CN1201739C - Medicine-release system of compound Rifampicin - Google Patents

Abstract

The present invention relates to a compound Rifampicin preparation. The preparation can be explained to be a medicine release system of the compound Rifampicin preparation. The preparation comprises Rifampicin and isoniazid. The preparation further comprises pyrazinamide or pyrazinamide and ethambutol dihydrochloride in a selectable mode, wherein each dosage accords with the latest synergy dosage requirement arranged in a bulletin of No. 1 (Vlume 79 Isue 1) of WHO in 2001. The present invention is characterized in that the isoniazid, the pyrazinamide and the ethambutol dihydrochloride can be dissolved in the stomach, and the Rifampicin can be dissolved in the intestine, or the isoniazid can be dissolved in the intestine, and other ingredients can be dissolved in the stomach; an intestine dissolution starting position of the medicine dissolved in the intestine is started from the upper part of the small intestine; specifically, when a pH value of the external environment of the preparation is equal to 5.0 to 5.5, an intestine skin starts to be dissolved, and the medicine is gradually released. A dosage form of the preparation of the present invention is selected from capsules, granules, tablets, multilayer tablets, or suspension. The present invention also provides a preparation method of compound Rifampicin.

Description

A kind of medicine-releasing system of compound rifampicin preparation

Invention field

The application is actually a kind of continuous application, is that a kind of prescription of compound rifampicin preparation is formed in the denomination of invention of first to file, submits on April 15th, 2002, and application number is 02116616.1, and its content this paper is in conjunction with quoting.

The present invention relates to a kind of antitubercular agent, be specifically related to a kind of compound rifampicin preparation, express its composition of medicine-releasing system and the preparation method that saying is a kind of compound rifampicin preparation more accurately with modern medicinal agents.

Technical background

Tuberculosis is the chronic infectious disease of serious harm people ' s health, and global epidemic situation rapid deterioration forms new rising peak since the intermediary and later stages eighties.According to The World Health Organization's communique (calendar year 2001) latest estimated, the whole world has 8,000,000 tuberculosis new patients to take place every year.Have 2,000,000 tuberculosis patient death at least.80% tuberculosis case occurs in the high burden of 22 tuberculosis country, and their great majority are in Asia and Africa.China also is one of tuberculosis country occurred frequently.Henan Province in 2000 has carried out the 4th tuberculosis epidemiological random sampling survey of the whole province according to the Ministry of Public Health requirement, and the result shows that Epidemic features is: high prevalence, high mortality, high infection rate, low degradation rate.Estimate that Henan Province has at least 3,000 ten thousand people to be subjected to tubercle bacillus affection, existing active tuberculosis patient is about 460,000, dies from people surplus the tuberculosis patient 9300 every year.Tuberculosis reason occurred frequently is that the consumptive diagnoses and thoroughly healing not in time, accurately.Because not thoroughly treatment, tulase develops immunity to drugs to medicine, causes this disease propagation, spreads.The popular most important measure of controlling tuberculosis is to eliminate the source of infection.The key of eliminating the source of infection is diagnosis and thoroughly treatment promptly and accurately.In order to instruct domestic tuberculosis and related discipline medical personnel to diagnosis lungy and treatment, phthisiology branch of Chinese Medical Association has formulated " (pulmonary tuberculosis diagnosis and treatment guide ".Wherein stipulate the definition of anti-multiple medicines tuberculosis, recommended just to control, control again, the phthisical therapeutic scheme commonly used of anti-multiple medicines, emphasized tuberculosis treatment management under the condition of not being in hospital and carried out the directly short-course chemotherapy under the inspection of medical worker, obtained certain effect.But tuberculosis treatment lack of standardization and " no matter only control " are the roots that causes anti-multiple medicines.

Since the mid-90 in last century, The World Health Organization (WHO) recommends to adopt multiple compatibility of drugs therapy (to claim the fixed dosage conjoint therapy again, be called for short FDC _S), but the end is promoted always.And this in recent years therapy has been familiar with gradually, effectively is subjected to various countries' popular welcome owing to it is cheap.Some countries have developed FDC _SThe preparation listing.China had also developed the FDC of several kinds in recent years _SPreparation is as rifampicin and isoniazid two compound preparations, three compound preparations of Rimactazid, pyrazinamide.Import RIFATER and RIFINAH.The former is three preparations of Rimactazid and pyrazinamide, and the latter is two preparations of rifampicin and isoniazid.But these medicines do not meet the intensity of the up-to-date recommendation of WHO, and in other words the dosage of each component does not meet the FDC of the up-to-date recommendation of WHO in these preparations _SThe compatibility dosage of Rimactazid, pyrazinamide, ebutol in the prescription.Market survey shows WHO in 1998 to antitubercular agent, has the FDC of multiple varying strength on the market _SMostly preparation is not meet the standard that WHO recommends; This state may produce the disorder of clinical treatment, is difficult to reach therapeutic purposes.They think FDC behind the product of different manufacturers relatively _SThe intensity of preparation lacks standardization.Therefore WHO and tuberculosis and pneumonopathy international federation (IUATLD) propose FDC _SStandardized problem.Recommended the FDC of four kinds of medicines in WHO technical research that hold in Geneva in August, 1998 and the consultative committee _SFDC with the child _STherapeutic regimen, and roll up the 1st phase WHO communique in calendar year 2001 the 79th and announced such scheme.See the following form:

1, the dosage (consumption of per kilogram of body weight) of basic antitubercular agent recommendation

Antitubercular agent	Model of action	Recommended dose (mg/kg)
						Every day	3 times/weekly
Isoniazid (H) rifampicin (R) pyrazinamide (P) ethambutol (E) streptomycin (S) thiacetazone (T)	Sterilization sterilization bactericidal bactericidal	5(4-6) 6 10(8-12) 25(20-30) 15(15-20) 15(12-18) 2.5	10 (8-12) 10 (8-12), 35 (30-40) 30 (25-35) 15 (12-18) need not

Bracket inner digital is dosage range mg/k

2, basic antitubercular agent FDC _SThe intensity that preparation is recommended

	Medicine	Dosage form	Intensity
				Every day	Rifampicin+isoniazid+pyrazinamide+ethambutol	Tablet	R150mg+H75mg+Z400mg+E275mg
Every day	Rifampicin+isoniazid+pyrazinamide	Tablet	R150mg+H75mg+Z400mg R60mg+H30mg+Z150mg (child uses)
				Every day	Rifampicin+isoniazid	Tablet	R300mg+H150mg or R150mg+H75mg R60mg+H30mg (child uses)
Every day	Isoniazid+ethambutol	Tablet	H150mg+E400mg
				Every day	Thiacetazone+isoniazid	Tablet	T50mg+H100mg or T150mg+H300mg
Intermittently	Rifampicin+isoniazid+pyrazinamide	Tablet	R150mg+H150mg+Z500mg
				Intermittently	Rifampicin+isoniazid	Tablet	R150mg+H150mg R60mg+H60mg (child uses)

E=ethambutol, H=isoniazid, R=rifampicin, T=thiacetazone, Z=pyrazinamide

Annotate: referring to every day use every day, is batch applications (3 times weekly) intermittently.

3, FDC _SWHO recommend adult's consumption (sheet number) of intensity

Patient body weight (kg)	2 months RHZE of initial period RHZ every day every day		4 months RH of continuing phase RH every day intermittently		6 months EH every days
						30-37 38-54 55-70 ≥71	2 3 4 5	2 3 4 5	2 3 4 5	2 3 4 5	1.5 2 3 3

R=rifampicin, H=isoniazid, Z=pyrazinamide, E=ethambutol

4, FDC _SWHO recommend child's consumption sheet number of intensity

Patient body weight (kg)	Initial period 2 months	Continuing phase 4 months
					RHZ every day	RH every day	RH×3weekly
≤7 8-9 10-14 15-19 20-24 25-29	1 1.5 2 3 4 5	1 1.5 2 3 4 5	1 1.5 2 3 4 5

R=rifampicin, H=isoniazid, Z=pyrazinamide.

FDC _SPreparation is compared with single pharmaceutically dosage form, and single Types of Medicine are obeyed a large amount of tablets every day, and the treatment initial period is taken the 9-16 sheet usually, after 2 months, obeys the 3-9 sheet continuously again to 4-6 month.And FDC _SSheet only need be obeyed 34.In addition, single pharmaceutically dosage form patient easily obeys mistake or few clothes, and FDC _SPreparation calculating dosage is the wrong few clothes of livery simply.FDC _SBecause dosage reduces, adverse reaction rate lowers.Another important advantage is FDC _SPreparation can prevent Drug resistance.

FDC by above-mentioned visible WHO recommendation _SSignificantly reduced total dosage.Regrettably present commercially available FDC _SThe tuberculosis FDC that comprises China's approved _SMedicine, its insufficient strength not only affects the treatment but also can produce drug resistance.Meet the FDC that WHO recommends intensity so must develop _SPreparation.

In addition, FDC _SThe quality of preparation also is the key of antituberculosis therapy.The up-to-date FDC that points out of WHO _SThe quality of the pharmaceutical preparations problem of tablet is the bioavailability basis that guarantees rifampicin.Known when rifampicin associating other medicines are in same preparation, if the manufacturing of preparation operation does not have strict control, the bioavailability of rifampicin will be subjected to negative effect.Therefore, the investigation of WHO is pointed out: the FDC that is now going on the market _SPreparation, the bioavailability of its rifampicin are the standards that is lower than WHO.In order to emphasize this problem, some laboratorys of WHO authenticating are to FDC _SPreparation is carried out bioavailability/equivalence test.At present existing two laboratorys are proved by WHO, and to FDC _S2,3 and 4 pharmaceutical preparation of preparation is tested.

Calendar year 2001 international tuberculosis and the pneumonopathy magazine delivered people's such as Laserson K.F investigation report.They survey sample the antitubercular agent on the world market.Collect sample from Colombia, Esfonia, India, Latvia, Russia and Vietnam.To single medicine and FDC _SThe preparation thin layer chromatography analysis test box analytic sample of exploitation recently.Simultaneously world CDC (CDC) has carried out that TLC checks and the TLC of U.S. FDA checks, and the UV of rifampicin is measured and the HPLC of isoniazid is measured.Check result shows: 4 medicine FDC _SPreparation is all defective, and rifampicin content only is 74.7%.3 medicine FDC _S1 of preparation product selective examination, the TLC of CDC checks defective, the TLC passed examination of FDA.Rifampicin and isoniazid two medicine FDC _SSpot-check 21 altogether.The TLC of CDC checks that to have 11 defective, and the TLC of FDA checks that to have 3 defective.This investigation is only analyzed content of drug.And the whether qualified still problem of the biological utilisation of these medicines.So preparation FDC _SDuring preparation, several drugs is mixed, make and conform with prescription, particularly meet the FDC that bioavailability requires _SPreparation, difficulty is bigger; Standard compliant qualified preparation does not fully appear at present as yet.

Exist the reason of the quality problems that cause the FDCX preparation to be at present: rifampicin hydrolysis in acid medium forms the insoluble difficult 3-formyl Rifamycin Sodium that absorbs, and in the presence of isoniazid, will speed up the hydrolysis of rifampicin.1999, Shishoo, C, J etc. have made isoniazid and have had the Study on Stability of rifampicin in dissolution medium down.They place No. 2 appearance wares of the dissolution instrument of USP regulation with 0.1N HCl solution 200ml, and the rifampicin 150mg that adds accurate weighing is dissolved in 0.1N HCl100ml.Draw samples during from 0 minute, later on every 15 minutes draw sampless once to 60 minutes.The sample chloroform extraction is with the content of dual-wavelength spectrophotometry and HPTLC mensuration rifampicin and 3-formyl Rifamycin Sodium.Also use the mixture of rifampicin and isoniazid simultaneously, compare tests and measurements as stated above.In addition, to some commercially available rifampicin and rimactazid preparation, also carried out tests and measurements as stated above.

Result of the test shows: rifampicin is unstable in 0.1NHCl solution, degrades.In the presence of isoniazid, rifampicin is more unstable in 0.1NHCl solution, and degradation rate almost increases more than 2 times during than the rifampicin individualism.With the degraded of single order speed, the constant K value is 2.1 * 10 to rifampicin in 0.1NHCl solution ^-3/ min forms 3-formyl Rifamycin Sodium.In the presence of isoniazid, degraded is quickened, and the K value is 4.6 * 10 ^-3Min ^-1

In to the dissolution medium of commercially available rifampicin and rimactazid preparation in the Study on Stability, 45 minutes the time, degraded 12.4% forms 3-formyl Rifamycin Sodium to experimental observation to Rimactane.And the rimactazid preparation, in the presence of isoniazid, the degraded of rifampicin was degraded about 21.5% in 45 minutes by catalysis.Because 3-formyl Rifamycin Sodium is difficult to absorb under one's belt, therefore, the degraded of rifampicin in acid medium influences the bioavailability of rifampicin greatly.In view of the above fact, investigation report suggestion Rimactane is preferably made upper part of small intestine and is discharged.

In order to verify Shishoo, C, the The above results of J etc., we have further made rifampicin and stability test and rifampicin and rifampicin+isoniazid the stability test in PH6.8 phosphate buffer (pH of similar upper part of small intestine) of rifampicin+isoniazid in 0.1mol/L HCl solution (acidity that is equivalent to gastric juice).Rifampicin+pyrazinamide, rifampicin+ethambutol, the stability test of rifampicin+pyrazinamide+ethambutol+isoniazid under above-mentioned two kinds of condition of different pH have also been carried out simultaneously, assay method HPLC external standard method, determination object is the percentage composition of rifampicin, and shown in following two tables of measurement result: the A group is rifampicin+pyrazinamide+ethambutol+isoniazid for rifampicin+pyrazinamide, D group for rifampicin+ethambutol, E group for rifampicin+isoniazid, C group for rifampicin, B group in the following table.

The degraded situation of rifampicin in pH=1 solution (0.1mol/L HCl solution is equivalent to Gastric pH)

Time packet	The A group	The B group	The C group	The D group	The E group
						0 hour	100.2	99.7	99.3	98.7	100.7
2 hours	94.6	92.4	94.9	95.7	92.6
						4 hours	92.3	85.0	92.2	92.0	86.5
6 hours	88.1	80.8	87.2	89.0	80.5

The degraded situation of rifampicin in pH=6.8 solution (phosphate buffer is equivalent to upper part of small intestine pH)

Time packet	The A group	The B group	The C group	The D group	The E group
						0 hour	99.4	98.2	98.4	99.2	99.1
2 hours	98.7	98.4	98.3	100.3	100.4
						4 hours	98.7	99.8	97.5	98.5	99.1
6 hours	99.8	98.1	97.0	97.9	98.6

Shishoo, C, usefulness UV methods such as J have only been carried out the stability test of acid solution, and we have carried out the stability test of acid solution and neutral solution with the HPLC method, and this is tested us and has carried out repeatedly the data metal and stone parts wherein of last two tables.Though the palliating degradation degree of rifampicin in acid tested difference (the measurement result difference that measuring method caused) for two kinds, but the trend of degraded is consistent with the result of these the two kinds of tests of trend that add isoniazid after-acceleration degraded, we also observe in practice simultaneously, along with the rising of temperature, the degraded of rifampicin self and isoniazid will aggravate the acceleration of rifampicin degraded.It can also be seen that from top test pyrazinamide and ethambutol play a part too big to the degraded of rifampicin hardly.But in neutral solution, the degraded of rifampicin self and isoniazid have obtained obvious control to the acceleration of rifampicin degraded, and this has verified Shishoo, and C, the Rimactane of J etc. preferably make the correctness that upper part of small intestine discharges suggestion.

According to above-mentioned situation, at present to antitubercular agent FDC _SPreparation must be emphasized following requirement: 1, enough intensity must be arranged, promptly press the dosage and administration of the up-to-date regulation of WHO, could thoroughly cure tuberculosis, prevent that drug-fast generation from (replenishing: Chinese Medicine's on June 29th, 2002 the 6th edition article: the mistaken ideas " normalized treatment can be cured the tuberculosis patient 95% or more; it treats mortality only is 3%, and the mortality that nonstandard chemotherapy causes is then up to about 50% " of walking out tuberculosis prevention and treatment).2, must strict control FDC _SThe quality of preparation will be considered influencing each other between compound medicine in preparation process, take certain measure, avoids this influence.3, must consider the bioavailability of rifampicin.WHO particularly points out FDC _SPreparation subject matter is the bioavailability of rifampicin.According to top test, rifampicin is degraded easily in acid medium, and when having isoniazid simultaneously, will speed up the degraded of rifampicin, therefore new FDC _SPreparation should be avoided the dissolving in the gastric juice of human body simultaneously of rifampicin and isoniazid.

But, the tuberculosis FDC of Xiao Shouing in the market _SPreparation does not almost meet the FDC of above-mentioned requirements _SPreparation.Be situated between this, press for research and development and meet the dose intensity of the up-to-date regulation of WHO, avoid the FDC of influence and the high bioavailability of rifampicin between medicine _SPreparation.

On June 14th, 1994, Mr. Liu Renming takes the lead in considering the advantage of rifampicin+pyrazinamide+ethambutol+isoniazid 4 compound anti-tuberculosis preparations, and declared china national practical new-type patent, and be given the ratification on March 20th, 1996 (patent No. is 94214080.X).The technical essential of this patent is: with the state filled capsules of rifampicin with medicated powder, isoniazid, pyrazinamide, ebutol are made tablet and coating or enteric coated back filled capsules, and drawn four kinds of capsule filling mode figure of powder and tablet.The shortcoming of this patent is not narrate the mechanism of degradation of rifampicin, does not disclose concrete coating adjuvant.As everyone knows, pharmaceutical preparation is the final form of expression of pharmaceutics research, the research of pharmaceutics is exactly the research of drug release mode, in order to allow medicine discharge in a certain way, will study compatibility between medicine and the compatibility situation between medicine and adjuvant, this situation should comprise external and intravital two kinds of situations.In addition, if according to the tetrad FDC of the up-to-date announcement of WHO _SThe compatibility dosage of preparation uses the preparation method of patent 94214080.X, has difficulties when practical operation.Because isoniazid, pyrazinamide, ebutol all are tablets, after tablet incapsulates, leave bigger space between tablet, though in imagination, can fill the gap with the rifampicin powder, but because the filling of capsule 's content substep on capsule filling machine is finished one by one, so the rifampicin powder does not have under the situation that three tablets existence are arranged in effect, the especially capsule of filling the tablet gap.Moreover present capsule filling machine has only four workers at most, can only fill three kinds of materials (another station is used to put capsule) in a capsule, be difficult to realize rifampicin filling dose accurately.

Summary of the invention

The object of the invention provides a kind of compound rifampicin preparation, and expressing more accurately with modern medicinal agents is a kind of medicine-releasing system of compound rifampicin preparation, and said preparation overcomes above-mentioned shortcoming, and its dose meets the newest F DC that WHO announces _SThe preparation compatibility standard, and ensure that in use rifampicin do not degrade substantially.

The invention provides a kind of compound rifampicin preparation, it is a kind of medicine-releasing system of compound rifampicin preparation that this preparation can be interpreted as, comprise rifampicin and isoniazid, further comprise pyrazinamide or pyrazinamide and ebutol alternatively, wherein each dose up-to-date compatibility dosage requirement of meeting The World Health Organization (WHO) calendar year 2001 No. 1 communique proposing, it is characterized in that isoniazid, pyrazinamide, ebutol be gastric solubleness and rifampicin is an enteric, perhaps isoniazid is an enteric and other are gastric solubleness, and the dissolved condition of enteric coating film is to be to begin dissolving between 5.0～5.5 at PH.The dosage form of preparation of the present invention is selected from capsule, granule, tablet, multilayer tablet, micropill, microcapsule or suspensoid.

Another object of the present invention provides a kind of preparation method of compound rifampicin preparation, and the enteric member is carried out enteric coating, then with the mixed preparation that forms of other members.

Further object of the present invention provides a kind of preparation method of compound rifampicin preparation, wherein the rifampicin member is made enteric coated micropill, and ebutol, isoniazid, pyrazinamide are made the gastric solubleness micropill respectively, is filled in capsule then and forms capsule preparations.This method also can be made enteric coated micropill with the isoniazid member, and ebutol, rifampicin, pyrazinamide are made the gastric solubleness micropill respectively, is filled in capsule then and forms capsule preparations.

The 4th purpose of the present invention provides a kind of preparation method of compound rifampicin preparation, wherein the rifampicin member is made enteric coatel tablets, the ebutol member makes gastric soluble tablet, and isoniazid and pyrazinamide are made gastric-soluble particle (or micropill) together, is filled in then and forms capsule preparations in the capsule.

DESCRIPTION OF THE PREFERRED

As everyone knows, the pH value of human gastric juice after the medicine oral administration is in the stomach, at first contacts with gastric juice about 1, when dissolving in gastric acid, degraded back are progressively absorbed, is sent to small intestinal under the wriggling of stomach, and is further absorbed in intestinal.And the pH value in the stomach, intestinal gradually becomes faintly acid until neutrality and alkalescence from highly acid.Therefore, the present invention carries out enteric coating with the enteric member, then with the mixed preparation of making of other members.The gastric solubleness member is coating not generally, but in order to guarantee dose, particularly also can use gastric solubleness adjuvant coating certainly when some member makes micropill.

Those skilled in the art know, the pH value of human body intestinal canal is progressively to change to about 7.6 by about 5.0, and according to the variation of intestinal PH, the dissolved PH environment of enteric adjuvant is different, and some is to be about 5 just to begin dissolving at PH; This situation, the release position of medicine is on the top of small intestinal.Some be PH be about 7 the dissolving, this situation, the release position of medicine is on bottom and ileum or the colon and even the rectum top of small intestinal.After medicament enteric-coated coating, the release of medicine will be delayed, and the dissolved pH value of enteric adjuvant is high more, and the release of medicine is slow more.Rimactazid, pyrazinamide are antibacterial, and ebutol is an antibacterial.No matter be that antibacterial or antibacterial all answer rapid release, the especially antibacterial more should be like this in vivo, otherwise just be easy to generate fungus resistance.In addition, severally kill, the purpose of inhibiting-bacteria preparation associating compatibility is to want synergism, too big if the interval that plays a role between the medicine differs, synergism each other will reduce.Two kinds of above-mentioned situations to clinical treatment all with totally unfavorable.Therefore for the technology of patent 94214080.X above-mentioned, isoniazid is enteric coated justified, but the enteric coating that is wrapped must use and can just begin dissolved material at upper part of small intestine, though prolonged the peak time of isoniazid in blood a little, what bring is that the effective bioavailability of rifampicin improves.And with pyrazinamide, ebutol also enteric coated or with the isoniazid bag could dissolved enteric coating under the environment of high pH value, be exactly unreasonable, also be disadvantageous.Therefore, the present invention selects the enteric coating adjuvant exactly, makes by the medicament of enteric coating to discharge at upper part of small intestine.

In a preferred embodiment, rifampicin is made enteric coated preparation.Progressively dissolving with pH value control enteric film, for ensureing that rifampicin just begins to discharge at upper part of small intestine, this programme selection pH value as enteric-coating material, again with isoniazid, pyrazinamide, ebutol compatibility forms single preparation behind the coating at 5～5.5 o'clock dissolved pharmaceutic adjuvants.Said preparation is the tetrad preparation, also three preparations or two preparations.Two preparations are meant rifampicin and isoniazid compatibility, and three preparations are meant rifampicin and isoniazid, pyrazinamide compatibility.Make two, three or the tetrad preparation according to market demand fully.In this embodiment, also rifampicin and isoniazid can be exchanged, isoniazid is made enteric coated preparation, rifampicin replaces the position of isoniazid.In this scheme, pyrazinamide, ebutol must be gastric solubleness, and rifampicin or isoniazid or dissolve in the stomach, or in the upper part of small intestine dissolving, discharge as soon as possible after medicine arrives in the body guaranteeing.

Preparation of the present invention generally is a peroral dosage form, can be capsule, granule, tablet, multilayer tablet, suspensoid or pill etc.Wherein preferred capsule formulation, medicament capsule are oral easily and without any abnormal flavour, for the patient and the children's of dysphagia, are easy to that also capsule 's content is toppled over out the back and take for the patient, guarantee to take medicine convenient and dosage is accurate.

When preparing multi-joint capsule preparations, each member can be made tablet or micropill refills capsule.For simplicity, when the tetrad preparation, the enteric member can be made coated tablet, other members make micropill or granule filling then.In order to simplify technology, it is mixed to make micropill or granule and enteric member after multiple member can being mixed.Some member detects dose separately in mixed back inconvenience, can wherein a kind ofly make tablet this moment and other convenient members that detect doses are mixed makes micropill or granule; Also the enteric member can be made enteric coated micropill, after other members make the gastric solubleness micropill respectively, according to dosage each micropill all be mixed or partially mixed back filled capsules.

The adjuvant that enteric coating is used does not have strict restriction, as long as meet the pharmacopeia rules and do not influence preparation drug effect of the present invention, and can guarantee at PH to be that about 5.0 beginning is dissolved all can use, and does not just begin dissolved coating adjuvant but do not use pH value to be higher than 7.0.The for example fine little plain class of described enteric adjuvant, wherein preferred hydroxypropylmethyl cellulose phthalate (HPMCP) and the fine little element (CAP) of phthalic acid acetic acid; Crylic acid resin is as acrylic resin I number and II number; The ethene polymers class is as polyvinyl alcohol phthalate ester (PVAP), polyvinyl alcohol phthalate ester (PVAP) aqueous dispersion.Use gastric solubleness coating raw material for example PVP and PEG etc. alternatively.These coating raw materials all are well known in the art, can both buy in market or make easily.

Use the conventional art for coating in this area during coating, to be placed in the coating pan of rotation by the medicated core of coating, the coating raw material is made coating solution, when spraying coating solution, feed the wind of proper temperature, control coating thickness according to medicated core quantity and coating solution quantity and jet velocity, coating thickness is controlled in initial foundation weightening finish, final adopt officinal inspection method and discrimination standard, make the enteric member in simulated gastric fluid or 0.1mol/L HCl solution and the requirement that in phosphate buffered solution, meets the pharmacopeia regulation to enteric coated preparation.Suitability for industrialized production is used ebullated bed (or claiming fluid bed) coating plant equipment more at present.

Prepare other dosage form as: the label of granule, tablet, multilayer tablet, suspensoid or tablet can be small pieces, granule, powder, the form of microcapsule.These preparation intermediate should at first be prepared to the medicine for the treatment of coating above-mentioned intermediate dosage form coating more in the preparation.This area common process is adopted in the preparation of above-mentioned preparation intermediate dosage form equally; Certainly, after need selecting adjuvant and dosage during above-mentioned dosage form, meet the pharmacopeia rules by detection again, preparation carries out coating.Need select to fill conventional adjuvants such as adjuvant, disintegrating agent, binding agent when for example preparing the chip of tablet and make tabloid.The pharmacopeia rules have the inspection of tablet friability, inspection disintegration and tablet weight variation limit test etc. to the regulation of tablet, by ability coating after detecting.Equally, other preparation intermediate dosage forms also will relevant criterion or preparation basic fundamental required standard by the pharmacopeia rules detect, qualified after coating again.The preparation of microcapsule also will be adopted the method for preparing microcapsule in the conventional formulation method, select suitable enteric-coated microcapsule coating material that the enteric member is carried out microcapsule and be wrapped to form the preparation intermediate.The purpose for preparing above-mentioned preparation intermediate be guarantee rifampicin in the multi-joint preparation and isoniazid the preparation intermediate respectively under one's belt or the upper intestines disintegrate discharge, rifampicin and isoniazid are not met under one's belt, and whenever the medication amount among the person of being unified into reaches the newest standards of WHO, final dosage form is to form single peroral dosage form, various peroral dosage forms such as for example above-mentioned granule, tablet, multilayer tablet, suspensoid or pill behind the compatibility.

Complex rifampin (fixed dosage conjoint therapy, abbreviation FDC by a preferred embodiment of the present invention preparation _S) preparation, after taking, isoniazid, pyrazinamide, ebutol at first begin after dissolved to absorb in gastric acid; rifampicin is owing to there is the protection of enteric coating; not dissolved under one's belt, can't meet with isoniazid, thereby avoid rifampicin degraded under one's belt.After medicine runs to intestinal, the enteric film of rifampicin is dissolved, rifampicin discharges, because the pH value of small intestinal is greater than more than 5, external solution trial according to us confirms, in nearly neutral environment, after rifampicin and isoniazid meet, rifampicin is non-degradable, thereby has guaranteed the rifampicin absorption in vivo.If the member is enteric coated with isoniazid, and rifampicin member not coating or bag gastric solubleness clothing, rifampicin at first discharges under one's belt, discharge in intestinal behind the isoniazid, its situation is also with identical, though rifampicin degraded to some extent in gastric acid like this, but owing to there is not the existence of isoniazid, degraded can not be accelerated, and is only relevant with rifampicin self, thereby can guarantee the rifampicin absorption in vivo substantially yet.

In another preferred embodiment of the present invention, final preparation adopts the pellet capsule dosage form.Wherein the plain ball of the rifampicin made is carried out enteric coating, other respectively the person of being unified into after making plain ball, carry out gastric solubleness coating, capsule charge then.Whenever the plain ball of the person of being unified into all needs to select separately adjuvant and quantity, and must detect after making could coating when up to standard.Prepare plain ball, the method for coating solution all adopts this area common process.When for example preparing micropill, generally with medicine and adjuvant crushing screening, proportionally mixing adds an amount of binding agent and makes the ball core.The coating solution that reuse is mixed with places rotation to spray coating solution in the coating pan in the ball core; Perhaps ball core limit injection coating solution is spread on the limit in the coating pan of rotation, dry then or the like.When having other advanced pills such as fluid bed and coating equipment, can adopt these equipment to prepare micropill or with the micropill coating, make after the coated micropill of the person of being unified into respectively, obtain end-product in each medicine ratio capsule charge of announcing in the WHO newest standards.(rifampicin is an enteric coated micropill to utilize our the complex rifampin pellet capsule 1 of preparation of the present invention, all the other are the gastric solubleness micropill) and complex rifampin pellet capsule 2 (can be described as compound recipe isoniazid pellet capsule again, isoniazid is an enteric coated micropill, all the other are the gastric solubleness micropill) with the listing conventional formulation (rifampicin capsules, isoniazid tablets, pyrazinamide tablet, hydrochloric acid clothing amine butanols sheet) be reference preparation, carried out the relative bioavailability experiment of hybrid dog, experimental result shows that the relative bioavailability of complex rifampin pellet capsule 1 is 124.7%, and the relative bioavailability of complex rifampin pellet capsule 2 is near 110%.

In another preferred embodiment of the present invention, dosage form is multilayer tablet or tablet.The way of implementing this scheme has two kinds of ways substantially: first kind of way is the enteric member to be made the preparation intermediate of enteric coated micropill, enteric-coated microcapsule, mix with other members then, add conventional pharmaceutic adjuvants such as suitable adhesive, filler, disintegrating agent, adopt the common process of preparation tablets to be pressed into tablet.Also but each member does not mix or the partially mixed multilayer tablet that is pressed into, and for example with enteric member one deck as slice, thin piece, other members are as one deck of slice, thin piece.Another kind of way is that the enteric member is made label, uses above-mentioned enteric-coating material with its coating then, and other members make granule, at last label and granule are pressed into the sandwich tablet together.Certainly adopt the mixing way of above-mentioned two kinds of its these ways also should be included in wherein.Make the involved adjuvant of this tablet and be the conventional adjuvant on general textbook and the handbook,, can implement for the professional though need certain screening.The used tablet machine of tabletting can not adopt common tablet machine, should adopt multistation multilamellar tablet machine, and this machinery is comparatively advanced, and existing procucts are sold at present, the product of for example Italian Yi Ma company, and subsidiary factory is had in China in the said firm.

Enforcement of the present invention will provide more perfect FDC for treatment lungy _SNovel formulation, this novel formulation is a kind of new drug-supplying system with the general introduction of the noun in the galenic pharmacy.

Hereinafter embodiment further specifies the present invention, but never is to mean that the present invention only limits to this.

Embodiment 1

A kind of tetrad complex rifampin capsule, wherein rifampicin is the enteric small pieces, and ebutol is common small pieces, and isoniazid and pyrazinamide are made granule together, can carry out gastric solubleness coating clothing, capsule charge then by grain for guaranteeing dose.Explanation in passing, granule can not carry out the gastric solubleness coating fully.

(1) prescription of rifampicin enteric coatel tablets and preparation technology:

(1) prescription and the technology of the plain sheet of rifampicin (label):

(A) prescription:

Rifampicin 75.0g

Low-substituted hydroxypropyl cellulose 20.0g

Starch 10.0g

Sodium lauryl sulphate 6.5g

10% starch slurry is an amount of

Magnesium stearate is an amount of

Make 1000

(B) preparation technology:

Above-mentioned raw materials, adjuvant are crossed 200 mesh sieves, correctly take by weighing by recipe quantity, mix homogeneously, add 10% starch slurry (about 8～9ml), make soft, cross 26 mesh sieves and granulate.Put in the baking oven 60 ℃ of dryings 2 hours, and took out with 26 mesh sieve granulate, after 60 mesh sieves, the granule rate is more than 75%.To sieve down behind fine powder and the magnesium stearate mixing again and the granule mixing, tabletting, control strip focuses between 140mg～160mg.

Press limit test of weight variation inspection technique under two appendix XG tablet friabilities of Chinese Pharmacopoeia (version in 2000) inspection technique, XA inspection technique disintegration and the IA tablet item to the plain sheet inspection of rifampicin, carry out the assay inspection after meeting the requirements, eligible carries out enteric coating.

(2) prescription of enteric coating liquid and compound method and art for coating:

(A) prescription of enteric coating:

Hydroxypropylmethyl cellulose phthalate 10.0g

Diethyl phthalate 1.0g

Pulvis Talci 10.0g

Acetone: ethanol (3: 7) liquid 200ml

(B) compound method of enteric coating liquid:

Correctly take by weighing the hydroxypropylmethyl cellulose phthalate of recipe quantity, add acetone liquid 200ml dissolving, add diethyl phthalate mixing, dissolving, add Pulvis Talci again and stir promptly.

(C) art for coating:

Correctly take by weighing label and put in the coating pan, the rolling coating pan, limit spray enteric coating liquid, the limit blowing hot-air wraps to sheet and heavily increases to about 10%, takes out and puts 60 ℃ of dryings of baking oven 1 hour.Take out, the release of checking this product in the 0.1M hydrochloric acid solution 2 hours burst size should be less than 10%, in phosphate buffer (PH6.8) 0.5 hour burst size should be greater than 70%, carry out painted coating after qualified.

(3) compound method of painted coating solution and art for coating:

(A) compound method of color coating solution:

100ml is in beaker in water intaking, is sprinkled into Opadry 03B 12g under the restir, continues stirring and makes into the opaque oar shape of even redness suspension in 30～40 minutes.

(B) art for coating:

The label that wrapped enteric coating is put in the coating pan, and painted clothing liquid is sprayed on the limit, and the limit blowing hot-air wraps to label weightening finish about 3%.Put 60 ℃ of dryings of baking oven 1 hour.Take out, the release of checking this product in the 0.1mol/L hydrochloric acid solution 2 hours burst size should be less than 10%, in phosphate buffer (PH6.8) 45 minutes burst size should be greater than 70% (detection method be with reference to the second method inspection of two appendix XD of Chinese Pharmacopoeia version in 2000 drug release determination method).

(2) prescription of ebutol sheet and preparation technology:

(1) prescription:

Ebutol 137.5g

Microcrystalline Cellulose 15g

Radix Acaciae senegalis is an amount of

Magnesium stearate is an amount of

Make 1000

(2) preparation technology:

Correctly take by weighing PVP 6g, add 70% ethanol liquid 60ml dissolving.Correctly take by weighing ethambutol 137.5g, add above-mentioned 10%PVP solution (using 10%PVP solution 50ml approximately) and make soft material, cross 26 eye mesh screens and granulate by prescription, put 60 ℃ of dryings of baking oven 2 hours, took out 26 mesh sieve granulate, and sifted out fine powder after 60 mesh sieves, granule should be more than 70%.With fine powder and magnesium stearate (amount of getting magnesium stearate be crude drug about 0.4%) mix homogeneously, again with the granule mixing of 30～60 mesh sieves.Select punch die tabletting on tablet machine of 7.5mm, control strip focuses between 140mg～155mg.

The limit test of weight variation inspection technique of pressing under two appendix XG tablet friabilities of Chinese Pharmacopoeia (version in 2000) inspection technique, XA inspection technique disintegration and the IA tablet item is checked the ethambutol sheet, carries out the assay inspection after meeting the requirements.

(3) prescription and the preparation technology of isoniazid, pyrazinamide coated granule:

(1) isoniazid, the particulate prescription of pyrazinamide and preparation technology:

(A) prescription:

Isoniazid 37.5g

Pyrazinamide 200.0g

Starch 30.0g

PVP is an amount of

Make the granule that becomes to be equivalent to adorn 1000 capsules

(B) technology:

Correctly taking by weighing PVP 9g is dissolved among the 70% ethanol 60ml.Correctly take by weighing isoniazid, pyrazinamide, the starch mix homogeneously of recipe quantity, add above-mentioned 15%PVP alcoholic solution (using 50ml approximately) and make soft material, cross 32 mesh sieves, put in the coating pan, with rotating speed is that 80～90 rev/mins rotating speed rolled 30 minutes, takes out, and puts 60 ℃ of dryings of baking oven 2 hours.

Check: particulate shaped property, hardness, surface smoothness and content should meet the pharmacopeia regulation.

(2) preparation of coating solution and art for coating:

(A) preparation of coating solution:

Correctly take by weighing PVP 6g, PEG6000 9g is dissolved among the 70% ethanol 60ml, and (solution of 10%PVP, 15%PEG) promptly gets coating solution.

(B) art for coating:

Dried granule is put in the coating pan, and rolling coating pan, rotating speed are 90 rev/mins, and spray coating solution limit, limit blowing hot-air to increasing weight about 3%, takes out the granule bag to put 60 ℃ of dryings of baking oven 1 hour.

Check: particulate shaped property, hardness, surface smoothness and content should be up to specification.

(4) capsular filling:

At first taking by weighing isoniazid, pyrazinamide coated granule (being equivalent to isoniazid 37.5mg, pyrazinamide 200mg) by recipe quantity is loaded in special No. 0 opaque capsule, respectively get 1 of rifampicin enteric coatel tablets again and be equivalent to rifampicin 75mg and 1 of ethambutol sheet and be equivalent to ethambutol 137.5mg and be loaded in the capsule, capsule lid promptly on the press seal.At present existing 4 station capsule filling machines can be realized the capsule filling of above-mentioned 3 kinds of different materials.

(5) if the position of rifampicin in this example and isoniazid is changed, still make in accordance with the law, also can reach isoniazid isoniazid and rifampicin are discharged the purpose of avoiding the rifampicin degraded with upper intestines respectively under one's belt.

Embodiment 2

A kind of complex rifampin pellet capsule, the every receipts or other documents in duplicate of tetrad member are solely made micropill back coating after testing, rifampicin enteric coating wherein, other member's gastric solubleness coatings.The present embodiment end-product has the tetrad capsule respectively, three capsules and two capsules.

(1) preparation of rifampicin enteric coated micropill

The preparation of the plain ball of rifampicin:

1. the prescription of the plain ball of rifampicin is formed: 1 part of rifampicin, add 0.0867 part in ball core, add fine little plain 0.2 part of crystallite, add 0.1333 part of sodium lauryl sulphate, add 0.0667 part of CMS-Na, 1%PVP (ethanol: water=1: 1) an amount of.(or write as: rifampicin 150g, ball core 13g, the fine little plain 30g of crystallite, sodium lauryl sulphate 20g, CMS-Na 10g, 1%PVP (ethanol: water=1: 1) an amount of.)

2. the preparation technology of the plain ball of rifampicin:

A takes by weighing above-mentioned former, adjuvant in proportion and sieves, and mixing is standby as medicated powder; Prepare in proportion 1%PVP (ethanol: liquid water=1: 1), standby.

B puts the ball core in the coating pan, and with suitable rotational speed coating pan, (ethanol: liquid water=1: 1), the limit powder that spreads pesticides, until medicated powder has been spread, this moment, the ball core diameter increased slightly between 0.8mm～1.5mm limit spray 1%PVP.Take out micropill, put in the baking oven, 60 ℃ of dryings 2 hours, standby.

The enteric coating of the plain ball of rifampicin:

1. the preparation of enteric coating liquid: configuration acetone: ethanol=4: 6 solution 100ml, add and face diethyl phthalate 0.5ml, add HP-55 5g, the dissolving mixing is standby.

2. the enteric coating technology of the plain ball of rifampicin: plain ball is put in the coating pan, the rolling coating pan, adjust rotating speed, plain ball is evenly rolled in coating pan, limit spray coating solution, limit blowing hot-air (about 40 ℃), limit bound edge test, micropill is not dissolved in the hydrochloric acid solution of 0.1mol/L (rule of thumb to be judged, but finally should shine the second method inspection of two appendix XD of Chinese Pharmacopoeia version in 2000 drug release determination method, the stripping quantity of micropill rifampicin should be less than below 10% of content of dispersion in the burst size 2 hours in the acid, and burst size 45 minutes should be greater than more than 70% in the buffer solution), at last with micropill in inherent 50 ℃ of dryings of baking oven 2 hours, promptly.The pastille rate of rifampicin enteric coated micropill is about 60%.

(2) preparation of isoniazid rapid release gastric solubleness micropill

The prescription of the plain ball of A isoniazid is formed: 1 part of isoniazid, add 0.05 part in ball core, add 0.02 part of starch, PVP0.01 part adds 50% ethanol an amount of (or write as: isoniazid 150g, ball core 7.5g, starch 3g, PVP1.5g, 50% ethanol is an amount of).

The preparation technology of the plain ball of B isoniazid: get each former, adjuvant of title by above-mentioned prescription, cross 100 mesh sieves, mixing, standby as medicated powder.The ball core is put in the coating pan, with suitable rotational speed coating pan, the limit spray ethanol liquid powder that just spreads pesticides, until medicated powder has been spread, this moment, the ball core diameter increased slightly between 0.8mm～1.5mm.Take out micropill, put in the baking oven, 60 ℃ of dryings 2 hours are sieved, granulate, and are standby.

The coating of the plain ball of C isoniazid: get stomach dissolution type film-coat pre-mixing agent (commercially available), it is 9% coating solution that the alcoholic solution with 50% is mixed with content.Plain ball is put in the coating pan, with suitable rotational speed coating pan, limit spray coating solution limit blowing hot-air (about 50 ℃), bag is put in the baking oven to plain ball weightening finish about 3.5%, 60 ℃ of dryings 2 hours, promptly.The pastille rate of isoniazid gastric solubleness micropill is about 92%.

(3) preparation of pyrazinamide rapid release gastric solubleness micropill

The prescription of the plain ball of A pyrazinamide is formed: pyrazinamide adds 0.05 part in ball core for 1 part, adds PVP0.02 part, adds 0.03 part of starch, and it is an amount of to add 50% ethanol.(or write as: pyrazinamide 200g, ball core 10g, PVP4g, starch 6g, 50% ethanol is an amount of)

The preparation technology of the plain ball of B pyrazinamide: get each former, adjuvant of title by above-mentioned prescription, cross 100 mesh sieves, mixing, standby as medicated powder.The ball core is put in the coating pan, with suitable rotational speed coating pan, the limit spray ethanol liquid powder that just spreads pesticides, until medicated powder has been spread, this moment, the ball core diameter increased slightly between 1mm～1.5mm.Take out micropill, put in the baking oven, 60 ℃ of dryings 2 hours are sieved, granulate, and are standby.

The coating of the plain ball of C pyrazinamide: get stomach dissolution type film-coat pre-mixing agent (commercially available), it is 9% coating solution that the alcoholic solution with 50% is mixed with content.Plain ball is put in the coating pan, with suitable rotational speed coating pan, limit spray coating solution limit blowing hot-air (about 50 ℃), bag is put in the baking oven to plain ball weightening finish about 3.5%, 60 ℃ of dryings 2 hours, promptly.The pastille rate of pyrazinamide gastric solubleness micropill is about 90%.

(4) preparation of ebutol rapid release gastric solubleness micropill

The prescription of the plain ball of alite acid diethylamide butanols is formed: 1 part of ebutol adds 0.2182 part in ball core and adds 0.4364 part of starch and add 0.1091 part in dextrin to add 50% ethanol an amount of.(or write as: ebutol 137.5g, ball core 30g, starch 60g, dextrin 15g, 50% ethanol is an amount of.)

The preparation technology of the plain ball of belit acid diethylamide butanols: get each former, adjuvant of title by above-mentioned prescription, cross 100 mesh sieves, mixing, standby as medicated powder.The ball core is put in the coating pan, with suitable rotational speed coating pan, the limit spray ethanol liquid powder that just spreads pesticides, until medicated powder has been spread, this moment, the ball core diameter increased slightly between 1mm～1.5mm.Take out micropill, put in the baking oven, 40 ℃ of dryings 3 hours are sieved, granulate, and are standby.

The coating of the plain ball of celite acid diethylamide butanols: get stomach dissolution type film-coat pre-mixing agent (commercially available), it is 9% coating solution that the alcoholic solution with 50% is mixed with content.Plain ball is put in the coating pan, with suitable rotational speed coating pan, limit spray coating solution limit blowing hot-air (about 40 ℃), bag is put in the baking oven to plain ball weightening finish about 3.5%, 40 ℃ of dryings 3 hours, promptly.The pastille rate of ebutol gastric solubleness micropill is about 55%.

(5) preparation of tetrad complex rifampin pellet capsule

Prescription: rifampicin 150mg, isoniazid 75mg, pyrazinamide 400mg, ebutol 275mg.

Technology: get the about 83300mg of rifampicin micropill, the about 27174mg of isoniazid micropill, the about 148111mg of pyrazinamide micropill, the about 166667mg of ebutol micropill, mix homogeneously is sub-packed in 1000 No. 00 capsules, should contain rifampicin 50mg ± 10% in every capsules, isoniazid 25mg ± 5%, pyrazinamide 133.3mg ± 5%, ebutol 91.7mg ± 7%, detection level, each medicine should be up to specification, as against regulation, should regulate the loading amount of each micropill.

The preparation of (6) three complex rifampin pellet capsules (totally three kinds)

Prescription: A rifampicin 150mg, isoniazid 75mg, pyrazinamide 400mg; ÷ 2

B rifampicin 60mg, isoniazid 30mg, pyrazinamide 150mg;

C rifampicin 150mg, isoniazid 150mg, pyrazinamide 500mg; ÷ 3

Technology:

A gets the about 125000mg of rifampicin micropill by prescription, the about 40761mg of isoniazid micropill, the about 222222mg of pyrazinamide micropill, mix homogeneously, be sub-packed in 1000 No. 00 capsules, should contain rifampicin 75mg ± 10% in every capsules, isoniazid 37.5mg ± 5%, pyrazinamide 200mg ± 5%, detection level, each medicine should be up to specification, as against regulation, should regulate the loading amount of each micropill.

B gets the about 100000mg of rifampicin micropill by prescription, the about 32609mg of isoniazid micropill, the about 166667mg of pyrazinamide micropill, mix homogeneously, be sub-packed in 1000 No. 0 capsules, should contain rifampicin 60mg ± 10% in every capsules, isoniazid 30mg ± 5%, pyrazinamide 150mg ± 5%, detection level, each medicine should be up to specification, as against regulation, should regulate the loading amount of each micropill.

C gets the about 125000mg of rifampicin micropill by prescription, the about 81522mg of isoniazid micropill, the about 277778mg of pyrazinamide micropill, mix homogeneously, be sub-packed in 1000 No. 00 capsules, should contain rifampicin 75mg ± 10% in every capsules, isoniazid 75mg ± 5%, pyrazinamide 250mg ± 5%, detection level, each medicine should be up to specification, as against regulation, should regulate the loading amount of each micropill.

Name reason: the same

The preparation of (7) two complex rifampin pellet capsules (totally four kinds)

Prescription: A rifampicin 150mg, isoniazid 75mg

B rifampicin 60mg, isoniazid 60mg

C rifampicin 150mg, isoniazid 150mg

D rifampicin 60mg, isoniazid 30mg,

Technology:

A gets the about 250000mg of rifampicin micropill by prescription, the about 81522mg of isoniazid micropill, mix homogeneously, be sub-packed in 1000 No. 0 capsules, should contain rifampicin 150mg ± 10% in every capsules, isoniazid 75mg ± 5%, detection level, each medicine should be up to specification, as against regulation, should regulate the loading amount of each micropill.

B gets the about 100000mg of rifampicin micropill by prescription, the about 65217mg of isoniazid micropill, mix homogeneously, be sub-packed in 1000 No. 2 capsules, should contain rifampicin 60mg ± 10% in every capsules, isoniazid 60mg ± 5%, detection level, each medicine should be up to specification, as against regulation, should regulate the loading amount of each micropill.

C gets the about 250000mg of rifampicin micropill by prescription, the about 163043mg of isoniazid micropill, mix homogeneously, be sub-packed in 1000 No. 00 capsules, should contain rifampicin 150mg ± 10% in every capsules, isoniazid 150mg ± 5%, detection level, each medicine should be up to specification, as against regulation, should regulate the loading amount of each micropill.

D gets the about 100000mg of rifampicin micropill by prescription, the about 32609mg of isoniazid micropill, mix homogeneously, be sub-packed in 1000 No. 2 capsules, should contain rifampicin 60mg ± 10% in every capsules, isoniazid 30mg ± 5%, detection level, each medicine should be up to specification, as against regulation, should regulate the loading amount of each micropill.

Embodiment 3

A kind of complex rifampin pellet capsule, the every receipts or other documents in duplicate of tetrad member are solely made micropill back coating after testing, isoniazid enteric coating wherein, other member's gastric solubleness coatings.The present embodiment end-product has the tetrad capsule respectively, three capsules and two capsules.Present embodiment is except carrying out enteric coating with rifampicin enteric coated micropill same process among plain ball employing of isoniazid and the embodiment 2, isoniazid gastric solubleness micropill same process carries out the gastric solubleness coating among plain ball employing of rifampicin and the embodiment 2, all the other contents are fully identical with embodiment 2, because length is limit, and repeats no more herein.Certainly, because the exchange of plain ball of isoniazid and the plain ball coating material of rifampicin, the minor variations of the medicine that brings content in micropill, also can cause the minor variations of micropill loading in capsule thus, these minor variations are general medicament technical staff institute general knowledge, and therefore concrete data also there is no need to list for example herein.

Embodiment 4

A kind of three complex rifampin sheets are wherein made small pieces respectively with each member, again with the one enteric coating then tabletting make oral tablet.

(1) prescription (three)

A rifampicin 150mg, isoniazid 75mg, pyrazinamide 400mg;

B rifampicin 60mg, isoniazid 30mg, pyrazinamide 150mg;

C rifampicin 150mg, isoniazid 150mg, pyrazinamide 500mg;

(2) prescription of rifampicin enteric coatel tablets and preparation technology:

(1) plain particulate prescription of sheet (label) of rifampicin and preparation technology:

(A) prescription: 1 part of rifampicin adds 0.2667 part of low-substituted hydroxypropyl cellulose and adds 0.1333 part of starch and add 0.0867 part of sodium lauryl sulphate and add 10% starch slurry to add magnesium stearate in right amount an amount of.

(B) preparation technology:

Get former, adjuvant in each ratio former, adjuvant of prescription, above-mentioned raw materials, adjuvant crossed 200 mesh sieves, mix homogeneously, add 10% starch slurry (about 8～9ml), make soft, cross 26 mesh sieves and granulate.Put in the baking oven 60 ℃ of dryings 2 hours, and took out with 26 mesh sieve granulate, after 60 mesh sieves, the granule rate is more than 75%.To sieve down behind fine powder and the magnesium stearate mixing standby with granule mixing tabletting again.

(2) prescription A (rifampicin 150mg, isoniazid 75mg, pyrazinamide 400mg) preparation of three sandwich plain sheets: with above-mentioned former prescription the out after 2, prescription becomes: rifampicin 75mg, isoniazid 37.5mg, pyrazinamide 200mg (purpose that prescription reduces by half is the volume that reduces tablet, is convenient to patient and takes).Get plain sheet (label) granule of above-mentioned rifampicin tabletting, control strip focuses on about 115mg, and the rifampicin content that makes every is 75mg ± 7%.Press limit test of weight variation inspection technique under two appendix XG tablet friabilities of Chinese Pharmacopoeia (version in 2000) inspection technique, XA inspection technique disintegration and the IA tablet item to the plain sheet inspection of rifampicin, carry out the assay inspection after meeting the requirements, eligible carries out coating.

The preparation of prescription B (rifampicin 60mg, isoniazid 30mg, pyrazinamide 150mg) three sandwich plain sheets: get plain sheet (label) granule of above-mentioned rifampicin tabletting, control strip focuses on about 92mg, and making every rifampicin content is 60mg ± 7%.Press limit test of weight variation inspection technique under two appendix XG tablet friabilities of Chinese Pharmacopoeia (version in 2000) inspection technique, XA inspection technique disintegration and the IA tablet item to the plain sheet inspection of rifampicin, carry out the assay inspection after meeting the requirements, eligible carries out coating.

The preparation of prescription C (rifampicin 150mg, isoniazid 150mg, pyrazinamide 500mg) three sandwich plain sheets: with above-mentioned former prescription the out after 2, prescription becomes: rifampicin 75mg, isoniazid 75mg, pyrazinamide 250mg (purpose that prescription reduces by half is the volume that reduces tablet, is convenient to patient and takes).Get plain sheet (label) granule of above-mentioned rifampicin tabletting, control strip focuses on about 115mg, and the rifampicin content that makes every is 75mg ± 7%.Press limit test of weight variation inspection technique under two appendix XG tablet friabilities of Chinese Pharmacopoeia (version in 2000) inspection technique, XA inspection technique disintegration and the IA tablet item to the plain sheet inspection of rifampicin, carry out the assay inspection after meeting the requirements, eligible carries out coating.

(3) prescription of enteric coating liquid and compound method and rifampicin art for coating:

1. the prescription of enteric coating:

Hydroxypropylmethyl cellulose phthalate 10.0g

Diethyl phthalate 1.0g

Pulvis Talci 10.0g

4: 6 liquid 200ml of acetone

2. the compound method of enteric coating liquid:

Correctly take by weighing the hydroxypropylmethyl cellulose phthalate of recipe quantity, add acetone liquid 200ml dissolving, add the dissolving of diethyl phthalate mixing, add Pulvis Talci again and stir promptly.

3. rifampicin art for coating:

Get the plain label of rifampicin and put in the coating pan, the rolling coating pan, limit spray enteric coating liquid, the limit blowing hot-air wraps to sheet and heavily increases to about 10%, takes out and puts 60 ℃ of dryings of baking oven 1 hour.Take out, the release of checking this product in the 0.1M hydrochloric acid solution 2 hours burst size should be less than 10%, in phosphate buffer (PH6.8) 0.5 hour burst size should be greater than 70%, (detection method is with reference to the second method inspection of two appendix XD of Chinese Pharmacopoeia version in 2000 drug release determination method).

(3) isoniazid, the outer field prescription of pyrazinamide and outer particulate preparation:

The outer field prescription of isoniazid, pyrazinamide and the outer particulate preparation of the three sandwich sheets of prescription A:

1. write out a prescription: isoniazid 37.5g

Pyrazinamide 200g

Low-substituted hydroxypropyl cellulose 50g

The 5%PVP70% alcoholic solution is an amount of

Hard magnesium is an amount of

Suitable 1000 skin

2. granule preparing process:

Take by weighing each supplementary material by prescription, cross 100 mesh sieves, mixing is a binding agent with the 5%PVP70% alcoholic solution, makes soft, crosses 20 mesh sieve system wet granulars, and 60 ℃～70 ℃ dryings 3～4 hours are taken out 20 order granulate, the count particles rate.Get less than 60 purpose granule fine powders and hard magnesium mixing,, measure the content of isoniazid, pyrazinamide again with other granule mixing, standby.

The outer field prescription of isoniazid, pyrazinamide and the outer particulate preparation of the three sandwich sheets of prescription B:

1. write out a prescription: isoniazid 30g

Pyrazinamide 150g

Low-substituted hydroxypropyl cellulose 20g

The 5%PVP70% alcoholic solution is an amount of

Hard magnesium is an amount of

Suitable 1000 skin

2. granule preparing process:

Take by weighing each supplementary material by prescription, cross 100 mesh sieves, mixing is a binding agent with the 5%PVP70% alcoholic solution, makes soft, crosses 20 mesh sieve system wet granulars, and 60 ℃～70 ℃ dryings 3～4 hours are taken out 20 order granulate, the count particles rate.Get less than 60 purpose granule fine powders and hard magnesium mixing,, measure the content of isoniazid, pyrazinamide again with other granule mixing, standby.

The outer field prescription of isoniazid, pyrazinamide and the outer particulate preparation of the three sandwich sheets of prescription C:

1. write out a prescription:

Isoniazid 75g

Pyrazinamide 250g

Low-substituted hydroxypropyl cellulose 50g

The 5%PVP70% alcoholic solution is an amount of

Hard magnesium is an amount of

Suitable 1000 skin

2. granule preparing process:

Take by weighing each supplementary material by prescription, cross 100 mesh sieves, mixing is a binding agent with the 5%PVP70% alcoholic solution, makes soft, crosses 20 mesh sieve system wet granulars, and 60 ℃～70 ℃ dryings 3～4 hours are taken out 20 order granulate, the count particles rate.Get less than 60 purpose granule fine powders and hard magnesium mixing,, measure the content of isoniazid, pyrazinamide again with other granule mixing, standby.

(4) three sandwich compacting:

Use sandwich die above-mentioned each rifampicin chip and outer isoniazid, pyrazine acyl granule of writing out a prescription to be pressed into sandwich with tablet machine.

(5) three sandwich outer coating:

Get stomach dissolution type film-coat pre-mixing agent (commercially available), it is 9% coating solution that the alcoholic solution with 50% is mixed with content.Three sandwich of having prepared are put in the coating pan, with suitable rotational speed coating pan, limit spray coating solution limit blowing hot-air (about 40 ℃), bag is put in the baking oven to sandwich weightening finish about 3.5%, 40 ℃ of dryings 3 hours, promptly.

Embodiment 5

Sandwich of a kind of two complex rifampins, wherein the technology similar embodiment 4.

(1) prescription (four)

A rifampicin 150mg, isoniazid 150mg;

B rifampicin 60mg, isoniazid 30mg;

C rifampicin 60mg, isoniazid 60mg;

D rifampicin 150mg, isoniazid 75mg;

(2) prescription of rifampicin enteric coatel tablets and preparation technology:

(1) plain particulate prescription of sheet (label) of rifampicin and preparation technology:

(A) prescription: (with three sandwich)

(B) preparation technology: (with three sandwich)

(2) preparation of prescription A two sandwich plain sheets: get plain sheet (label) granule of above-mentioned rifampicin tabletting, control strip focuses on about 230mg, and the rifampicin content that makes every is 150mg ± 7%.Press limit test of weight variation inspection technique under two appendix XG tablet friabilities of Chinese Pharmacopoeia (version in 2000) inspection technique, XA inspection technique disintegration and the IA tablet item to the plain sheet inspection of rifampicin, carry out the assay inspection after meeting the requirements, eligible carries out coating.

The preparation of prescription B two sandwich plain sheets: get plain sheet (label) granule of above-mentioned rifampicin tabletting, control strip focuses on about 92mg, and making every rifampicin content is 60mg ± 7%.Press limit test of weight variation inspection technique under two appendix XG tablet friabilities of Chinese Pharmacopoeia (version in 2000) inspection technique, XA inspection technique disintegration and the IA tablet item to the plain sheet inspection of rifampicin, carry out the assay inspection after meeting the requirements, eligible carries out coating.

The preparation of prescription C two sandwich plain sheets: with prescription B.

The preparation of prescription D two sandwich plain sheets: with prescription A.

(3) prescription of enteric coating liquid and compound method and rifampicin art for coating: (with three sandwich)

(3) outer field prescription of isoniazid and outer particulate preparation:

The outer field prescription of isoniazid and the outer particulate preparation of the two sandwich sheets of prescription A:

1. write out a prescription:

Isoniazid 75g

Low-substituted hydroxypropyl cellulose 75g

The fine little plain 100g of crystallite

2%CMS-Na solution is an amount of

Hard magnesium is an amount of

Suitable 1000 skin

2. granule preparing process:

Take by weighing each supplementary material by prescription, cross 100 mesh sieves, mixing is a binding agent with 2%CMS-Na solution, makes soft, crosses 20 mesh sieve system wet granulars, and 60 ℃～70 ℃ dryings 3～4 hours are taken out 20 order granulate, the count particles rate.Get less than 60 purpose granule fine powders and hard magnesium mixing,, measure the content of isoniazid again with other granule mixing, standby.

The outer field prescription of isoniazid and the outer particulate preparation of the two sandwich sheets of prescription B:

With prescription A.

The outer field prescription of isoniazid and the outer particulate preparation of the two sandwich sheets of prescription C:

With prescription A.

The outer field prescription of isoniazid and the outer particulate preparation of the two sandwich sheets of prescription C:

With prescription A.

(4) two sandwich compacting:

Use sandwich die above-mentioned each the rifampicin chip and outer isoniazid granule of writing out a prescription to be pressed into sandwich with tablet machine.

(5) two sandwich outer coating:

Get stomach dissolution type film-coat pre-mixing agent (commercially available), it is 9% coating solution that the alcoholic solution with 50% is mixed with content.Three sandwich of having prepared are put in the coating pan, with suitable rotational speed coating pan, limit spray coating solution limit blowing hot-air (about 40 ℃), bag is put in the baking oven to sandwich weightening finish about 3.5%, 40 ℃ of dryings 3 hours, promptly.

The present invention has been described in detail in detail above, and obviously, those skilled in the art can do many improvement and variation and not deviate from the present invention's spirit scope after knowing the present invention.

Claims (8)

1. the compound rifampicin preparation of a capsule formulation, comprise rifampicin and isoniazid, further comprise pyrazinamide or pyrazinamide and ebutol alternatively, wherein each dose meets the standard compatibility dosage requirement that The World Health Organization's calendar year 2001 number one (79 the 1st phase of volume) bulletin is proposed, isoniazid, pyrazinamide, ebutol be gastric solubleness and rifampicin is an enteric, and the dissolved condition of enteric coating film be PH be begin between 5.0～5.5 the dissolving, it is characterized in that wherein that respectively the person of being unified into makes capsule charge behind the micropill separately, the ball core diameter increases slightly to 0.8-1.5mm, and the pastille rate of rifampicin enteric coated micropill is about 60%.

2. according to the preparation of claim 1, it is characterized in that enteric-coating material is selected from cellulose family, crylic acid resin or ethene polymers class.

3. according to the preparation of claim 2, wherein said coating material is a cellulose family.

4. according to the preparation of claim 3, wherein said coating material is selected from hydroxypropylmethyl cellulose phthalate or cellulose acetate-phthalate ester.

5. according to the preparation of claim 2, wherein said coating material is a crylic acid resin, is selected from acrylic resin I or II number.

6. according to the preparation of claim 2, wherein said coating material is the ethene polymers class, is selected from the polyvinyl alcohol phthalate ester, the polyvinyl alcohol Phthalate Aqueous Dispersion.

7. the preparation method of claim 1 preparation, comprise that respectively the person of being unified into is made the coated back of micropill capsule charge separately, wherein isoniazid be gastric solubleness and rifampicin is an enteric coating, bound edge test in limit when it is characterized in that the rifampicin coating, micropill is not dissolved in the hydrochloric acid solution of 0.1mol/L, finally should shine the second method inspection of two appendix XD of Chinese Pharmacopoeia version in 2000 drug release determination method, in the acid in the burst size 2 hours less than below 10% of content of dispersion, burst size 45 minutes should be greater than more than 70% in the buffer solution.

8. according to the method for claim 7, wherein optional pyrazinamide, ebutol are carried out the gastric solubleness coating.