CN101524355A - Compound preparation of antituberculosis medicaments, and preparation method thereof - Google Patents
Compound preparation of antituberculosis medicaments, and preparation method thereof Download PDFInfo
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- CN101524355A CN101524355A CN200810010531A CN200810010531A CN101524355A CN 101524355 A CN101524355 A CN 101524355A CN 200810010531 A CN200810010531 A CN 200810010531A CN 200810010531 A CN200810010531 A CN 200810010531A CN 101524355 A CN101524355 A CN 101524355A
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- pyrazinamide
- ebutol
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Abstract
The invention belongs to the technical field of medicines, and provides a compound preparation of antituberculosis medicaments, and a preparation method thereof. Rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as four leading antituberculosis medicaments are prepared into the compound preparation according to specific mixture ratio. The method comprises the steps of evenly mixing the leading drugs with an appropriate quantity of disintegrant and diluent, performing dry-process granulation, finishing granules, adding other auxiliary materials to the granules and preparing the obtained product into a suitable preparation. The invention solves the problems that patients are difficult to cooperate closely and complete normal chemotherapys because the antituberculosis medicaments are high in dosage, large in dosage form and troublesome in medicine-taking method, and the compound preparation and the preparation method accord with global tuberculosis direct-observation short-range supervision chemotherapy strategy (DOTS) recommended by the WHO. The antituberculosis fixed-dose compound preparation has important significance for simplifying medicine-taking method, carrying out the DOTS and controlling tuberculosis prevalence.
Description
Technical field
The present invention relates to medical technical field, is compound preparation of antituberculotics and preparation method thereof.
Background technology
Tuberculosis is the chronic infectious disease that is caused by tubercule bacillus, can invade and many internal organs, gets involved with pulmonary that to form pulmonary tuberculosis the most common, and tuberculosis is a kind of ancient disease, is again the whole world urgent public health and the social problem that are faced at present.After nineteen nineties, global sickness rate lungy gos up rapidly.International anti-tuberculosis association and pulmonary disease community (IUATLD) and The World Health Organization (WHO) classify these 6 kinds of medicines of Rimactazid, pyrazinamide, ebutol, streptomycin and thiacetazone as a main line antituberculotics.Wherein streptomycin is generally injection.Thiacetazone is big because of toxicity in China, patient's toleration difference and eliminate already need not.
Rifampicin (RFP) is a Ryfamycin derivative, and tubercule bacillus is had powerful sterilization and sterilization functions, especially at sterilization speed with kill that effect more is better than isoniazid aspect the persisting bacilli.The oral back of RFP absorbs rapidly, is distributed in body tissue, and 1～2h reaches the blood concentration peak, and half-life 3～8h is mainly by discharging from bile and urine behind the liver metabolism.There is " liver sausage circulation " in RFP in human body, so can keep higher concentration in human body.List produces the height drug resistance very easily rapidly with RFP, and has crossing drug resistant with other rifamycin drug, but does not have crossing drug resistant with other anti-nuclear pharmaceuticals, and drug combination can prevent and reduce drug resistance and produce.
Isoniazid (INH) is efficient because of it for a long time, low toxicity, convenience, advantage such as inexpensive become tuberculosis chemotherapy choice drug.Isoniazid has powerful bactericidal action to tubercule bacillus, can penetrate pathological tissues rapidly, is not subjected to the influence of environment pH, and the vigorous tubercule bacillus bactericidal action of pair cell outgrowth is the strongest, in the pair cell slowly the persisting bacilli of growth stronger killing action is also arranged.Oral absorption is good, and 1～2h reaches the blood concentration peak, and mean half-life is about 6h, mainly by liver metabolism after kidney from urine, discharge.List drug resistance occurs very soon with INH, but does not have crossing drug resistant with other antituberculotics, and drug combination can prevent and reduce drug resistance and produce.
Pyrazinamide (PZA) is former only as the careful use of two wires medicine.Rise the seventies in last century, and people are greatly improved to the evaluation of pyrazinamide, now is acknowledged as indispensable important drugs in the short-course chemotherapy.The power of pyrazinamide antibacterial action and the acid-base value of environment are closely related.PH 〉=7 o'clock almost do not have effect, pH between 5～5.5 the time effect the strongest, have unique sterilization functions.In the cell is sour environment, and pyrazinamide required Mlc in cell only is extracellular 1/10.Tubercule bacillus in phagocyte is because anoxia and pH value is low and metabolism is slow, and most germ killing drugs are difficult to play effect, but pyrazinamide is the most effective to this type of persisting bacilli.These characteristics of pyrazinamide play crucial effects to shortening the course of treatment and reducing late relapse.
Ebutol (EMB) to the antibacterial action of tubercule bacillus a little less than, only the tubercule bacillus to various growth and breeding states has effect, to a few nothing influences of the antibacterial of resting state, there is not crossing drug resistant with other antituberculotics, be particularly useful for to tolerate the patient of streptomycin injection, can replace the reinforcement phase of streptomycin use in conjunction in the tuberculosis chemotherapy.The oral back of ebutol 2～4h reaches the blood concentration peak, half-life 3～4h, and major part is discharged from urine through kidney with original shape.It is relatively slow that ebutol produces drug-fast speed, because its toxic and side effects is less, uses always to substitute para-aminosalicylic acid (PAS) and use as the compatibility drug in the chemotherapy regimen.
The drug resistance problem is outstanding all the more in recent years.Informal medication is to produce chemical sproof main cause, and lacks system and measure to the tuberculosis patient strict control, is the major reason that causes irregular medication.In addition, current antituberculotics dosage is many, and dosage form is big, and method of administration is loaded down with trivial details also to be a factor that can not be ignored that is difficult to obtain patient's hand-in-glove, is difficult for finishing regular chemotherapy.Therefore exploitation is taken easy novel antituberculotics and is had important practical significance.Short distance inspection chemotherapy strategy (DOTS) under the direct observation is the global tuberculosis control strategy that WHO recommends.Fixed-dose combination of antituberculosis drugs is carried out the DOTS strategy to simplifying method of administration, and controlling tuberculosis is popular significant.World Health Organization (WHO) and international anti-tuberculosis association and pulmonary disease community recommend to replace the first-selected medicine of single medicine as tuberculosis patient with fixed-dose combination for this reason.
Existing partial monopoly report aspect the tuberculosis compound preparation.The method that discloses 2 kinds of wet granulations as indian patent NO.181730 prepares compound preparation.The first is earlier granulated rifampicin and ebutol, isoniazid and pyrazinamide is granulated, at last with two kinds of granules mix homogeneously according to a certain ratio again; It two is earlier rifampicin to be granulated separately, other three kinds of medicines is granulated, at last with two kinds of granules mix homogeneously according to a certain ratio again.This invention need be granulated for twice.
Among the international monopoly WO 02/087547, the method that discloses several wet granulations prepares the tuberculosis compound preparation.Wherein can adopt 3 step granulations, be about to rifampicin, ebutol is granulated separately respectively, and isoniazid, pyrazinamide are granulated jointly, more above-mentioned three kinds of granules are mixed in the prescription ratio; 4 step granulations are about to mix in the prescription ratio after four kinds of principal agent compositions are granulated respectively again.This invention needs 3～4 times granulation just can make the compound preparation that Rimactazid, pyrazinamide, four kinds of one-tenth of ebutol are grouped into.
The Chinese patent publication number is that the patent of invention of CN1611218A discloses several compound anti-tuberculosis preparations.Wherein the compound preparation of four kind of one line antitubercular agent has a kind of; its dosage ratio is different with the present invention; preparation technology is earlier with the disintegrating agent of Rimactazid, pyrazinamide and ebutol, binding agent and 2/3 recipe quantity and diluent (lubricant) mix homogeneously of 1/4 recipe quantity; dry granulation; granulate will remain disintegrating agent and the diluent (lubricant) and above-mentioned granule mix homogeneously of recipe quantity again, and tabletting gets final product.
The Chinese patent publication number is that the patent of invention of CN1602872A also discloses a kind of antitubercular agent compound pharmaceutical of being made up of Rimactazid, pyrazinamide, ebutol, its dosage ratio is also different with the present invention, and its preparation technology is with tabletting behind Rimactazid, pyrazinamide and ebutol and microcrystalline Cellulose and Henan gelling starch, the magnesium stearate mixing promptly.This method, the flowability of material deindustrialization greatly production.
Summary of the invention
The present invention is new tuberculosis compound preparation, and its principal agent composition is Rimactazid, pyrazinamide and ebutol.This compound preparation, the optimum quality ratio of Rimactazid, pyrazinamide and ebutol are a) 120: 100: 300: 200; B) 90: 60: 300: 150.
Rimactazid, pyrazinamide and ebutol and disintegrating agent, mixing diluents is even, carry out dry granulation after, granulate, tabletting or fill get final product after adding other auxiliary materials and mixing.
The preparation of above-mentioned preparation can be capsule, tablet, and the best is a tablet.
Can add an amount of disintegrating agent in the above-mentioned preparation process, its addition accounts for a) 8～22% of total formulation weight; B) 10～25%.Disintegrating agent has: polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, hydroxypropyl cellulose, starch, gas-producing disintegrant.
Can add an amount of diluent in the above-mentioned preparation process, its addition accounts for 0～6% of total formulation weight.Diluent has: starch, pregelatinized Starch, microcrystalline Cellulose, dextrin, lactose, glucose, calcium phosphate, sucrose, sucrose stearate and esters thereof, sorbitol, mannitol.
Other adjuvants in the above-mentioned preparation process, its addition account for a) 0.5～1.8% of preparation total amount; B) 0.6～2.1%.Mainly contain: magnesium stearate, zinc stearate, calcium stearate, stearic acid, PEG6000, Pulvis Talci.
For attractive in appearance and better storage, can carry out coating to above-mentioned preparation.
By the preparation of method for preparing, curative effect and toxicity and single agent are united when using similar.The release of compound preparation medicine is very easy to patient and takes medicine, and has improved the compliance of patient to chemotherapy, plays an important role in implementing short distance inspection chemotherapy.
The present invention has done the work aspect the detailed quality research in research process, control from aspects such as the character of medicine, discriminating, dissolution, content, related substance inspections, to guarantee the quality of medicine.
Dissolution according to the sample of preparation of the present invention all reaches more than 90%, has guaranteed that compound preparation can reach the identical therapeutic effect of single preparations of ephedrine.Concrete outcome sees Table 1.
Table 1 sample dissolution result
For assay of the present invention, all adopted two cover high performance liquid chromatogram systems to measure.For the mensuration of three of Rimactazids, pyrazinamide, main reference the content assaying method of different good fortune amide sheet in the Chinese Pharmacopoeia 2005 editions; And for the mensuration of ebutol, with reference to the assay method of the compound preparation in the American Pharmacopeia 27 editions.This method can be avoided the complex operation of existing method pre-column derivatization method, reappears the shortcoming of row difference, can to ebutol carry out more convenient, measure accurately, measurement result sees Table 2.
Table 2 sample size measurement result
In order to improve the ground safety of medication, the present invention has also formulated new inspection scheme with reference to the inspection method to the related substance of Rimactazid, pyrazinamide, ebutol compound preparation in the International Pharmacopoeia.Check result to the present invention's three batch samples sees Table 3.
Table 3 sample related substance check result
The specific embodiment
Example 1
Prescription 1:
Rifampicin: 120g
Isoniazid: 100g
Pyrazinamide: 300g
Ethambutol: 200g
Microcrystalline Cellulose: 50g
Cross-linking sodium carboxymethyl cellulose: 75g
Magnesium stearate: 5g
The coating prescription
Coating powder 25.5g
Water is an amount of
The preparation of label: with Rimactazid, pyrazinamide, ebutol and microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously, carry out dry granulation after, granulate, add magnesium stearate again after, press 1000 behind the mixing and get final product.
Prescription 2:
Rifampicin: 90g
Isoniazid: 60g
Pyrazinamide: 300g
Ethambutol: 150g
Cross-linking sodium carboxymethyl cellulose: 130g
Magnesium stearate: 10g
The coating prescription:
Coating powder 22.2g
Water is an amount of
The preparation of label: with Rimactazid, pyrazinamide, ebutol and cross-linking sodium carboxymethyl cellulose mix homogeneously, carry out dry granulation after, granulate adds after the magnesium stearate behind the mixing again, presses 1000 and gets final product.
Art for coating:
The preparation of coating solution: in appropriate vessel, add an amount of water, start blender, the coating powder of recipe quantity is joined in the vortex equably, avoided powder to float simultaneously as far as possible at liquid surface, in case of necessity, can improve rotating speed to keep suitable vortex, after treating that all coating powders all add, reduce mixing speed, vortex is disappeared, continue to stir 45min, promptly.The preparation of thin membrane coated tablet: label is put in the coating bed, kept 40 ℃ ± 5 ℃ of bed temperatures, carry out coating, promptly.
Example 2
Prescription 1
Rifampicin: 60g
Isoniazid: 50g
Pyrazinamide: 150g
Ethambutol: 100g
Lactose: 15g
Polyvinylpolypyrrolidone: 50g
Magnesium stearate: 3.5g
The coating prescription:
Coating powder 12.9g
Water is an amount of
The preparation of label: with isoniazid, rifampicin, pyrazinamide, ebutol and lactose, polyvinylpolypyrrolidone mix homogeneously, carry out dry granulation after, granulate is pressed 1000 behind the mixing and is got final product after adding magnesium stearate.
Prescription 2:
Rifampicin: 45g
Isoniazid: 30g
Pyrazinamide: 150g
Ethambutol: 75g
Lactose: 5g
Polyvinylpolypyrrolidone: 40g
Magnesium stearate: 5.5g
The coating prescription:
Coating powder 10.6g
Water is an amount of
The preparation of label: with Rimactazid, pyrazinamide and ebutol and lactose, polyvinylpolypyrrolidone mix homogeneously, carry out dry granulation, behind the granulate, add magnesium stearate, behind the mix homogeneously, press 1000 and get final product.
Art for coating:
The preparation of coating solution: in appropriate vessel, add an amount of water, start blender, the coating powder of recipe quantity is joined in the vortex equably, avoided powder to float simultaneously as far as possible at liquid surface, in case of necessity, can improve rotating speed to keep suitable vortex, after treating that all coating powders all add, reduce mixing speed, vortex is disappeared, continue to stir 45min, promptly.The preparation of thin membrane coated tablet: label is put in the coating bed, kept 40 ℃ ± 5 ℃ of bed temperatures, carry out coating, promptly.
Example 3
Prescription 1
Rifampicin: 120g
Isoniazid: 100g
Pyrazinamide: 300g
Ethambutol: 200g
Hydroxypropyl cellulose: 90g
Magnesium stearate: 10g
The coating prescription:
Coating powder 24.6g
Water is an amount of
The preparation of label: with isoniazid, rifampicin, pyrazinamide, ebutol and hydroxypropyl cellulose mix homogeneously, carry out dry granulation after, granulate is pressed 1000 behind the mixing and is got final product after adding magnesium stearate.
Prescription 2:
Rifampicin: 90g
Isoniazid: 60g
Pyrazinamide: 300g
Ethambutol: 150g
Hydroxypropyl cellulose: 120g
Magnesium stearate: 7g
The coating prescription:
Coating powder 21.9g
Water is an amount of
Technology 2: with Rimactazid, pyrazinamide and ebutol and hydroxypropyl cellulose mix homogeneously, carry out dry granulation, drying behind the granulate, adds magnesium stearate, behind the mix homogeneously, presses 1000 and gets final product.
Art for coating:
The preparation of coating solution: in appropriate vessel, add an amount of water, start blender, the coating powder of recipe quantity is joined in the vortex equably, avoided powder to float simultaneously as far as possible at liquid surface, in case of necessity, can improve rotating speed to keep suitable vortex, after treating that all coating powders all add, reduce mixing speed, vortex is disappeared, continue to stir 45min, promptly.
The preparation of thin membrane coated tablet: label is put in the coating bed, kept 40 ℃ ± 5 ℃ of bed temperatures, carry out coating, promptly.
Claims (8)
1. the compound preparation of antituberculotics is characterized by four kinds of antituberculotics Rimactazids, pyrazinamide and ebutol and forms.
2. according to right 1 described compound preparation, it is characterized by principal agent Rimactazid, pyrazinamide and ebutol optimum quality ratio can for: a) 120: 100: 300: 200; B) 90: 60: 300: 150.
3. according to right 1 and 2 described compound preparations, it is characterized in that preparation can be capsule, tablet, the best is a tablet.
4. according to right 1 and 2 described compound preparations, it is characterized by except that Rimactazid, pyrazinamide and ebutol and can add an amount of disintegrating agent, its addition accounts for a) 8～22% of total formulation weight; B) 10～25%.Disintegrating agent has: polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, hydroxypropyl cellulose, starch, gas-producing disintegrant.
5. according to right 1 and 2 described compound preparations, it is characterized by except that Rimactazid, pyrazinamide and ebutol, can optionally add proper amount of diluting, account for 0～6% of total formulation weight.Diluent has: starch, pregelatinized Starch, microcrystalline Cellulose, dextrin, lactose, glucose, calcium phosphate, sucrose, sucrose stearate and esters thereof, sorbitol, mannitol.
6. according to right 1 and 2 described compound preparations, it is characterized by and can add other an amount of adjuvants except that Rimactazid, pyrazinamide and ebutol, its addition accounts for a) 0.5～1.8% of preparation total amount; B) 0.6～2.1%.Mainly contain: magnesium stearate, zinc stearate, calcium stearate, stearic acid, PEG6000, Pulvis Talci.
7. according to right 1 and 2 described compound preparations, it is characterized by and to adopt the method for dry granulation to be prepared.Principal agent and disintegrating agent, mixing diluents is even, carry out dry granulation after, granulate can carry out the preparation of preparation after adding other adjuvants.
8. according to right 1 and 2 described compound preparations, the best is a tablet, for attractive in appearance and better storage, can carry out coating.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2008100105313A CN101524355B (en) | 2008-03-04 | 2008-03-04 | Compound preparation of antituberculosis medicaments, and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2008100105313A CN101524355B (en) | 2008-03-04 | 2008-03-04 | Compound preparation of antituberculosis medicaments, and preparation method thereof |
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| CN101524355A true CN101524355A (en) | 2009-09-09 |
| CN101524355B CN101524355B (en) | 2011-04-20 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579447A (en) * | 2011-12-31 | 2012-07-18 | 沈阳药科大学 | Preparation method for anti-tuberculosis medicinal compound preparation |
| WO2012139485A1 (en) * | 2011-04-12 | 2012-10-18 | 浙江海正药业股份有限公司 | Oral solid preparation of compound antituberculosis drug and preparation method thereof |
| CN104274456A (en) * | 2013-07-02 | 2015-01-14 | 安徽贝克生物制药有限公司 | Quadrigeminal compound preparation of anti-tuberculosis medicines and preparation method thereof |
| CN110169954A (en) * | 2019-06-20 | 2019-08-27 | 江苏四环生物制药有限公司 | It is a kind of to dissolve out stable pyrazinamide tablet and preparation method thereof |
-
2008
- 2008-03-04 CN CN2008100105313A patent/CN101524355B/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012139485A1 (en) * | 2011-04-12 | 2012-10-18 | 浙江海正药业股份有限公司 | Oral solid preparation of compound antituberculosis drug and preparation method thereof |
| RU2605388C2 (en) * | 2011-04-12 | 2016-12-20 | Чжэцзян Хисун Фармасьютикал Ко., Лтд. | Oral solid preparation of compound antituberculosis drug and preparation method thereof |
| US9555003B2 (en) | 2011-04-12 | 2017-01-31 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Oral solid formulation of compound anti-tubercular drug and preparation method thereof |
| CN102579447A (en) * | 2011-12-31 | 2012-07-18 | 沈阳药科大学 | Preparation method for anti-tuberculosis medicinal compound preparation |
| CN102579447B (en) * | 2011-12-31 | 2014-10-15 | 沈阳药科大学 | Preparation method for anti-tuberculosis medicinal compound preparation |
| CN104274456A (en) * | 2013-07-02 | 2015-01-14 | 安徽贝克生物制药有限公司 | Quadrigeminal compound preparation of anti-tuberculosis medicines and preparation method thereof |
| CN110169954A (en) * | 2019-06-20 | 2019-08-27 | 江苏四环生物制药有限公司 | It is a kind of to dissolve out stable pyrazinamide tablet and preparation method thereof |
| CN110169954B (en) * | 2019-06-20 | 2021-10-15 | 江苏四环生物制药有限公司 | Stable-dissolution pyrazinamide tablet and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN101524355B (en) | 2011-04-20 |
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