CN1864683A - A preparation method of compound rifampicin preparation - Google Patents
A preparation method of compound rifampicin preparation Download PDFInfo
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- CN1864683A CN1864683A CN 200610092091 CN200610092091A CN1864683A CN 1864683 A CN1864683 A CN 1864683A CN 200610092091 CN200610092091 CN 200610092091 CN 200610092091 A CN200610092091 A CN 200610092091A CN 1864683 A CN1864683 A CN 1864683A
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- rifampicin
- isoniazid
- pyrazinamide
- ebutol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 115
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 title claims abstract description 92
- 229960001225 rifampicin Drugs 0.000 title claims abstract description 87
- 150000001875 compounds Chemical class 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 96
- 239000008187 granular material Substances 0.000 claims abstract description 85
- 229960003350 isoniazid Drugs 0.000 claims abstract description 50
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229960005206 pyrazinamide Drugs 0.000 claims abstract description 42
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000000576 coating method Methods 0.000 claims description 69
- 239000011248 coating agent Substances 0.000 claims description 66
- 239000002245 particle Substances 0.000 claims description 59
- 229940079593 drug Drugs 0.000 claims description 58
- 239000002775 capsule Substances 0.000 claims description 50
- AUAHHJJRFHRVPV-BZDVOYDHSA-N ethambutol dihydrochloride Chemical compound [Cl-].[Cl-].CC[C@@H](CO)[NH2+]CC[NH2+][C@@H](CC)CO AUAHHJJRFHRVPV-BZDVOYDHSA-N 0.000 claims description 38
- 239000000463 material Substances 0.000 claims description 23
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- 238000002156 mixing Methods 0.000 claims description 15
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- 239000002702 enteric coating Substances 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 5
- 229940049413 rifampicin and isoniazid Drugs 0.000 claims description 4
- 239000007787 solid Substances 0.000 abstract description 4
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 abstract description 3
- 229960001618 ethambutol hydrochloride Drugs 0.000 abstract 1
- 238000000034 method Methods 0.000 description 32
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
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- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
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- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- -1 rifampicin compound Chemical class 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- FRPHFZCDPYBUAU-UHFFFAOYSA-N Bromocresolgreen Chemical compound CC1=C(Br)C(O)=C(Br)C=C1C1(C=2C(=C(Br)C(O)=C(Br)C=2)C)C2=CC=CC=C2S(=O)(=O)O1 FRPHFZCDPYBUAU-UHFFFAOYSA-N 0.000 description 3
- 101100327917 Caenorhabditis elegans chup-1 gene Proteins 0.000 description 3
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229930003268 Vitamin C Natural products 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
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- 235000019154 vitamin C Nutrition 0.000 description 3
- 239000011718 vitamin C Substances 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
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- 230000036541 health Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229940080507 isoniazid 150 mg Drugs 0.000 description 2
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- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
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- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
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- 230000007423 decrease Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 208000015355 drug-resistant tuberculosis Diseases 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229940049560 rimactane Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The preparation process of new compound rifampicin preparation features that rifampicin, isoniazide, pyrazinamide and ethambutol hydrochloride are first prepared into granule, then coated and finally encapsulated. The preparation process can isolate the medicine components at most to avoid the avoid close contact of medicine components in the solid preparation environment so as to ensure the stability of the compound rifampicin preparation.
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 03101211.6, its granted patent certificate number is 208518, the application be according to research further deeply, be the tiny flaw that overcomes patent 03101211.6 preparation method of neoteric a kind of compound rifampicin preparation on its basis.
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 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, the result of study about this respect can reduce following 3 points:
1, the degraded of rifampicin is the function of environment 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.Under the isoniazid and the situation of depositing, the degraded of rifampicin will speed up.The prompting of this result of study should make rifampicin avoid sour environment and meet with isoniazid in sour environment before absorption when FDC makes as far as possible, has proposed therefrom the notion of rifampicin in upper part of small intestine release.
2, in FDC preparation solid environment, rifampicin contacts with isoniazid, and not only rifampicin produces degraded, and isoniazid also produces degraded, and simultaneously, pyrazinamide, ebutol, humidity, temperature play catalytic action to this degraded.Therefore, prompting should avoid rifampicin to contact closely with isoniazid in the FDC preparation, and damp proof to the FDC preparation, keep away temperature.
3, because if there is the above-mentioned degradation problem that is difficult to overcome in the FDC preparation according to common compound preparation manufacture method, in the process that the FDC preparation is made and stored and transported, be 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 the control of the dissolution of tackling each drug component and conventional indexs such as release, content, and what is more important should be controlled the catabolite of each drug component.Yet, by the end of also do not have so far easy and effectively analytical technology can be to tuberculosis FDC 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 WO02/087547A1 for example, WO2004/041284 etc.These patents all disclose some effective methods of dealing with problems, yet, also there is certain defective simultaneously.The defective that the present invention only exists at patent 03101211.6 proposes improved measure, sets up a kind of manufacture method of new compound rifampicin preparation, and perhaps its improvement is small, still, in real suitability for industrialized production the marked improvement meaning will be arranged.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 the preparation method of four kinds of medicament pellets, and the drug dose of the standard prescription of announcing according to World Health Organization (WHO) respectively by these four kinds of micropills, 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 the bioavailability of rifampicin.
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, and this in fact also is a kind of preparation method of compound rifampicin preparation.
The manufacture method of this tuberculosis FDC preparation has solved rifampicin and isoniazid contacting in preparation effectively, has avoided because the degradation problem that contact produces.Yet, in Product industrialization is produced, run into certain difficulty.Because, for spherical object, when two or more spherical objects mixes, in any case be mix uneven.For this serier compound Rimactane, owing to be that the standard prescription that proposes according to WHO fully is prepared, just certainly will there be 4 kinds of needs, 3 kinds, the 2 kinds problems that medicine cooperatively interacts, that is to say and 2 kinds or 3 kinds or 4 kinds of micropills need be loaded in the same capsule shells.
For the common capsule filling machine tool of the overwhelming majority, all be only to fill a material.Because the spheroidal micropill can't mix homogeneously, therefore, need respectively micropill is filled in the capsule successively to go.Obviously, common capsule filling machine tool is in case of failure.Now there have been 2,3,4 station capsule filling machine tools can realize successively the micropill below 4 kinds quantitatively being filled in the capsule respectively.But this machinery costs an arm and a leg, and the price of 2 station capsule filling machines is about 5 times of conventional capsule filling machine, and 3 station capsule filling machines reach 12 times, and 4 station capsule filling machines reach 30 times.Obviously adopt this machinery to need high equipment investment undoubtedly, high equipment investment just means that production cost of products improves.
WHO has proposed 5 basic demands to the tuberculosis medicine in recommending tuberculosis FDC standard preparation prescription: the dosage that 1, meets the standard prescription of WHO proposition; 2, ensure product quality, especially will ensure the bioavailability of rifampicin; 3, good compliance; 4, be convenient to accumulating, distribution ﹠ management; 5, cheap.
For patent 03101211.6 described tuberculosis FDC preparation manufacture method, though many advantages are arranged, for example two delivery systmes can be avoided rifampicin degraded in vivo effectively, can avoid rifampicin under the solid environment of FDC preparation contacts with the direct of other medicines, can set up easily the various drug components in the FDC preparation are carried out the catabolite detection method, yet, unique shortcoming is to use the multistation capsule filling machine, finally cause the production cost of tuberculosis FDC preparation to increase relatively, this obviously is unfavorable for implementing all sidedly the above-mentioned requirements of WHO.
In order to overcome the shortcoming of patent 03101211.6, and keep the core advantage of patent 03101211.6 as far as possible, in realizing patent 03101211.6 skilled industry production process, the inventor has worked out the preparation technique of the new compound rifampicin preparation that is different from patent 03101211.6 slightly.
The core of this new preparation technique is exactly: respectively Rimactazid, pyrazinamide, ebutol are prepared into single medicine granule earlier, then, the drug ratio of writing out a prescription according to the tuberculosis FDC standard preparation of WH0 concerns, get each drug particles respectively and mix, get mixture and be packed into and make tuberculosis FDC preparation in the capsule shells; Perhaps isoniazid, pyrazinamide or isoniazid, pyrazinamide, ebutol or pyrazinamide, ebutol are made compound granular according to the drug ratio relation of the tuberculosis FDC standard preparation prescription of WHO; the drug ratio relation of the standard prescription that proposes according to WHO then; (the rifampicin component can be the folk prescription granule to divide the drug particles get each medicine or compound granular and rifampicin component; also can be crude drug) mix; at last mixture is packed in the capsule shells, makes tuberculosis FDC preparation.
The existence of the gentle isoniazid component of all favourable good fortune of capsular content of this tuberculosis FDC preparation that contains the rifampicin component, but different is with other preparations that contain rifampicin: rifampicin component and other components are not with very little granularity, for example granularity is carried out mixed uniformly arbitrarily less than 0.02mm, especially extensively contact closely with the isoniazid component is formed after fully mixed, the purpose of doing like this be avoid as far as possible to greatest extent rifampicin in preparation with the contacting of other drug composition, thereby avoid as much as possible in FDC solid environment, fully contact the degraded that produces owing to rifampicin and other drug component.This shows, if the rifampicin component is implemented coating, perhaps rifampicin component coating not, but other components are implemented coating, perhaps all components is all implemented coating, then with more effective rifampicin and the other drug component cut apart in preparation.It is to be noted, if medicine is all made granularity greater than the granule more than the 0.02mm, like this rifampicin is mixed with other drug, though mix homogeneously then, but because it is bigger to participate in the fineness ratio of blended medicine, the surface area that contacts between the medicine like this is just relatively very little, like this, even if contact is arranged, but because the surface area ratio of contact is less, its rifampicin also will significantly reduce owing to contacting the degradation reaction that produces with other drug, but will avoid fully, preferably medicine is implemented coating and isolates.
In order to implement coating, except medicine is made the way of micropill described in patent 03101211.6, another the most effective way is made granule with medicine exactly.
No matter be folk prescription drug particles or compound medicine granule, this short grained mean diameter is between 0.1mm～0.8mm, and minimum is not less than 0.02mm, and maximum is not greater than 2.0mm.The granule profile is irregularly shaped, is the best with triangle cone, small prism shape wherein, and particle surface should be smooth as far as possible.
Preparing particulate prescription and method has multiple, in the reference book of these methods in general pharmaceutical preparation field basic means introduction is arranged all, again in conjunction with the adjuvant that prescription adopted of the micropill preparation of introducing in the patent 03101211.6, some important adjuvants especially wherein, sodium lauryl sulphate for example, vitamin C etc., content in conjunction with above-mentioned two aspects, implement simple experiment again, be not difficult to find out the particulate prescription of this several drugs, and adopt and extrude, fluid bed, conventional granulates manufacture methods such as dry granulation just can be prepared the various drug particles that meet above-mentioned particle size, for saving space, repeat no more herein.
To above-mentioned drug particles, can carry out coating, thereby form as patent 03101211.6 described two medicine-releasing systems that discharge.With the granule difference coating of each medicine, coating has three kinds of different situations:
1, the rifampicin granule is carried out the enteric coating material coating, get final product as the coating material of introducing in the patent 03101211.6.Because require the rifampicin granule to discharge at the upper part of small intestine of human body, therefore, coating material is best between pH5.0～pH5.5 to the sensitive spot of pH.Other isoniazid, pyrazinamide, ebutol granule adopt gastric solubleness material coating, certainly, and also coating not.
The purpose that adopts this coating scheme is that requirement rifampicin granule discharges at upper part of small intestine, and the other medicines granule discharges under one's belt.
2, the isoniazid granule is carried out the enteric coating material coating, get final product as the coating material of introducing in the patent 03101211.6.Because require the isoniazid granule to discharge at the upper part of small intestine of human body, therefore, coating material is best between pH5.0～pH5.5 to the sensitive spot of pH.Other rifampicin, pyrazinamide, ebutol granule adopt gastric solubleness material coating, certainly, and also coating not.
The purpose that adopts this coating scheme is that requirement isoniazid granule discharges at upper part of small intestine, and the other medicines granule discharges under one's belt.
3, Rimactazid, pyrazinamide, ebutol granule are all adopted gastric solubleness material coating, certainly, also can be coating or only the rifampicin granule is carried out the gastric solubleness coating not, to avoid contacting of rifampicin and other drug.
The purpose that adopts this coating scheme is that all drug particles of requirement all discharge under one's belt.
The release situation that above-mentioned three kinds of formed drug particles of coating scheme are combined in the human body all has special characteristics, and cuts both ways.But preferred version 1 and 2 wherein.
After respectively drug particles being implemented coating, just need get the drug particles of relative medicine dosage according to the ratio of the FDC standard preparation drug prescription of WHO proposition respectively according to different pharmaceutical formulations, mix then.Be blended in pharmaceuticals industry produce in the general mixing machinery that adopts, the selection of mixing machinery is not had special requirement, for example conventional V-Mixer that uses, Multidimensionblender etc.No matter use any mixing machinery, its objective is that with the drug particles mix homogeneously if mix inhomogeneously, the component that will cause medicine is after filling capsule, the content of dispersion of preparation does not meet the WHO requirement, and this is that pharmaceutical preparation institute is unallowed.
For the granule of mix homogeneously, just can use the conventional capsule filling machine to implement the capsule filling, thereby finish the preparation overall process of whole tuberculosis FDC preparation.
In the preparation process of above-mentioned tuberculosis FDC preparation, should note following some:
1, particulate average-size is unsuitable too small or excessive.The too small then particulate surface area of granule is too big, and the coating material of consumption is too much, when coating material surpass medication amount 50% after just not ideal, be that pharmaceutical preparation institute is unallowed when surpassing 1 times.More satisfactory is coating material is coating object 2%～30% between, conventional about 5%; Granule is excessive, even if mix homogeneously, it is inhomogeneous also can to cause capsule to fill, because prescription requirement according to WHO, in the most standard prescription, the amount of isoniazid is 50% of a rifampicin, is 19% of pyrazinamide, is 27% of ebutol, so, after the combination of several drugs granule, the grain amount of isoniazid is less, and capsular inner capacities is also smaller, so, granule is excessive just to cause the particulate loading of isoniazid inaccurate easily, surpasses the scope of pharmaceutical preparation content uniformity, promptly but also there is similar problem in rifampicin.Therefore particulate size is unsuitable excessive, generally between 0.1mm～1.2mm for well, the best is best between 0.2mm～1.0mm.
2, when granule mixes, blended action is difficult for too violent, and this is through coating because of granule, but granule has corner angle, and it is too violent to mix action, just causes the coatings breakage of particulate edges and corners easily, finally causes coating incomplete.For preceding 1,2 kind of coating situation, will cause enteric-coating material to discharge in the examination at the environment through gastric solubleness liquid, medicine is revealed in the gastric solubleness coating solution too much, under certain conditions, when the amount of leakage of medicine surpasses 10%, promptly think the defective of pharmaceutical preparation.This condition is meant rotating speed, the temperature and time when pharmaceutical preparation is carried out drug release determination on the dissolution instrument.Therefore, after finishing granule and mixing, at first should check the particulate uniformity, secondly, must check particulate release and stripping situation, in granule, contain the granule of enteric coating particularly important.
3, in order to implement the enteric material coating better, can on granule, 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, HPMC etc.The reason of carrying out water solublity contagion gown parcel is the initial stage of carrying out enteric coating at granule, have a spot of drug powder and break away from granule, in the coating environment, form the fine drug 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 the quality control of preparation.Certainly, if through overtesting, the granule medicament fine 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, biggest advantage is exactly to carry out the mixing of arbitrary proportion to the granule of different pharmaceutical, using 1 station conventional capsule filling machine to carry out capsule then fills, perhaps use 2 relatively cheap station capsule filling machines of price to realize the FDC preparation filling of 2 medicines, 3 medicines and 4 medicines, reduce equipment investment so to greatest extent, also just reduced production cost of products to greatest extent.
But, the shortcoming that adopts this method is to use straightforward procedure to set up various ingredient degradation material detection methods in the complex rifampin FDC preparation, and various ingredients in the tuberculosis FDC preparation are set up important link in the research and development that detection method is a tuberculosis FDC preparation.
So said method is compared with the complex rifampin preparation method that patent 03101211.6 is described, merits and demerits has both.But, if modern pharmaceutical analysis technology has solved the catabolite detection method of each ingredient in Rimactazid, pyrazinamide and the ebutol hybrid medicine granule, then the preparation method of the described compound rifampicin preparation of this patent will have bigger allure in the advantage that is had aspect the reduction production equipment cost 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 micropill 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 coated particles:
1, the preparation of isoniazid enteric coated particles
The particulate prescription of isoniazid is formed: isoniazid 75g, and starch 6g, 5% polyvidone (K30) solution is an amount of.
Granulate: get each former, adjuvant of title by above-mentioned prescription, mixing behind 100 mesh sieves is granulated with 5% polyvidone (K30) solution excessively, puts 60 ℃ of dryings in the baking oven, sieve, and granulate, standby.
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 coated particles: the granule 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 granule 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 hydrochloric acid solution (9 → 1000) 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 coated particles
(1) experiment purpose: measure the stripping curve of enteric isoniazid granule in hydrochloric acid solution (9 → 1000), 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 (being equivalent to isoniazid 150mg) respectively according to dissolution method first subtraction unit, be solvent with hydrochloric acid solution (9 → 1000), 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 5ml in 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, filter, replenish solvent simultaneously with volume, getting subsequent filtrate 1ml places the 10ml 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:
The preparation and the release behaviour in vitro of embodiment 2 rifampicin enteric coated particles
1, the preparation of rifampicin enteric coated particles
The particulate prescription of rifampicin is formed: rifampicin 150g, microcrystalline Cellulose 45g, vitamin C 3g, carboxymethyl starch sodium 2g.
Granulate: get each former, adjuvant of title by above-mentioned prescription, mixing behind mistake 80 mesh sieves, dry granulation, granulate, standby.
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 granule for preparing 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 granule 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 coated particles: the granule that will wrap film-coat is put in the coating pan, the rolling coating pan, limit spray enteric coating liquid, the limit blowing hot-air, wrap to the granule weightening finish to about 10%, take out and put 50 ℃ of dryings of baking oven 1 hour.Take out, 2 hours burst size should be less than 10% in hydrochloric acid solution (9 → 1000) 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 coated particles
(1) experiment purpose: measure the stripping curve of enteric rifampicin micropill in hydrochloric acid solution (9 → 1000), water, pH5.0, pH5.6, pH6.8 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 (being equivalent to rifampicin 50mg) respectively according to dissolution method first subtraction unit, be solvent with hydrochloric acid solution (9 → 1000), 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 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, filters, replenish solvent simultaneously with volume, get subsequent filtrate 4ml and place the 10ml measuring bottle to be diluted to scale, shake up, as sample solution with corresponding solvent; 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 | 9.82 | 47.22 | 86.11 | 92.26 | 99.88 | 99.92 |
| The pH5.6 buffer | 10.63 | 49.53 | 88.02 | 93.42 | 99.86 | 99.99 |
| The pH6.8 buffer | 10.88 | 49.85 | 88.46 | 99.25 | 100.23 | 99.89 |
The preparation and the release behaviour in vitro of embodiment 3 rifampicin gastric-soluble particles
1, the 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: take by weighing each former, adjuvant by above-mentioned prescription, mixing behind mistake 80 mesh sieves, dry granulation, 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 50 ℃ of dryings of baking oven and took out promptly in 1 hour.
2, the release behaviour in vitro of rifampicin gastric-soluble particle
(1) experiment purpose: measure the stripping curve of rifampicin gastric solubleness micropill in hydrochloric acid solution (9 → 1000).
(2) experimental basis: Chinese Pharmacopoeia two appendix of version " dissolution method " in 2005; get this product (being equivalent to rifampicin 50mg) according to dissolution method first method; 900ml is a solvent with hydrochloric acid solution (9 → 1000), adopt 50 rev/mins rotating speed, operation in accordance with the law; Got solution 10ml, filtration, additional simultaneously solvent respectively at 5,10,20,30,45,60 minutes with volume.Precision is measured subsequent filtrate 4ml, puts in the 10ml measuring bottle, is diluted to scale with hydrochloric acid solution (9 → 1000), as need testing solution; Other gets the rifampicin reference substance, is diluted to the solution that contains 25ug among every 1ml approximately with hydrochloric acid solution (9 → 1000), 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 | |
| 5 minutes | 12.2 | 11.6 | 10.9 | 12.7 | 13.4 | 10.1 | 11.8 |
| 10 minutes | 53.1 | 52.0 | 50.5 | 53.4 | 54.8 | 49.9 | 52.3 |
| 20 minutes | 89.2 | 87.2 | 86.5 | 91.3 | 92.5 | 87.4 | 89.0 |
| 30 minutes | 99.5 | 99.1 | 99.2 | 98.6 | 99.1 | 99.5 | 99.2 |
| 45 minutes | 99.9 | 100.3 | 99.3 | 99.5 | 100.1 | 99.6 | 99.8 |
| 60 minutes | 99.9 | 99.1 | 98.8 | 99.2 | 99.5 | 99.6 | 99.4 |
The preparation and the release behaviour in vitro of embodiment 4 isoniazid gastric-soluble particles
1, the 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, the release behaviour in vitro of isoniazid gastric-soluble particle
(1) experiment purpose: measure the stripping curve of gastric solubleness isoniazid granule 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 (being equivalent to isoniazid 150mg), is solvent with water 900ml, 50 rev/mins of rotating speeds, operation in accordance with the law; Respectively at getting solution 5ml in 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, filter, replenish solvent simultaneously with volume, get subsequent filtrate 1ml and place the 10ml 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 | |
| 5 minutes | 53.4 | 50.1 | 50.8 | 56.7 | 55.9 | 57.3 | 54.0 |
| 10 minutes | 83.9 | 81.7 | 80.8 | 85.4 | 85.1 | 86.7 | 83.9 |
| 20 minutes | 95.8 | 93.9 | 92.2 | 97.9 | 97.2 | 97.6 | 95.8 |
| 30 minutes | 100.1 | 100.8 | 98.4 | 99.8 | 101.7 | 101.4 | 100.4 |
| 45 minutes | 100.0 | 101.3 | 99.7 | 99.3 | 100.4 | 100.3 | 100.2 |
| 60 minutes | 99.7 | 100.2 | 99.4 | 99.1 | 99.8 | 99.6 | 99.6 |
The preparation and the release behaviour in vitro of embodiment 5 pyrazinamide gastric-soluble particles
1, the 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 took out promptly in 1 hour.
2, the release behaviour in vitro of pyrazinamide gastric-soluble particle
(1) experiment purpose: measure the stripping curve of gastric solubleness pyrazinamide granule 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 (being equivalent to pyrazinamide 250mg), is solvent with water 900ml, 50 rev/mins of rotating speeds, operation in accordance with the law; In the time of 5,10,20,30,45,60 minutes, get solution 5ml, replenish solvent simultaneously with volume, filter, get subsequent filtrate 1ml and put in the 25ml 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 | |
| 5 minutes | 44.4 | 43.0 | 41.0 | 41.9 | 44.0 | 39.8 | 42.4 |
| 10 minutes | 84.1 | 81.3 | 80.4 | 79.8 | 84.4 | 78.3 | 81.4 |
| 20 minutes | 99.9 | 98.1 | 98.9 | 97.7 | 99.3 | 98.6 | 98.8 |
| 30 minutes | 100.4 | 101.3 | 100.1 | 99.1 | 99.0 | 100.9 | 100.1 |
| 45 minutes | 100.1 | 100.3 | 99.6 | 100.1 | 99.9 | 100.4 | 100.1 |
| 60 minutes | 99.7 | 100.1 | 99.3 | 100.0 | 99.4 | 99.9 | 99.7 |
The preparation and the release behaviour in vitro of embodiment 6 ebutol gastric-soluble particles
1, the 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.
2, the release behaviour in vitro of ebutol gastric-soluble particle
(1) experiment purpose: measure the stripping curve of gastric solubleness ebutol granule 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 (being equivalent to ebutol 92mg), is solvent with water 900ml, 50 rev/mins of rotating speeds, operation in accordance with the law.Respectively at 5,10,20,30,45, in the time of 60 minutes, get solution 5ml, replenish solvent simultaneously with volume, filter, get subsequent filtrate 1ml, 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 100ug among every 1ml) 1ml 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 | |
| 5 minutes | 51.7 | 49.4 | 53.2 | 50.8 | 52.6 | 51.1 | 51.5 |
| 10 minutes | 69.6 | 68.5 | 72.1 | 84.3 | 70.5 | 68.9 | 72.3 |
| 20 minutes | 99.2 | 98.1 | 99.9 | 101.4 | 97.4 | 99.5 | 99.2 |
| 30 minutes | 100.8 | 99.8 | 101.4 | 102.5 | 99.2 | 101.3 | 100.8 |
| 45 minutes | 99.5 | 98.5 | 100.9 | 101.6 | 98.7 | 100.9 | 100.0 |
| 60 minutes | 99.0 | 98.3 | 100.2 | 101.4 | 98.8 | 100.8 | 99.8 |
The capsule of embodiment 7 complex rifampin capsules (the rifampicin granule is an enteric, and all the other are gastric-soluble particle) 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 coated particles, isoniazid gastric-soluble particle, pyrazinamide gastric-soluble particle, ebutol gastric-soluble particle that the foregoing description describes an amount of, put in the three-dimensional mixer and mix, medication amount according to standard prescription is carried out the uniformity of dosage units inspection, and calculates the capsule loading.Select 1 station conventional capsule filling machine for use, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
The capsule of embodiment 8 complex rifampin capsules (the isoniazid granule is an enteric, and all the other are gastric-soluble particle) is filled
As mentioned above, isoniazid enteric coated particles, rifampicin gastric-soluble particle, pyrazinamide gastric-soluble particle, the ebutol gastric-soluble particle of getting the foregoing description description according to the standard prescription that WHO proposed are an amount of, put in the three-dimensional mixer and mix, medication amount according to standard prescription is carried out the uniformity of dosage units inspection, and calculates the capsule loading.Select 1 station conventional capsule filling machine for use, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
The capsule of embodiment 9 complex rifampin capsules (all granules are gastric-soluble particle) is filled
As mentioned above, isoniazid gastric-soluble particle, rifampicin gastric-soluble particle, pyrazinamide gastric-soluble particle, the ebutol gastric-soluble particle of getting the foregoing description description according to the standard prescription that WHO proposed are an amount of, put in the three-dimensional mixer and mix, medication amount according to standard prescription is carried out the uniformity of dosage units inspection, and calculates the capsule loading.Select 1 station conventional capsule filling machine for use, the capsule loading of adjusting capsule filling machine carries out capsule and fills.
The preparation of embodiment 10 compound granulars and capsule are filled
Select and preparation method with reference to the particulate adjuvant of above-mentioned folk prescription, 2 recurrence due to taking drug side's granules that can prepare isoniazid and pyrazinamide, or 2 recurrence due to taking drug side's granules of preparation isoniazid and ebutol, or the compound granular of preparation pyrazinamide, ebutol 2 medicines, or the compound granular of preparation isoniazid, pyrazinamide, ebutol 3 medicines.
Use above-mentioned compound granular,, or use the folk prescription granule of Rimactazid and the compound granular of pyrazinamide, ebutol 2 medicines with the combination of the folk prescription granule of rifampicin, thus 2,3,4 medicine FDC preparations of formation WHO defined.
Use above-mentioned granule, after should mixing granule according to the dosage of WHO, use common (1 station capsule filling machine) to carry out capsule and fill;
Or use 2 station capsule filling machines respectively granule to be implemented capsule according to the recipe quantity of WHO and fill, finally finish the production of 2,3,4 medicine FDC preparations of WHO defined.
Because after having set up the above-mentioned group method of the present invention, the preparation production of finishing present embodiment is the work that those of ordinary skill just should be finished, and just repeats no more herein.
Claims (9)
1, a kind of compound rifampicin preparation, comprise rifampicin and isoniazid, further comprise pyrazinamide or pyrazinamide and ebutol alternatively, wherein each dose meets the up-to-date compatibility dosage requirement that WHO calendar year 2001 number one (79 the 1st phase of volume) bulletin is proposed, with rifampicin, isoniazid, pyrazinamide, ebutol requires to incapsulate according to the compatibility of WHO, it is characterized in that the rifampicin component not with isoniazid, comprise that further pyrazinamide and ebutol carry out any uniform mixing of each drug particle size less than 0.02mm
Its rifampicin can be a material powder, also can be single medicine granule,
Its isoniazid, pyrazinamide, ebutol can be single medicine granules,
Its isoniazid, pyrazinamide can be 2 recurrence due to taking drug side's granules,
Its isoniazid, ebutol can be 2 recurrence due to taking drug side's granules,
Its pyrazinamide, ebutol can be 2 recurrence due to taking drug side's granules.
Its rifampicin granule is a coating,
The folk prescription granule of its isoniazid, pyrazinamide, ebutol is a coating,
The various compound granulars that its isoniazid, pyrazinamide, ebutol are formed are coatings.
2, according to claim 1, its particulate diameter is between 0.02mm～2.0mm, and its best is 0.1mm～0.8mm.
3, according to claim 1, the particulate coating material of single medicine of its rifampicin and isoniazid is an enteric-coating material, and the dissolved condition of enteric coating film be pH be begin between 5.0～5.5 the dissolving.
4, according to claim 1,2, the coating of its drug particles can adopt gastric solubleness coating material coating.
5,, after it is characterized in that the rifampicin component made enteric coated particles,, after mixing, the gastric-soluble particle that further comprises pyrazinamide and ebutol is packed into capsule again with the isoniazid gastric-soluble particle according to claim 1,2,3,4 preparation.
6,, after it is characterized in that the isoniazid component made enteric coated particles,, after mixing, the gastric-soluble particle that further comprises pyrazinamide and ebutol is packed into capsule again with the rifampicin gastric-soluble particle according to claim 1,2,3,4 preparation.
7, according to claim 1,2,3,4 preparation, it is characterized in that all components all are gastric solubleness coating material coatings.
8, according to claim 5,7, it is characterized in that isoniazid, pyrazinamide, comprise that further isoniazid, pyrazinamide, ebutol are the compound granulars of 2 medicines and 3 medicines.
9,, it is characterized in that pyrazinamide and ebutol are the compound granulars of 2 medicines according to claim 6,7.
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Cited By (2)
| 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 |
| CN102342940A (en) * | 2010-07-29 | 2012-02-08 | 信东生技股份有限公司 | Improved method for preparing anti-tuberculosis combination and pharmaceutical composition prepared by same |
-
2006
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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 |
| CN102342940A (en) * | 2010-07-29 | 2012-02-08 | 信东生技股份有限公司 | Improved method for preparing anti-tuberculosis combination and pharmaceutical composition prepared by same |
| CN102342940B (en) * | 2010-07-29 | 2013-11-27 | 信东生技股份有限公司 | Improved process for the preparation of anti-tuberculosis combinations and pharmaceutical compositions prepared therefrom |
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