CN101797238A - Method for preparing medicinal preparation for releasing rifampicin on upper part of small intestine and characteristics of medicinal preparation - Google Patents
Method for preparing medicinal preparation for releasing rifampicin on upper part of small intestine and characteristics of medicinal preparation Download PDFInfo
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Abstract
The invention discloses a method for preparing a medicinal preparation for releasing rifampicin as an anti-tuberculous first-line medicament on the upper part of small intestine and characteristics of in vitro medicament dissolution and in vivo release and absorption which the medicinal preparation should have. The method is characterized in that: the weight increment of a micro-pellet enteric coating material is between 1 and 9.9 percent; the weight increment of a granular enteric coating material is between 1.5 and 10.9 percent; the weight increment of a micro-tablet enteric coating material is between 0.5 and 8.9 percent; a release and absorption curve of a rifampicin micro-pellet in vivo should show that the blood medicament concentration is 16+/-0 to 26 percent of a peak value of the blood medicament concentration within 20 minutes after oral administration and is 23 to 77 percent of the peak value of the blood medicament concentration within 40 minutes; and during a time interval between 20 and 40 minutes, a rising speed of the blood medicament concentration is 0.63 to 2.73 percent of that of the peak concentration.
Description
Technical field
The present invention relates to the antituberculotics rifampicin at the preparation method of upper part of small intestine release preparation and the drug release characteristic of its inside and outside, and the medical usage in tuberculosis prevention and treatment.
Technical background
The present invention is patent ZL03101211.6 and patent application 200610092088X, 2006100920911,2006100920860 continuous application.
The World Health Organization (WHO) begins to recommend successively the standard prescription of the fixed dosage compound formulation (FDC preparation) of tuberculosis one line medicament benemicin, isoniazid, pyrazinamide, ebutol from 1998 beginnings to the whole world, requires it is used in the control of the clinical line of tuberculosis.WHO is when recommending above-mentioned standard prescription FDC preparation, to the very worry that suffers a loss of bioavailability in the quality of rifampicin component in the FDC preparation and the body, require the FDC preparation should ensure rifampicin in preparation stability and body in bioavailability not/or suffer a loss less.
The research group that the applicant participates in has carried out years of researches to above-mentioned FDC preparation, and has submitted above-mentioned a series of patent application to according to the above-mentioned requirements of WHO.The application is on the basis of above-mentioned a series of patent application research work, continues preparation method and its inside and outside drug release characteristic of disclosed rifampicin upper part of small intestine release preparation.
Summary of the invention
If rifampicin contacts with isoniazid, pyrazinamide, ebutol in preparation, then will produce degraded, its main degradation products is a 3-[ftivazide methyl] and rifampicin (HYD, isonicotinylhydrazone), and in the presence of micro-moisture, this degraded will aggravate.Prove according to applicant's years of researches, with Rimactazid, pyrazinamide, ebutol respectively coating carry out physical isolation, and then carry out capsule according to the dosage of the standard prescription of the FDC preparation that WHO proposed and fill, finally form the FDC preparation.In the preparation method of this FDC preparation, first-selected is to adopt enteric-coating material to carry out coating rifampicin component or isoniazid component, its physical isolation effect will be better, and making in this way, the effect duration of the above-mentioned FDC preparation of prepared one-tenth can surpass more than 2 years.These results of study are statement successively in the above-mentioned patent application of applicant.
Need to prove that the enteric-coating material that allows to use is various, carrying out respectively separately to drug component, coating also is a formulation method common in the pharmaceutical preparation, but in conjunction with concrete medicine, especially Rimactazid, pyrazinamide, ebutol being made the FDC preparation according to the standard prescription of WHO behind the coating respectively is to propose the standard prescription of FDC preparation and specification requirement for many years later at WHO, and the research group that the applicant participates in is through the preparation method of a kind of above-mentioned FDC preparation that just searches out on the years of researches basis.
This preparation method comprises that Rimactazid, pyrazinamide, ebutol are prepared into micropill, microplate, granule respectively to carry out being packed into capsule behind the coating, finally forms the FDC preparation.Wherein the rifampicin component can be wrapped the gastric solubleness clothing, also can be enteric coated; The isoniazid component can be wrapped the gastric solubleness clothing, also can be enteric coated.But when these two kinds of components appear in the FDC preparation simultaneously, it is the gastric solubleness coating combination that the rifampicin component is carried out enteric coating and isoniazid component, be the enteric coating combination that the rifampicin component is carried out gastric solubleness coating and isoniazid component, can not or there is no need is that these two kinds of components adopt identical coating material to carry out coating in same FDC preparation.Pyrazinamide, ebutol then are to adopt the gastric solubleness coating all the time, there is no need to adopt enteric coating.Above-mentioned described FDC formulation preparation method is describing in the patent application that the applicant submitted to successively, but above-mentioned recapitulative description then is first.
Rifampicin belongs to insoluble drug, and it can produce degraded in acid solution, isoniazid, pyrazinamide, ebutol simultaneously in the presence of, the degraded of rifampicin will be accelerated.At this situation, the applicant has proposed that in above-mentioned patent application the rifampicin component is made micropill, microplate, granule and has carried out making behind the enteric coating it to discharge or isoniazid made the technical scheme that micropill, microplate, granule make it discharge at upper part of small intestine after carrying out enteric coating at upper part of small intestine.
Yet in the research practice of tuberculosis one line medicine FDC preparation, make medicine discharge not a duck soup at upper part of small intestine by the method that adopts enteric coating.Because according to the notion of general pharmaceutical preparation, adopt the enteric material coating generally to belong to enteric coated preparation, and enteric coated preparation generally have certain external stripping requirement.This requirement is basic norm with pharmacopeia to the requirement of enteric coated preparation generally, so that " Chinese pharmacopoeia is an example, and enteric coated preparation generally requires (to be generally 2 hours) in the regular hour, and burst size is in 10% in the hydrochloric acid solution (9 → 1000).
And rifampicin medicine belongs to concentration type antibacterial, wishes to reach very soon after the administration of rifampicin oral administration the peak of blood drug level clinically.If it is prepared into the enteric coated preparation of standard, even if select the enteric-coating material of the more approaching PH=5.0 of pH value and upper part of small intestine pH value for use, then, medicine just begins to melt owing to entering the later enteric-coating material of small intestinal, then medicine can not discharge from pharmaceutical preparation very soon after entering small intestinal, form medicine group with coating material and adjuvant, along with enterokinesia absorbs along small intestinal release limit in limit in lower digestive tract moves, this situation will be apparent in view the postponement rifampicin reach time of blood peak concentration of drug, and the situation that the rifampicin peak time moves after undue obviously is very not need clinically in the present tuberculosis clinical treatment.Because the secular tuberculosis medication of rifampicin practice all is the preparation that does not carry out enteric coating based on rifampicin, just just find the degraded situation of rifampicin in gastric acid in nearly about 10 years basic research.And have release curve in the rifampicin body of drug release characteristic in the remarkable enteric coated preparation body is the checking of not passing through clinical practice, although can prevent rifampicin degraded in vivo, improve the bioavailability of rifampicin, examine the life period obstacle but the rifampicin FDC preparation with remarkable enteric coated preparation feature will obtain the listing registration of medicine.
For the FDC preparation that isoniazid is adopted the gastric solubleness coating, just must mean and the rifampicin component need be carried out enteric coating.For this FDC preparation; if rifampicin is not protected; then rifampicin will partly be degraded in gastric acid; the part degraded suffers a loss with regard to the bioavailability that means rifampicin; and the rifampicin bioavailability suffers a loss and will mean the insufficient therapeutic dose of rifampicin, then will cause the generation of drug-resistant tuberculosis.And if simply rifampicin is made enteric coated preparation, although the bioavailability of rifampicin has obtained effective raising (seeing the data of the application's following table 1), but the hysteresis of rifampicin peak time has appearred, then the clinical practice with long-term rifampicin has difference, its therapeutic effect need relatively could be confirmed through clinical, just above-mentioned said " the life period obstacle is examined in the listing registration that obtains medicine ".Obviously simply the rifampicin component is made the technical problem that gastric solubility preparation or enteric coated preparation all can not well solve FDC preparation under the standard prescription that WHO proposes in the FDC preparation, the FDC preparation of characteristics of pharmacokinetics in the body that matches with current tuberculosis clinical application practice can not be provided.
Discover, rifampicin is an insoluble drug, though in gastric acid, dissolve, but absorbing not is fully under one's belt, because containing the preparation of rifampicin requires at auf nuechternen Magen einnehmen, and stomach is through the aggravation of the wriggling of the stimulation after taking medicine behind the auf nuechternen Magen einnehmen, and the medicine in the stomach under the effect of gastric peristalsis quite a few very fast (the shortest time is just to begin in a few minutes usually) enters upper part of small intestine by pylorus, so thinks under the convention that rifampicin is that the notion that absorbs under one's belt is inaccurate.
After having understood above-mentioned situation, by study we obtained rifampicin bioavailability in a kind of FDC of solution preparation not/or the method that suffers a loss less.In the technical program, still adopt the rifampicin component is carried out enteric coating, and make enteric coated preparation under the general concept if desired, then the gain in weight of enteric coating need reach more than 10% for micropill, gain in weight for particulate enteric coating need reach more than 11%, need reach more than 9% for the enteric coating gain in weight of microplate.And we adopt the enteric coating gain in weight to micropill to be controlled between 1%～9.9%, the best is about 3.0%～8.0%, to particulate enteric coating gain in weight between 1.5%～10.9%, the best is about 3.5%～6.5%, to the enteric coating gain in weight of microplate between 0.5%～8.9%, the best is about 2%～5.5%, then just can well solve above-mentioned contradiction, both can play good interception, can make the peak reaching time of blood concentration basically identical of peak time and not enteric coated rifampicin of the blood drug level of rifampicin again rifampicin degraded under one's belt.
The research group that the applicant participated in is found as far as possible to use less in the plain ball preparation of the rifampicin micropill of enteric material coating such organic solvent such as for example ethanol, methanol, acetone etc. to absorb in to the body of rifampicin and is good in the follow-up study of the described research work of above-mentioned patent application.This is because rifampicin can dissolve under the effect of organic solvent, has so just destroyed the crystal formation of rifampicin.And show according to after deliberation result, in the crystal formation of rifampicin the absorption of I type crystalline substance best, we just select this crystal formation when selecting to do the rifampicin raw material of micropill.If in the preparation process of micropill,, will cause the low absorption in vivo of the ruined rifampicin of crystal formation owing to the crystal formation that has destroyed the part rifampicin that is partly dissolved of solvent.For this reason, we are in the described technology of above-mentioned patent application that the applicant had submitted to, employed wetting agent in the micropill preparation process generally adopts the mixed solvent of alcohol and water, and the ratio of alcohol in water is between 0～80%, and best wetting agent is a pure water.And can in wetting agent, add then better effects if of binding agent, lubricant, short absorbent.
In the process of rifampicin pill, to for example consumption of sodium lauryl sulphate (SDS) also to some extent by a relatively large margin decline in follow-up research of solubilizing agent, optimum amount should be the rifampicin recipe quantity 0.001%～5% between, optimum amount is between 0.1～1.0%.The consumption of solubilizing agent is excessive, is not only waste, also can produce ill effect to body, and the consumption in the above-mentioned scope then is necessary, also can not produce ill effect to body.
In the process of rifampicin pill, in adjuvant, add antioxidant, for example vitamin C, sodium ascorbate, malic acid, sodium sulfite, sodium sulfite.With the vitamin C is example, and it is to having good prevention effect to the degraded because of the too high rifampicin that causes of water content in preparation process.Ascorbic consumption should be controlled at and the ratio (weight ratio) of rifampicin amount between 0.001～3%, the best is 0.02～2.5%.
In the process of rifampicin pill, be crucial to the moisture Control in the ball.Because the moisture in the ball is high the serious stability to the rifampicin micropill is caused a hidden trouble, so the moisture of micropill inside should be controlled at below 7% at least, preferably be controlled at below 4%, Optimal Control is below 2%.
In the process of rifampicin pill, baking temperature is also very important, and exsiccant temperature should be controlled between 1 ℃～95 ℃, and preferred range is between 25 ℃～70 ℃, and optimum temperature is between 30 ℃～55 ℃.
It is very tight that rifampicin micropill discomfort is fit to do, should relax under the situation of step process operation under not influencing as far as possible, because micropill is too tight, be unfavorable for that micropill enters the channel by porogen of the intravital moisture in back in the body and do not break at outer membrane and advance in the micropill, will influence the rifampicin fast Absorption in vivo in the micropill like this.The compactness of micropill is that the density by the drug loading of rifampicin and micropill characterizes.Obtain according to experiment, the drug loading of rifampicin should be controlled in 10%～90% the scope in the micropill, and is best in 40%～80% scope.The proportion of micropill should be controlled at 0.1～1.0 scope, and the best should be in 0.4～0.8 scope.All multifactor meetings such as the consumption of the character of supplementary material, the granularity of supplementary material, wetting agent, adhesive consumption have influence on the compactness of micropill.Wherein the granularity of rifampicin raw material is most important in the micropill preparation process, and the micropill of the more little preparation of raw material granularity is tight more, and the surface is also smooth more, otherwise the micropill of the big more preparation of rifampicin raw material granularity is loose more.In order to reach less granularity, the rifampicin raw material carried out inappropriate pulverizing after, can destroy the crystal formation of rifampicin, this is worthless way.As previously mentioned, absorb with its crystal formation in stability of Rifampicin and the body closely relatedly, for guaranteeing that rifampicin raw material crystal formation is not changed, micropill can not carry out big change to the granularity of rifampicin raw material in preparation process.
Adopt the rifampicin micropill of the made enteric-coating material coating of technique scheme to have tangible inside and outside stripping feature.It is in 0.1mol/L hydrochloric acid solution (9 → 1000), rotating speed is that per minute 50 changes, should should be 1%～34% and 35%～90% respectively mutually at 15 minutes stripping quantities during with 30 minutes, the best is 10%～30% and 35%～65% (assay method according to " two appendix dissolution methods of Chinese pharmacopoeia version in 2005 (appendix X C first method) mensuration).
Applicant's problem group adopts the preparation technology of patent ZL03101211.6 rifampicin enteric coated micropill to manufacture experimently 3 kinds of micropills, the formulation and technology basically identical of these three kinds of micropills, the thickness of different is micropill coating membrane shows the difference of weightening finish before and after the micropill coating: the weightening finish of micropill 1 is 13%, the weightening finish of micropill 2 is 4%, the weightening finish of micropill 3 is 7%, and the weightening finish of micropill 4 is 0%.
We have carried out absorbing in the body contrast test on the experimental animal pig.The contrast medicine is the rifampicin capsules that has adopted listing to buy.The dosage of the standard prescription of the 4 medicine FDC preparations that taking dose proposes according to WHO, and be equipped with gastric solubleness isoniazid, pyrazinamide, the ebutol listing preparation of same dose; Micropill 1,2,3 is actually three kinds of different enteric coated-pellets of thickness, adopts isoniazid, pyrazinamide, ebutol micropill all to adopt the gastric solubleness coating when taking medicine, and dosage is identical with the dosage of the standard prescription of 4 medicine FDC preparations of WHO proposition.Micropill 4 is actually does not have enteric coated rifampicin micropill, we are equipped with isoniazid, pyrazinamide, ebutol micropill with 4 medicine FDC preparation same doses, wherein the isoniazid micropill has adopted enteric coating, and pyrazinamide, ebutol micropill all adopt the gastric solubleness coating.
Measured pharmacokinetic parameters result is as shown in table 1 below: (number of animals n=6, the data in the table are average)
| Be subjected to reagent | ??T max(h) | ??C max(mg/L) | ??AUC 0→8 | Bioavailability % |
| Listing medicine 1 (folk prescription) | ??1.4 | ??11.53 | ??49.13 | ??100％ |
| Listing medicine 2 (compound recipe) | ??1.8 | ??11.39 | ??42.94 | ??87.4％ |
| Micropill 1 (compound recipe) | ??4.2 | ??10.86 | ??52.78 | ??107.4％ |
| Micropill 2 (compound recipe) | ??1.3 | ??11.35 | ??49.34 | ??100.4％ |
| Micropill 3 (compound recipe) | ??1.4 | ??11.88 | ??54.31 | ??110.5％ |
| Micropill 4 (compound recipe) | ??1.4 | ??12.12 | ??48.59 | ??98.9％ |
Last table 1 micropill 1 is the thickest micropill of coating membrane, and micropill 4 is the micropills that do not have coating, and micropill the 2, the 3rd is intervenient.By the intravital absorption characteristic of last table 1 animal as seen, the bioavailability of supposing rifampicin list medicine is 100%, and after then rifampicin list medicine added other three medicine, its bioavailability was 87.4%, illustrate because the existence of other three medicine, cause the bioavailability of rifampicin to be lower than the bioavailability of single medicine.Micropill 4 is not have enteric coated micropill, compares with rifampicin listing preparation, and bioavailability is near lower slightly, but than listing four medicine height, illustrate that because isoniazid has been implemented enteric coating the loss of the bioavailability of rifampicin reduces significantly, with to take rifampicin separately consistent.The coating membrane of micropill 2 is slightly thinner and since isoniazid be the gastric solubleness coating then its bioavailability illustrate that with to take rifampicin separately suitable the enteric coating film of rifampicin has played protective effect.The bioavailability of micropill 1 significantly improves, and illustrates that coating membrane plays a very good protection, but peak time is 4.2 hours, obviously lags behind.The bioavailability of micropill 3 also significantly improves; but its peak time with take the rifampicin basically identical separately; the coating thickness that micropill 3 is described both can play the better protect effect to rifampicin degraded under one's belt, did not have again because the existence of enteric coating film causes tangible peak time to lag behind.If micropill 3 and the administration of listing compound recipe are compared, its micropill 3 is 126.5% of listing compound recipe administration bioavailability.This shows, select the rifampicin component is implemented enteric coating, and the thickness of control enteric coating film is suitable, be ensure rifampicin in the FDC preparation bioavailability not/or the effective measures that suffer a loss less.
The rifampicin micropill of the enteric coating that thickness is suitable absorption curve in the body of the intravital absorption of pig and the not enteric coated rifampicin micropill and the rifampicin list medicine preparation that goes on the market takes on a different character, as shown in table 2 below: (unit of time in the table is hour, blood drug level is mg/L, data in the number of animals n=6, parantheses are the percentage ratio of this time point blood drug level and peak point blood drug level)
| Blood medicinal herb grower degree/preparation/time (h) | Listing medicine 1 (folk prescription) | Listing medicine 2 (compound recipe) | Micropill 1 (compound recipe) | Micropill 2 (compound recipe) | Micropill 3 (compound recipe) | Micropill 4 (compound recipe) |
| ??0h | ??0 | ??0 | ??0 | ??0 | ??0 | ??0 |
| ??0.33h | ??3.01 | ??2.15 | ??0.00 | ??2.18 | ??1.94 | ??4.32 |
| ??0.67h | ??5.97 | ??5.01 | ??0.28 | ??6.48 | ??6.00 | ??6.89 |
| ??1h | ??9.96 | ??8.41 | ??1.61 | ??10.01 | ??9.56 | ??10.56 |
| ??1.5h | ??10.82 | ??10.43 | ??4.28 | ??10.85 | ??10.56 | ??11.29 |
| ??2h | ??10.31 | ??9.80 | ??5.92 | ??9.66 | ??10.41 | ??10.35 |
| ??2.5h | ??9.47 | ??8.70 | ??7.29 | ??8.96 | ??9.77 | ??8.61 |
| ??3h | ??8.65 | ??7.67 | ??8.38 | ??8.41 | ??8.94 | ??8.35 |
| ??3.5h | ??7.81 | ??6.90 | ??9.37 | ??7.55 | ??8.26 | ??7.06 |
| ??4h | ??6.88 | ??6.30 | ??10.46 | ??6.65 | ??7.68 | ??6.55 |
| ??4.5h | ??5.95 | ??5.24 | ??9.88 | ??6.01 | ??7.11 | ??5.43 |
| ??5h | ??4.88 | ??3.98 | ??9.05 | ??4.99 | ??6.39 | ??4.53 |
| ??6h | ??3.71 | ??3.06 | ??7.43 | ??4.23 | ??5.11 | ??3.67 |
| ??8h | ??2.82 | ??1.96 | ??6.30 | ??3.15 | ??3.87 | ??2.74 |
By the data of last table 2 as can be seen, enteric coating rifampicin micropill drug release before 20 minutes that thickness is suitable is fewer, between 20 minutes～40 minutes time period, the stage that blood drug level has a quick blood drug level to rise, in this body release curve just the research group that participates in of applicant wish the biological intravital release curve that obtains.Following table 3 is the data that rise according to the blood drug level that original experiment data calculates:
| Blood medicinal herb grower degree/preparation/time (h) | Listing medicine 1 (folk prescription) | Listing medicine 2 (compound recipe) | Micropill 1 (compound recipe) | Micropill 2 (compound recipe) | Micropill 3 (compound recipe) | Micropill 4 (compound recipe) |
| 0.33h % with respect to peak concentration | ??19％??SD＝18％ | ??0 | ??28％??SD＝10％ | ??19％??SD＝5％ | ??16％??SD＝26％ | ??36％??SD＝18％ |
| Blood medicinal herb grower degree/preparation/time (h) | Listing medicine 1 (folk prescription) | Listing medicine 2 (compound recipe) | Micropill 1 (compound recipe) | Micropill 2 (compound recipe) | Micropill 3 (compound recipe) | Micropill 4 (compound recipe) |
| 0.67h % with respect to peak concentration | ??43％??SD＝23％ | ??2％??SD＝5％ | ??55％??SD＝13％ | ??57％??SD＝25％ | ??50％??SD＝27％ | ??57％??SD＝16％ |
| The average peak concentration | ??11.53 | ??11.39 | ??10.86 | ??11.35 | ??11.88 | ??12.12 |
| A 0.33-0.67h blood drug level climbing speed (mg/min) | ??0.140??SD＝0.090 | ??0.0138??SD＝0.0267 | ??0.145??SD＝0.086 | ??0.211??SD＝0.137 | ??0.199??SD＝0.125 | ??0.126??SD＝0.074 |
| The blood drug level climbing speed is equivalent to the ratio % of peak value blood drug level | ??0.12％??±0.8％ | ??0.12％??±0.2％ | ??0.12％??±0.8％ | ??1.86％??±1.21％ | ??1.68％??±1.05％ | ??1.04％??±0.62％ |
By last table 3 as seen, suitable enteric coated-pellet (micropill 3) is about the oral back 20 minutes time period, has only about 16% of peak concentration, about 40 minutes after taking medicine, blood drug level is about 50% of peak concentration, the climbing speed of blood drug level is about 0.199mg/L during this time, the biological utilisation degrees of data that shows in the form in conjunction with the front as seen, the data of micropill 3 are ideal data.
We use micropill 3 and listing medicine 2 compound recipes to carry out the human bioavailability comparative test.Result of the test demonstrate with the very approaching body of test pig in the release curve, can infer thus, with the rifampicin micropill of the suitable enteric coating of the thickness of micropill 3 representatives with the approaching organism of human body in similar absorption curve is arranged.Because the private data that the human trial data are applicants submits to medicine to register, for regent, the application does not include wherein, but the data of above-mentioned experimental animal pig are enough to illustrate all.
Certainly; above-mentioned research is the data that record under the condition of number of animals n=6; in practice; coating membrane had not only played intravital protective effect to rifampicin but also the scope that has with the absorption feature basically identical that does not wrap the enteric coating film compares broad; but be still between the enteric coating of the enteric coated preparation that does not carry out enteric coating and standard, have one can dependency the thickness range interval, and have with the coating thickness of the enteric coated preparation of standard and belong to two different intervals.The difference in these two intervals has also just illustrated preparation and the preparation of stomach release and the difference between the enteric coated preparation three that discharges at upper part of small intestine, and we know from experience the existence of this difference by above-mentioned research.In fact pharmaceutical preparation is not being carried out enteric coating and carried out seeking between the enteric coated preparation coating a suitable coating amount and just can effectively take precautions against gastric juice to the erosion of medicine with ensure that medicine absorbs fast at upper part of small intestine.
The moisture effect of enteric-coating material is better generally speaking, therefore, the rifampicin component is after having wrapped enteric coating, moisture effect in the FDC preparation is better than the gastric solubleness coating, its physical isolation effect is also better, so just can ensure effectively that the FDC preparation has good stable in the effect duration in 2 years.
At present tuberculosis one line medicine FDC stability of formulation being passed judgment on is to require to detect according to the limit handling to [related substance] in the quality standard of 2,3,4 medicine FDC preparations in the International Pharmacopoeia (IP2008) of version in 2008, and prepared according to the method described above FDC stability of formulation can be easy to the detection by IP2008.
The kind that it should be noted that enteric-coating material is a lot, announced the technical scheme of rifampicin and isoniazid component use nonaqueous dispersion enteric-coating material in the patent application that the applicant formerly submits to, in this application the technical scheme of having announced has been carried out technique complementary once more, made the technical scheme of having announced more be tending towards perfect.
On the basis of the continuous research of the described research of patent application that present patent application is formerly submitted to, disclose first and adopted the aqueous dispersion enteric-coating material to carry out the technical scheme of enteric coating rifampicin component and isoniazid component.Although the aqueous dispersion enteric-coating material is used in the other drug component, but, carry out coating for these two kinds of drug use aqueous dispersion enteric-coating materials of Rimactazid, the applicant does not see relevant bibliographical information, therefore belongs to open first.
Whether different medicines can use enteric-coating material to carry out coating, the meaning that does not possess universality, because whether the physicochemical property of medicine and coating material be compatible, especially whether stability of drug had influence, all need through determining after deep research and the long medicine stability investigation, not a duck soup must be paid careful research screening, could obtain technology further investigation and secular check and analysis.
It is a challenging research that the employing aqueous dispersion enteric-coating material that the application proposes is first implemented enteric coating to rifampicin.Because stability of Rifampicin has very strong sensitivity to moisture, higher time of contact with moisture in preparation than length or temperature, in the process of preparation, will cause the rifampicin degraded.Therefore, in the coating pan process, should repeatedly implement coating, coating limit, limit drying on a small quantity in batches.Especially exsiccant temperature is an important parameters, and through test of many times, exsiccant temperature should be controlled between 1 ℃～95 ℃, and preferred range is between 25 ℃～70 ℃, and optimum temperature is between 30 ℃～55 ℃.
Aqueous dispersion can all be rejected organic solvent, and its biggest advantage is that solids content height, viscosity are low, easy to operate, film forming is fast, the coating time is short etc.Aqueous dispersion in the coating solution can adopt polyacrylic resin class aqueous dispersion, as Eudragit NE 30D, M
r[ethyl acrylate-methyl methacrylate (2: 1) copolymer 30% aqueous dispersion], Kollicoat
MAE 30DP[methacrylic acid-ethyl acrylate (1: 1) copolymer 30% aqueous dispersion]; Aquacoat is as Sulisi; Cellulose acetate latex.What employed aqueous dispersion was best in the coating solution is polyacrylic resin class aqueous dispersion.
The ratio of aqueous dispersion and water is also very important in the coating solution, and the ratio of water should be controlled in whole coating solution between 10%～90%, and the best is about 50%.
The selection of the ratio of porogen is also very important in the coating solution, porogen commonly used has hydroxypropyl emthylcellulose (HPMC), polyethylene glycol 6000, Macrogol 4000, dextrin, mannitol etc., the ratio of porogen should be controlled in whole coating solution between 0.001%～10%, and the best is 0.1～2%.Best porogen is hydroxypropyl emthylcellulose (HPMC).
Equally, the drug loading of rifampicin should be controlled in 10%～90% the scope in the micropill, and is best in 40%～80% scope.The density of micropill should be controlled at 0.1～1.0 scope, and the best should be in 0.4～0.8 scope.The moisture of micropill inside should be controlled at below 7% at least, preferably is controlled at below 4%, and Optimal Control is below 2%.To solubilizing agent for example the optimum amount of sodium lauryl sulphate (SDS) should be the rifampicin recipe quantity 0.001%～5% between, optimum amount is between 0.1～1.0%.
The coating weightening finish of adopting aqueous dispersion to carry out micropill, granule, microplate requires basically identical with preceding described employing nonaqueous dispersion enteric-coating material.The enteric coating gain in weight of micropill is controlled between 1%～9.9%, the best is about 3.0%～8.0%, to particulate enteric coating gain in weight between 1.5%～10.9%, the best is about 3.5%～6.5%, between 0.5%～8.9%, the best is about 2%～5.5% to the enteric coating gain in weight of microplate.The coating weightening finish decreases after adopting aqueous dispersion, obtain the not inside and outside drug release feature similar with the nonaqueous dispersion enteric-coating material, rule of thumb generally reduces about 15%～40% on the basis of the above.
Different coating equipment, different enteric-coating materials, coating weightening finish is deviation to some extent also, but obtain rifampicin micropill, the granule of the described enteric coating of the application, the inside and outside drug release feature of microplate, all do not exceed the weightening finish scope of enteric-coating material that this patent is described.
The inside and outside drug release feature that adopts the aqueous dispersion enteric-coating material to wrap later rifampicin micropill according to above-mentioned technology is consistent with the inside and outside drug release feature that the enteric-coating material of nonaqueous dispersion carries out the rifampicin micropill of coating, the application is limit by length, gives unnecessary details no longer one by one.
Adopt enteric coating about isoniazid, rifampicin adopts technical scheme the applicant of gastric solubleness coating to set forth in patent application 200610092088X, and this patent is in the examination as to substances stage at present, and the application is limit by length, no longer repeats to give unnecessary details.
The specific embodiment
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.
The preparation example of embodiment 1 rifampicin enteric coated-pellet
1-1 ball core prescription: starch: dextrin=2～4: 1～2
Preparation technology: get starch and dextrin according to the above ratio, uniform mixing mixed the wet grain of 36 mesh sieve systems, the cold ball of making in coating pan with an amount of ethanol (40%) then.30 ℃～55 ℃ dryings, sieve is got 35～40 orders, and to get the ball core standby.
1-2 prepares the plain ball of rifampicin
The 1-2-1 prescription
Ball core 20～40g
Rifampicin 150g
Diluent 5～60g
Vitamin C 0.5～3g
Sodium lauryl sulphate 0.001g～7.5%
Disintegrating agent 5～20g
Polyvidone (PVP) 2～25g
1～5%PVP, 1～4%PEG6000 aqueous solution are an amount of
The 1-2-2 operating procedure
1), took by weighing the adjuvant of 80 mesh sieves and crossed the rifampicin raw material of 60 mesh sieves, by the equivalent method mix homogeneously that progressively increases, as the medicated powder that packs plain ball by prescription;
2), take by weighing the celphere of recipe quantity, put in the coating pan, regulate the rotating speed of coating pan, spray wetting agent (3%PVP, 2%PEG6000 aqueous solution), the powder that spreads pesticides while spraying wraps till plain ball increasing diameter to 0.8～1.0mm;
3), with 30 ℃～55 ℃ dryings of plain ball 2 hours;
4), taking-up, 18～20 eye mesh screen granulate excessively.
5), about 63%, moisture is 1.8% at drug loading for the plain ball of detection.
(2), the preparation of micropill
The preparation of methocel solution: get methylcellulose 5.1g, add water 100ml and make dissolving, standby;
The preparation of HP-50 solution: get 3.6gHP-50, add mixed solvent (ethanol: 100m acetone=70: 30), jolting adds diethyl phthalate 0.35g after making dissolving, shakes up, and is standby;
Divide and get methocel solution 18ml, HP-50 solution 60ml, jolting makes abundant mixing, and the content of methylcellulose is 1.15% in the coating solution, and the amount of HP-50 is 2.7%.
Art for coating: it is an amount of to take by weighing the plain ball of rifampicin, places in the bottom spraying type fluidized-bed coating machine, regulates coating temperature, spray gun tolerance, gun traffic, wind speed.Micropill behind the coating is placed vacuum desiccator, 30 ℃～55 ℃ dryings 1 hour; Coating weightening finish 1～9.9%.Detect drug loading at 33～60%, moisture is 1.5%, dissolution 15 minutes 20%, 30 minute 50%.
Embodiment 2 aqueous dispersion enteric-coating material technologies
2-1 ball core prescription: starch: dextrin=2～4: 1～2
Preparation technology: get starch and dextrin according to the above ratio, uniform mixing mixed the wet grain of 36 mesh sieve systems, the cold ball of making in coating pan with an amount of ethanol (40%) then.30 ℃～55 ℃ dryings, sieve is got 35～40 orders, and to get the ball core standby.
The preparation of the plain ball of 2-2 rifampicin: the same embodiment 1.
*The coating solution prescription:
Percentage ratio (%)
Kollicoat
MAE?30?DP????????????????50
Propylene glycol 2.25
HPMC????????????????????????????????0.1～5
Water 47.65～42.75
Compound method:
(1) preparation of 5%HPMC: take by weighing 5gHPMC (3CP) 5g, add in 80 ℃ of hot water of 100ml, the limit edged stirs, and makes fully to disperse, and puts and is chilled to room temperature, makes abundant swelling, and is standby.
(2) propylene glycol with recipe quantity joins in the water of recipe quantity, stirs;
(3) in the water that has added propylene glycol, add the Kollicoat of recipe quantity
MAE 30 DP, the limit edged stirs;
(4) stir after, add 5%HPMC liquid, stir, and continue to stir 30 minutes.
*The art for coating of the plain ball of rifampicin
Fluidized bed coating: it is an amount of to take by weighing the plain ball of rifampicin, places in the fluid bed that before regulates spray gun atomizing area, regulates wind speed, spray gun tolerance, coating solution flow, and the three is regulated according to the situation of ball in the fluid bed in good time.30 ℃～55 ℃ of coating temperature.Theoretical weightening finish 1～9.9%.
Drying and granulate: enteric coated micropill is placed vacuum desiccator, and drying is taken out granulate.
The quality control checking of micropill: outward appearance: red piller, rounding, smooth surface; Hardness: hands is pinched non-friable; Assay: measure according to the content assaying method under the BP2000 version rifampicin item, content should be controlled between 35%～68%; Dissolution determination: in hydrochloric acid solution (9 → 1000), rotating speed is that per minute 50 changes at 50 rotating speeds, should should be mutually between 1%～34% and 35%～90% respectively at 15 minutes stripping quantities during with 30 minutes.(assay method according to " two appendix dissolution methods of Chinese pharmacopoeia version in 2005 (appendix X C first method) mensuration).
Claims (9)
1. tuberculosis one line medicament benemicin, isoniazid, pyrazinamide, the preparation method of ebutol fixed dosage compound formulation (FDC preparation), this preparation method is that these four kinds of medication preparation are become micropill, granule, microplate, wherein other composition enforcement gastric solubleness coating material of rifampicin enforcement enteric material coating or wherein other composition enforcement gastric solubleness coating material of isoniazid enforcement enteric material coating, the dose filling of writing out a prescription according to the FDC standard preparation of WHO proposition goes into to form the FDC preparation in the capsule then, and the weightening finish that it is characterized in that the micropill enteric-coating material is between 1%～9.9%, the weightening finish of granule enteric-coating material is between 1.5%～10.9%, the weightening finish of microplate enteric-coating material is between 0.5%～8.9%.
2. the mixed solvent that the employed in the preparation wetting agent of rifampicin micropill is ethanol and water in the claim 1, the ratio of alcohol in water is between 0～80%.
3. the employed in the preparation wetting agent of the rifampicin micropill of claim 2 is preferably water.
4. the employed enteric-coating material of claim 1 is the aqueous dispersion enteric-coating material, preferred Kollicoat
MAE 30DP[methacrylic acid/ethyl acrylate (1: 1) copolymer 30% aqueous dispersion].
5. the content of water is between 10%～90% in the aqueous dispersion coating solution of claim 4; The consumption of porogen is between 0.001%～10%, and best porogen is hydroxypropyl emthylcellulose (HPMC).
6. according to claim 1, the consumption of the antioxidant of 4 rifampicin micropills is between 0.001～3%, and first-selected antioxidant is a vitamin C; The water content of rifampicin micropill should be less than below 7%; The drug loading of rifampicin is between 10%～90% in the rifampicin micropill; The density of rifampicin micropill should be between 0.1～1.0; The amount of the employed solubilizing agent of rifampicin micropill should be between 0.001%～5%, and first-selected solubilizing agent is sodium lauryl sulphate (SDS).
7. in the technology of claim 1,4 when the rifampicin micropill becomes ball and enteric coating, its baking temperature should be controlled between 1 ℃～95 ℃.
8. claim 1,4 rifampicin micropill are in hydrochloric acid solution (9 → 1000), and rotating speed is that per minute 50 changes, and should should be mutually between 1%～34% and 35%～90% respectively at 15 minutes stripping quantities during with 30 minutes.[assay method is according to " two appendix dissolution methods of Chinese pharmacopoeia version in 2005 (appendix X C first method) mensuration].
Claim 1,4 rifampicin micropill release absorption curve in vivo should possess its blood drug level in behind oral administration 20 minutes with respect to peak value blood drug level 16% ± 0～26%, its blood drug level is with respect to 50% ± 27% of peak value blood drug level 40 minutes the time, the climbing speed of blood drug level is 1.68% ± 1.05% of a peak concentration in 20 minutes to 40 minutes time intervals.
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| CN201010105082A CN101797238A (en) | 2010-01-23 | 2010-01-23 | Method for preparing medicinal preparation for releasing rifampicin on upper part of small intestine and characteristics of medicinal preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103816545A (en) * | 2013-10-30 | 2014-05-28 | 安徽万邦医药科技有限公司 | Pharmaceutical composition containing rifampicin and sodium dodecyl sulfate |
| CN104706638A (en) * | 2015-02-04 | 2015-06-17 | 上海华源安徽仁济制药有限公司 | Compound rifampin capsules and preparation method thereof |
| US10434138B2 (en) | 2013-11-08 | 2019-10-08 | Sublimity Therapeutics Limited | Formulations |
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| CN1437946A (en) * | 2002-04-15 | 2003-08-27 | 高华 | Medicine-release system of compound Rifampicin |
| CN1864681A (en) * | 2006-06-09 | 2006-11-22 | 高华 | Preparation method of composite rifampicin micro-tablet capsule |
| CN1864683A (en) * | 2006-06-09 | 2006-11-22 | 高华 | A preparation method of compound rifampicin preparation |
| CN1864682A (en) * | 2006-06-09 | 2006-11-22 | 高华 | In-vitro in-vivo drug release characteristics of various drug pills in compound anti-tuberculosis preparation and application thereof |
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| CN1437946A (en) * | 2002-04-15 | 2003-08-27 | 高华 | Medicine-release system of compound Rifampicin |
| CN1864681A (en) * | 2006-06-09 | 2006-11-22 | 高华 | Preparation method of composite rifampicin micro-tablet capsule |
| CN1864683A (en) * | 2006-06-09 | 2006-11-22 | 高华 | A preparation method of compound rifampicin preparation |
| CN1864682A (en) * | 2006-06-09 | 2006-11-22 | 高华 | In-vitro in-vivo drug release characteristics of various drug pills in compound anti-tuberculosis preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103816545A (en) * | 2013-10-30 | 2014-05-28 | 安徽万邦医药科技有限公司 | Pharmaceutical composition containing rifampicin and sodium dodecyl sulfate |
| US10434138B2 (en) | 2013-11-08 | 2019-10-08 | Sublimity Therapeutics Limited | Formulations |
| AU2014345543B2 (en) * | 2013-11-08 | 2020-02-20 | Sublimity Therapeutics Limited | Formulations |
| AU2014345543C1 (en) * | 2013-11-08 | 2020-09-03 | Sublimity Therapeutics Limited | Formulations |
| CN104706638A (en) * | 2015-02-04 | 2015-06-17 | 上海华源安徽仁济制药有限公司 | Compound rifampin capsules and preparation method thereof |
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