring bottle to be diluted to scale with corresponding solvent with volume, shake up, as sample solution; Other gets the contrast solution that the rifampicin reference substance is mixed with 25ug/ml in right amount.Between 360～700nm wavelength, scan its maximum absorption wavelength and survey its trap according to spectrophotography, calculate stripping quantity in the maximum absorption wave strong point.
(3) experimental result is shown in the following table data:
| The pH5.0 buffer | 38.36 | 76.52 | 85.11 | 99.32 | 99.86 |
| The pH5.6 buffer | 40.71 | 78.31 | 91.69 | 99.42 | 99.91 |
| The pH6.8 buffer | 43.61 | 80.77 | 93.82 | 99.88 | 99.78 |
The preparation and the release behaviour in vitro of embodiment 3 rifampicin gastric solubleness microplates
1, the preparation of rifampicin gastric solubleness microplate
The plain tablet recipe rifampicin of rifampicin 50g, microcrystalline Cellulose 15g, vitamin C 2g, low-substituted hydroxypropyl cellulose 4g, magnesium stearate 0.3g makes 1000 altogether.
Method for making takes by weighing each former, adjuvant by above-mentioned prescription, and mixing behind 80 mesh sieves is granulated excessively, granulate, and tabletting, sheet diameter are 5.5mm.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric solubleness microplate: the plain sheet that will prepare is put in the coating pan, the rolling coating pan, limit spray gastric solubleness clothing liquid, the limit blowing hot-air, wrap to the sheet weightening finish to about 4%, take out and put 50 ℃ of dryings of baking oven and took out promptly in 1 hour.
2, the release behaviour in vitro of rifampicin gastric solubleness microplate
(1) experiment purpose: measure the stripping curve of rifampicin gastric solubleness microplate in the 0.1mol/L hydrochloric acid solution.
(2) experimental basis: Chinese Pharmacopoeia two appendix of version " dissolution method " in 2005.Getting this product, according to dissolution method first method, is solvent with 0.1mol/L hydrochloric acid solution 900ml, adopts 50 rev/mins rotating speed, in accordance with the law operation; Got solution 10ml, filtration, additional simultaneously solvent respectively at 10,20,30,45,60 minutes with volume.Precision is measured subsequent filtrate 4ml, puts in the 10ml measuring bottle, is diluted to scale with the 0.1mol/L hydrochloric acid solution, as need testing solution; Other gets the rifampicin reference substance, is diluted to the solution that contains 25ug among every 1ml approximately with the 0.1mol/L hydrochloric acid solution, as reference substance solution.Between 360～700nm wavelength, scan its maximum absorption wavelength and survey its trap according to spectrophotography, calculate stripping quantity in the maximum absorption wave strong point.
(3) experimental result is shown in the following table data:
| Time | Burst size (being equivalent to labelled amount %) | ||||||
| Cup 1 | Cup 2 | Cup 3 | Cup 4 | Cup 5 | Cup 6 | Average | |
| 10 minutes | 44.1 | 42.2 | 40.8 | 41.7 | 46.1 | 40.9 | 42.6 |
| 20 minutes | 80.4 | 78.8 | 76.1 | 77.7 | 81.6 | 77.2 | 78.6 |
| 30 minutes | 98.4 | 97.8 | 97.1 | 97.6 | 99.1 | 97.5 | 97.9 |
| 45 minutes | 99.7 | 99.3 | 99.1 | 99.5 | 100.2 | 98.6 | 99.4 |
| 60 minutes | 99.8 | 99.4 | 99.8 | 99.3 | 99.7 | 99.5 | 99.6 |
The preparation and the release behaviour in vitro of embodiment 4 isoniazid gastric solubleness microplates
1, the preparation of isoniazid gastric solubleness microplate
The plain tablet recipe isoniazid of isoniazid 25g, starch 5g, low-substituted hydroxypropyl cellulose 1g, 5% starch slurry is an amount of, and magnesium stearate 0.12g makes 1000 altogether.
Method for making takes by weighing isoniazid, starch and low-substituted hydroxypropyl cellulose respectively by recipe quantity, and mixing behind 100 mesh sieves is granulated with 5% starch slurry excessively, puts 60 ℃ of dryings in the baking oven, sieves, and granulate adds the magnesium stearate mixing, and tabletting, sheet diameter are 4mm.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric solubleness microplate: the plain sheet that will prepare is put in the coating pan, the rolling coating pan, limit spray gastric solubleness coating solution, the limit blowing hot-air, wrap to the sheet weightening finish to about 4%, take out and put 60 ℃ of dryings of baking oven and took out promptly in 1 hour.
2, the release behaviour in vitro of isoniazid gastric solubleness microplate
(1) experiment purpose: measure the stripping curve of gastric solubleness isoniazid microplate in water.
(2) experimental basis: Chinese Pharmacopoeia two appendix of version " dissolution method " in 2005 item is the method for first method down.Getting this product, is solvent with water 900ml, 50 rev/mins of rotating speeds, operation in accordance with the law; Respectively at getting solution 10ml in 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, filter, replenish solvent simultaneously with volume, get subsequent filtrate 3ml and place the 5ml measuring bottle to be diluted to scale with corresponding solvent, shake up, as sample solution; Other gets the contrast solution that the isoniazid reference substance is mixed with 16ug/ml in right amount.Between 200～350nm wavelength, scan its maximum absorption wavelength and survey its trap according to spectrophotography, calculate stripping quantity in the maximum absorption wave strong point.
(3) experimental result is shown in the following table data:
| Time | Stripping quantity (being equivalent to labelled amount %) | ||||||
| Cup 1 | Cup 2 | Cup 3 | Cup 4 | Cup 5 | Cup 6 | Average | |
| 10 minutes | 72.4 | 70.5 | 70.6 | 75.1 | 75.7 | 76.9 | 73.5 |
| 20 minutes | 85.6 | 83.4 | 82.3 | 87.8 | 86.5 | 86.1 | 85.3 |
| 30 minutes | 99.1 | 99.8 | 99.4 | 100.8 | 100.7 | 101.1 | 100.2 |
| 45 minutes | 99.8 | 100.3 | 99.9 | 100.3 | 99.4 | 100.5 | 100.0 |
| 60 minutes | 99.6 | 99.7 | 99.9 | 99.8 | 99.6 | 100.1 | 99.8 |
The preparation and the release behaviour in vitro of embodiment 5 pyrazinamide gastric solubleness microplates
1, the preparation of pyrazinamide gastric solubleness microplate
The plain tablet recipe pyrazinamide of pyrazinamide 66.7g, starch 5g, hydroxypropyl cellulose 1g, starch slurry is an amount of, and magnesium stearate 0.3g makes 1000 altogether.
Method for making takes by weighing pyrazinamide, starch and hydroxypropyl cellulose respectively by recipe quantity, and mixing behind 100 mesh sieves is granulated with 5% starch slurry excessively, puts 60 ℃ of dryings in the baking oven, sieves, and granulate adds the magnesium stearate mixing, and tabletting, sheet diameter are 5.5mm.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100m1 dissolving evenly promptly.
The preparation of gastric solubleness microplate: the plain sheet that will prepare is put in the coating pan, the rolling coating pan, limit spray gastric solubleness clothing liquid, the limit blowing hot-air, wrap to the sheet weightening finish to about 4%, take out and put 60 ℃ of dryings of baking oven and took out promptly in 1 hour.
2, the release behaviour in vitro of pyrazinamide gastric solubleness microplate
(1) experiment purpose: measure the stripping curve in the gastric solubleness pyrazinamide microplate water.
(2) experimental basis: Chinese Pharmacopoeia two appendix of version " dissolution method " in 2005 item is the method for first method down.Getting this product, is solvent with water 900ml, 50 rev/mins of rotating speeds, operation in accordance with the law; In the time of 10,20,30,45,60 minutes, get solution 5ml, replenish solvent simultaneously with volume, filter, get subsequent filtrate 1.5ml and put in the 10ml measuring bottle, be diluted with water to scale, as need testing solution; Other gets the pyrazinamide reference substance, is diluted with water to the solution that contains 10ug among every 1ml approximately, as reference substance solution.Between 200～350nm wavelength, scan its maximum absorption wavelength and survey its trap according to spectrophotography, calculate stripping quantity in the maximum absorption wave strong point.
| Time | Stripping quantity (being equivalent to labelled amount %) | ||||||
| Cup 1 | Cup 2 | Cup 3 | Cup 4 | Cup 5 | Cup 6 | Average | |
| 10 minutes | 73.7 | 71.5 | 70.7 | 72.3 | 75.9 | 73.4 | 72.9 |
| 20 minutes | 89.7 | 88.3 | 87.6 | 88.4 | 90.5 | 88.9 | 88.9 |
| 30 minutes | 99.7 | 98.3 | 97.9 | 99.4 | 99.6 | 98.7 | 98.9 |
| 45 minutes | 100.4 | 99.7 | 99.8 | 100.3 | 100.8 | 100.1 | 100.2 |
| 60 minutes | 99.8 | 100.4 | 99.9 | 99.7 | 99.1 | 99.7 | 99.8 |
The preparation and the release behaviour in vitro of embodiment 6 ebutol gastric solubleness microplates
1, the preparation of ebutol gastric solubleness microplate
The plain tablet recipe ebutol of ebutol 45.8g, starch 5g, dextrin 2g, 5% starch slurry is an amount of, and magnesium stearate 0.2g makes 1000 altogether.。
Method for making takes by weighing ebutol, starch and dextrin respectively by recipe quantity, and mixing behind 100 mesh sieves is granulated with 5% starch slurry excessively, puts 60 ℃ of dryings in the baking oven, sieves, and granulate adds the magnesium stearate mixing, and tabletting, sheet diameter are 5mm.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric soluble tablet: the plain sheet that will prepare is put in the coating pan, the rolling coating pan, limit spray gastric solubleness clothing liquid, the limit blowing hot-air, wrap to the sheet weightening finish to about 4%, take out and put 60 ℃ of dryings of baking oven and took out promptly in 1 hour.
2, the release behaviour in vitro of ebutol gastric solubleness microplate
(1) experiment purpose: measure the stripping curve of gastric solubleness ebutol gastric solubleness microplate in water.
(2) experimental basis: Chinese Pharmacopoeia two appendix of version " dissolution method " in 2005 item is the method for first method down.Getting this product, is solvent with water 900ml, 50 rev/mins of rotating speeds, operation in accordance with the law.Respectively at 10,20,30,45, in the time of 60 minutes, get solution 5ml, replenish solvent simultaneously with volume, filter, get subsequent filtrate 2ml, add bromocresol green solution and (get bromocresol green 0.2g, add water 30ml and 0.1mol/L sodium hydroxide solution 6.5ml makes dissolving, add biphosphate sodium 19.0g and sodium hydrogen phosphate 2.5g, thin up shakes up to 500ml, and adding 0.1mol/L hydrochloric acid solution adjusting pH value is 4.6 ± 0.1) 10ml, shake up, precision adds chloroform 20ml, and jolting is left standstill and made layering after extracting, divide and get chloroform solution, between 360～700nm wavelength, scan its maximum absorption wavelength and survey its trap in the maximum absorption wave strong point according to spectrophotography.Precision is measured ebutol reference substance solution (hydrochloric ethambutol reference substance 50ug among every 1ml) 2ml in addition, as stated above from " bromocresol green solution ", measures trap with method, calculates stripping quantity.
(3) experimental result is shown in the following table data:
| Time | Stripping quantity (being equivalent to labelled amount %) | ||||||
| 1 | 2 | 3 | 4 | 5 | 6 | Average | |
| 10 minutes | 59.8 | 58.4 | 62.1 | 64.5 | 60.3 | 61.2 | 61.0 |
| 20 minutes | 90.3 | 91.2 | 92.5 | 93.6 | 91.4 | 92.3 | 91.9 |
| 30 minutes | 99.8 | 100.3 | 100.6 | 99.8 | 99.2 | 99.6 | 99.9 |
| 45 minutes | 99.7 | 99.5 | 99.5 | 99.6 | 99.7 | 100.3 | 99.7 |
| 60 minutes | 99.1 | 98.8 | 100.1 | 99.9 | 98.9 | 100.1 | 99.5 |
The preparation of embodiment 7 isoniazids, pyrazinamide, ebutol compound recipe microplate
Prescription isoniazid 8.3g, pyrazinamide 44.4g, ebutol 30.6g, starch 10g, dextrin 3g, 5% starch slurry is an amount of, and magnesium stearate 0.4g makes 1000 altogether.。
Method for making takes by weighing isoniazid, pyrazinamide, ebutol, starch and dextrin respectively by recipe quantity, and mixing behind 100 mesh sieves is granulated with 5% starch slurry excessively, puts 60 ℃ of dryings in the baking oven, sieves, and granulate adds the magnesium stearate mixing, and tabletting, sheet diameter are 6mm.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric soluble tablet: the plain sheet that will prepare is put in the coating pan, the rolling coating pan, limit spray gastric solubleness clothing liquid, the limit blowing hot-air, wrap to the sheet weightening finish to about 4%, take out and put 60 ℃ of dryings of baking oven and took out promptly in 1 hour.
The preparation of embodiment 8 pyrazinamide, ebutol compound recipe microplate
Prescription pyrazinamide 44.4g, ebutol 30.6g, starch 6g, low-substituted hydroxypropyl cellulose 1g, 5% starch slurry is an amount of, and magnesium stearate 0.3g makes 1000 altogether.。
Method for making takes by weighing pyrazinamide, ebutol, starch and low-substituted hydroxypropyl cellulose respectively by recipe quantity, and mixing behind 100 mesh sieves is granulated with 5% starch slurry excessively, put 60 ℃ of dryings in the baking oven, sieve granulate, add the magnesium stearate mixing, tabletting, sheet diameter are 6mm.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric soluble tablet: the plain sheet that will prepare is put in the coating pan, the rolling coating pan, limit spray gastric solubleness clothing liquid, the limit blowing hot-air, wrap to the sheet weightening finish to about 4%, take out and put 60 ℃ of dryings of baking oven and got promptly in 1 hour.
The preparation of embodiment 9 isoniazids, ebutol compound recipe microplate
Prescription isoniazid 12.5g, ebutol 45.8g, 5% polyvidone (K30) solution is an amount of, and magnesium stearate 0.25g makes 1000 altogether.。
Method for making takes by weighing isoniazid, ebutol, starch and low-substituted hydroxypropyl cellulose respectively by recipe quantity, and mixing behind 100 mesh sieves is granulated with 5% polyvidone (K30) solution excessively, put 60 ℃ of dryings in the baking oven, sieve granulate, add the magnesium stearate mixing, tabletting, sheet diameter are 5mm.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric soluble tablet: the plain sheet that will prepare is put in the coating pan, the rolling coating pan, limit spray gastric solubleness clothing liquid, the limit blowing hot-air, wrap to the sheet weightening finish to about 4%, take out and put 60 ℃ of dryings of baking oven and took out promptly in 1 hour.
The capsule of embodiment 10 composite rifampicin micro-tablet capsules 1 (the rifampicin microplate is an enteric, and all the other are the gastric solubleness microplate) is filled
(description is arranged in patent 03101211.6 according to the standard prescription that WHO proposed, repeat no more for saving space herein) to get rifampicin enteric microplate, isoniazid gastric solubleness microplate, pyrazinamide gastric solubleness microplate, ebutol gastric solubleness microplate that the foregoing description describes an amount of, on 4 station capsule filling machines, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
The capsule of embodiment 11 complex rifampin capsules 2 (the isoniazid microplate is an enteric, and all the other are the gastric solubleness microplate) is filled
(description is arranged in patent 03101211.6 according to the standard prescription that WHO proposed, repeat no more for saving space herein) to get isoniazid enteric microplate, rifampicin gastric solubleness microplate, pyrazinamide gastric solubleness microplate, ebutol gastric solubleness microplate that the foregoing description describes an amount of, on 4 station capsule filling machines, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
The capsule of embodiment 12 complex rifampin capsules 3 (rifampicin is the enteric microplate, and isoniazid, pyrazinamide, ebutol are compound recipe gastric solubleness microplate) is filled
(description is arranged in patent 03101211.6 according to the standard prescription that WHO proposed, repeat no more for saving space herein) to get rifampicin enteric microplate, isoniazid, pyrazinamide, ebutol compound recipe gastric solubleness microplate that the foregoing description describes an amount of, on 2 station capsule filling machines, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
The capsule of embodiment 13 complex rifampin capsules 4 (isoniazid is that enteric microplate, rifampicin are the gastric solubleness microplate, and pyrazinamide, ebutol are compound recipe gastric solubleness microplate) is filled
(description is arranged in patent 03101211.6 according to the standard prescription that WHO proposed, repeat no more for saving space herein) to get isoniazid enteric microplate, rifampicin gastric solubleness microplate, pyrazinamide, ebutol compound recipe gastric solubleness microplate that the foregoing description describes an amount of, on 3 station capsule filling machines, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
The capsule of embodiment 14 complex rifampin capsules 5 (rifampicin is the enteric microplate, and isoniazid, pyrazinamide are compound recipe gastric solubleness microplate) is filled
(description is arranged in patent 03101211.6 according to the standard prescription that WHO proposed, repeat no more for saving space herein) to get rifampicin enteric microplate, isoniazid, pyrazinamide compound recipe gastric solubleness microplate that the foregoing description describes an amount of, on 2 station capsule filling machines, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
The capsule preparation of embodiment 15 complex rifampin capsules 6 (rifampicin is the enteric microplate, and isoniazid, pyrazinamide, ebutol are gastric-soluble particle)
(1) preparation of isoniazid gastric-soluble particle
The particulate prescription of isoniazid is formed: isoniazid 75g, and starch 10g, low-substituted hydroxypropyl cellulose 3g, 5% starch slurry is an amount of.
Granulate: get each former, adjuvant of title by above-mentioned prescription, mixing behind 100 mesh sieves is granulated with 5% starch slurry excessively, puts 60 ℃ of dryings in the baking oven, sieve, and granulate, standby.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric-soluble particle: the granule for preparing is put in the coating pan, the rolling coating pan, limit spray gastric solubleness coating solution, the limit blowing hot-air, wrap to the granule weightening finish to about 4%, take out and put 60 ℃ of dryings of baking oven and took out promptly in 1 hour.
(2) preparation of pyrazinamide gastric-soluble particle
The particulate prescription of pyrazinamide is formed: pyrazinamide 400g, and starch 40g, hydroxypropyl cellulose 10g, starch slurry is an amount of.
Granulate: get each former, adjuvant of title by above-mentioned prescription, mixing behind 100 mesh sieves is granulated with starch slurry excessively, puts 60 ℃ of dryings in the baking oven, sieve, and granulate, standby.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric-soluble particle: the granule for preparing is put in the coating pan, the rolling coating pan, limit spray gastric solubleness clothing liquid, the limit blowing hot-air, wrap to the granule weightening finish to about 4%, take out and put 60 ℃ of dryings of baking oven and got promptly in 1 hour.
(3) preparation of ebutol gastric-soluble particle
The particulate prescription of ebutol is formed: ebutol 275g, and starch 40g, dextrin 10g, 5% starch slurry is an amount of.
Granulate: get each former, adjuvant of title by above-mentioned prescription, mixing behind 100 mesh sieves is granulated with 5% starch slurry excessively, puts 60 ℃ of dryings in the baking oven, sieve, and granulate, standby.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric-soluble particle: the granule for preparing is put in the coating pan, the rolling coating pan, limit spray gastric solubleness clothing liquid, the limit blowing hot-air, wrap to the granule weightening finish to about 4%, take out and put 60 ℃ of dryings of baking oven and got promptly in 1 hour.
(4) particulate mixing: the drug regimen amount according to the WHO standard prescription (has description in patent 03101211.6, repeat no more for saving space) herein, get above-mentioned isoniazid, pyrazinamide, ebutol gastric-soluble particle and put mix homogeneously in the 3 dimension mixers, and uniformity coefficient is detected.
(5) capsular filling (has description according to the standard prescription that WHO proposed in patent 03101211.6; repeat no more for saving space herein) to get rifampicin enteric microplate, isoniazid, pyrazinamide, ebutol gastric-soluble particle hybrid particles that the foregoing description describes an amount of; on 2 station capsule filling machines, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
The capsule preparation of embodiment 16 complex rifampin capsules 7 (rifampicin is a gastric-soluble particle, and isoniazid, pyrazinamide, ebutol are compound recipe gastric solubleness microplate)
(1) preparation of rifampicin gastric-soluble particle
The particulate prescription of rifampicin is formed: rifampicin 150g, microcrystalline Cellulose 30g, vitamin C 3g, low-substituted hydroxypropyl cellulose 10g.
Granulate: get each former, adjuvant of title by above-mentioned prescription, mixing behind 80 mesh sieves is granulated excessively, and granulate is standby.
The preparation of gastric solubleness coating solution: get stomach dissolved film coating pre-mix dose 9g, add 50% ethanol liquid 100ml dissolving evenly promptly.
The preparation of gastric-soluble particle: the granule for preparing is put in the coating pan, the rolling coating pan, limit spray gastric solubleness clothing liquid, the limit blowing hot-air, wrap to the granule weightening finish to about 4%, take out and put 50 ℃ of dryings of baking oven and got promptly in 1 hour.
(2) capsular filling (has description according to the standard prescription that WHO proposed in patent 03101211.6, repeat no more for saving space herein) to get rifampicin gastric-soluble particle, isoniazid, pyrazinamide, ebutol compound recipe gastric solubleness microplate that the foregoing description describes an amount of, on 2 station capsule filling machines, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
Claims (7)
1, a kind of manufacture method of composite rifampicin micro-tablet capsule, it is characterized in that Rimactazid, further comprise pyrazinamide, further comprise pyrazinamide and ebutol and be crude drug and carry out compound compatibility when making the capsule preparations of medicine, having a kind of medicine wherein at least is after at first being prepared into the medicine microplate, to reinstall in the capsule, and the diameter range of its microplate is between 3mm～7.8mm, the optimum diameter scope is between 4mm～7.9mm
Its component rifampicin is the form of microplate, and other medicines also are the forms of microplate,
Its component rifampicin is the form of microplate, and other medicines can be the forms of micropill,
Its component rifampicin is the form of microplate, and other medicines can be form of powder,
Its component rifampicin is the form of folk prescription microplate, isoniazid and pyrazinamide, and further comprising pyrazinamide and ebutol is compound recipe microplate, micropill, particulate form,
Its component isoniazid is the form of folk prescription microplate, and rifampicin can be micropill, granule, form of powder, comprises that further pyrazinamide and ebutol are compound recipe microplate, micropill, particulate form.
2, according to claim 1, it is characterized in that the rifampicin microplate is an enteric coating, the isoniazid component comprises that further pyrazinamide and ebutol component are the gastric solubleness coatings.
3, according to claim 1, it is characterized in that the isoniazid microplate is an enteric coating, the rifampicin microplate comprises that further pyrazinamide and ebutol component are the gastric solubleness coatings.
4, according to claim 1, the profile of microplate is outside round convex shape, and the disk periphery has the inclination corner angle.
5, according to claim 1, the hardness of rifampicin microplate is at 3～8kg/cm
2Between, the best is 3kg/cm
2
6, according to claim 1,2 hours planted agents are less than 10% of labelled amount for the burst size of rifampicin enteric microplate in acid, and 45 minutes planted agents of the burst size in buffer solution are greater than 75% of labelled amount, and the best should be greater than more than 85%.
7, according to claim 1,2 hours planted agents are less than 10% of labelled amount for the burst size of isoniazid enteric microplate in acid, and 45 minutes planted agents of the burst size in buffer solution are greater than 75% of labelled amount, and the best should be greater than more than 85%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200610092086 CN1864681A (en) | 2006-06-09 | 2006-06-09 | Preparation method of composite rifampicin micro-tablet capsule |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797238A (en) * | 2010-01-23 | 2010-08-11 | 高华 | Method for preparing medicinal preparation for releasing rifampicin on upper part of small intestine and characteristics of medicinal preparation |
| CN106420669A (en) * | 2016-10-25 | 2017-02-22 | 赛乐医药科技(上海)有限公司 | Propafenone hydrochloride sustained-release micro-tablet capsule and preparation method and application thereof |
| CN110200933A (en) * | 2019-07-11 | 2019-09-06 | 重庆华邦制药有限公司 | It is used to prepare the composition and its preparation method and application for treating phthisical three compound preparation |
-
2006
- 2006-06-09 CN CN 200610092086 patent/CN1864681A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797238A (en) * | 2010-01-23 | 2010-08-11 | 高华 | Method for preparing medicinal preparation for releasing rifampicin on upper part of small intestine and characteristics of medicinal preparation |
| CN106420669A (en) * | 2016-10-25 | 2017-02-22 | 赛乐医药科技(上海)有限公司 | Propafenone hydrochloride sustained-release micro-tablet capsule and preparation method and application thereof |
| CN110200933A (en) * | 2019-07-11 | 2019-09-06 | 重庆华邦制药有限公司 | It is used to prepare the composition and its preparation method and application for treating phthisical three compound preparation |
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