CN101623273B - Rifaximin medicament combination dispersible tablet and preparation method thereof - Google Patents
Rifaximin medicament combination dispersible tablet and preparation method thereof Download PDFInfo
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- CN101623273B CN101623273B CN200910305621XA CN200910305621A CN101623273B CN 101623273 B CN101623273 B CN 101623273B CN 200910305621X A CN200910305621X A CN 200910305621XA CN 200910305621 A CN200910305621 A CN 200910305621A CN 101623273 B CN101623273 B CN 101623273B
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Abstract
The invention relates to a Rifaximin medicament combination dispersible tablet and a preparation method thereof. The medicament combination dispersible tablet comprises the following components by weight portion: 50-250 portions of Rifaximin, 10-150 portions of lactose, 50-160 portions of microcrystalline cellulose, 15-45 portions of partially substituted hydroxy propyl cellulose, 2-12 portions of acesulfame potassium, 15-45 portions of sodium carboxymethyl starch and 0.5-2.5 portions of magnesium stearte. Although the medicament combination dose not contain lauryl sodium sulfate as a cosolvent, the solubility property is favorable, and the dispersion property and the dissolution rate are both favorable. The preparation method of the medicament combination is simple to realize and is suitable for industrial production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly a kind of Rifaximin medicament combination dispersible tablet and preparation method thereof.
Background technology
Diarrhoea is a kind of common sympton, and the serious threat human health is considered to one of five big clinical common symptons, is one of five big killers that cause death of child below five years old.Diarrhoea mainly is restraint to the mankind's influence, hinders social interactions, makes many people's cisco unity malfunctions, is having a strong impact on people's quality of life.Diarrhoea is the severe problem that whole world people must face, and its M ﹠ M is very high.According to statistics, the whole world has at least 1,000,000,000 people to infect diarrhoea every year, and just there is 100,000 people morbidity each hour.According to The World Health Organization (WHO), there is every day the people more than 10,000 dead because of diarrhoea, people's death is just arranged per 10 seconds.According to WHO investigation, the childhood infection diarrhoea below 1,200,000,000 five years old is arranged every year, there are 400 ten thousand children to die from diarrhoea, developing country especially, among the child below 5 years old, it is not only quite general suffer from diarrhoea, and is the major reason that causes death.On average suffer from 1-3 time diarrhoeal diseases for each person every year in developed country, the child that country distinguishes poorly in tropical development on average suffers from 5-18 time diarrhoeal diseases for each person every year.Wherein see at most with infectious diarrhea especially.Have first of the infectious disease at the sickness rate shelter of China's infectious diarrhea.20 provinces of China 1988 (autonomous region) investigation 126956 people, the sick annual morbidity of 0-4 year group children's diarrhae is 1.9 times/people/year, and organizing sickness rate more than 5 years old and 5 years old is 0.6 time/people/year, and total incidence is 0.7 time/people/year.Statistics in 2000 shows that the whole nation has 8.36 hundred million person-times to suffer from diarrhoea every year approximately.The loss that diarrhoea causes for body health of people and socio-economic development is self-evident.Children's diarrhae influences family's fiscal revenues significantly, also brings enormous impact to social economy simultaneously.In some developing countries, the berth child that suffered from diarrhoea that is in hospital is accounting for the department of pediatrics more than 1/3.The old people is because each organ dysfunction fails, and immunity degradation also is the high-risk group of infectious diarrhea.In recent years, because the fast development of countries in the world tourist industry, the number of travelling to various places constantly increases, and thing followed traveller's infectious diarrhea can not be ignored.More than startling numeral show diarrheal sickness rate height, the crowd that is injured is wide, and then develops effective and safe anti-infection property diarrhoea medicine and become the person of noble aspirations's of the world of medicine the task of top priority now.
Rifaximin is a kind of intestinal antibiotic, is a kind of derivant of rifamycin.Maximum characteristics are that oral back is not absorbed in gastrointestinal tract, and antibacterial action is strong, has a broad antifungal spectrum.Compare with aminoglycosides antibiotics, this product is to aureus Mlicrococcus Pyogenes var in the Gram-positive aerobe, to staphylococcus epidermidis and enterococcus, difficult bacillus fusiformis in the gram-positive anaerobic bacterium is had high activity, and the activity of the anti-above-mentioned strain of aminoglycosides antibiotics is very low or extremely low.Rifaximin also has high activity to bacteroid, and aminoglycosides does not then have.The untoward reaction of rifaximin is well below aminoglycosides, and it does not damage auditory function, does not cause that renal function is incomplete, and can avoid superinfection.Compare with quinolone antibiotic such as ciprofloxacin, though curative effect is similar or a little more than the latter, the former antimicrobial spectrum is than latter's height (to streptococcus than latter's sensitivity), and safety is not than the latter big (the former produces central nervous system's side effect) yet.Thereby rifaximin is a kind of intestinal antibiotic of high-efficiency low-toxicity.
Rifaximin is developed by Italian Alfa Wassermann company, goes on the market in Italy with trade name Normix as anti-infection property diarrhoea medicine in 1987.The history that clinical practice in 15 years is arranged abroad still is extensive use of so far.At present, at tens national registrations such as Italy, Germany, Switzerland, Britain, Korea S.Rifaximin is patented in Italy, and the patent No. is 1154655.The purposes of this medicine in the diarrhoea that treatment is caused by cryptosporidiosis patents in China, and the patent No. is CN1214244.
The amount of rifaximin can not satisfy the demand of extensive patients on the market, and because it is water insoluble, bioavailability is low, developed in the prior art have taking convenience, the dispersible tablet of characteristics such as the medicine stripping is fast, curative effect height.The prescription and the technology of preparation rifaximin dispersible tablet have been inquired into as " development of rifaximin dispersible tablet and quality control " (referring to " number reason medicine and pharmacology magazine ", 2007 the 20th the 6th phases of volume).In this prescription, increased the adjuvant sodium lauryl sulphate as cosolvent at the water-fast characteristics of rifaximin, to increase its dissolubility.
The inventor is through a large amount of screenings of discovering process prescription kind and consumption thereof, and having developed does not need to add cosolvent and the same good dispersible tablet of its effect, and this dispersible tablet has the stripping property of better dispersive property and Geng Gao.
Summary of the invention
First purpose of the present invention is to provide a kind of Rifaximin medicament combination dispersible tablet, this medicament combination dispersible tablet need not add sodium lauryl sulphate etc. as cosolvent, its solute effect is good equally, and this dispersible tablet has the stripping property of better dispersive property and Geng Gao.
Second purpose of the present invention is to provide the preparation method of above-mentioned Rifaximin medicament combination dispersible tablet, this prescription and preparation technology are feasible, be suitable for large-scale production, it is good equally as its solute effect of cosolvent that prepared rifaximin dispersible tablet need not add sodium lauryl sulphate etc., and this dispersible tablet has the stripping property of better dispersive property and Geng Gao.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
A kind of Rifaximin medicament combination dispersible tablet, wherein: described medicament combination dispersible tablet composed as follows:
Rifaximin 100-200 weight portion
Lactose 50-100 weight portion
Microcrystalline Cellulose 70-140 weight portion
Low-substituted hydroxypropyl cellulose 20-40 weight portion
Acesulfame potassium 5-10 weight portion
Carboxymethyl starch sodium 10-40 weight portion
Magnesium stearate 1-2 weight portion.
According to aforesaid Rifaximin medicament combination dispersible tablet, wherein: carboxymethyl starch sodium is the 20-40 weight portion in the composition of described medicament combination dispersible tablet.
For realizing second purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation method of Rifaximin medicament combination dispersible tablet of the present invention, wherein: this method comprises the steps:
Described method comprises raw material rifaximin and adjuvant lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, sieves, and the system wet granular is made dried granule, tabletting and packing.
According to aforesaid preparation method, wherein: described rifaximin is crossed 100 mesh sieves, and described lactose, acesulfame potassium and carboxymethyl starch sodium are crossed 120 mesh sieves respectively, and microcrystalline Cellulose and low-substituted hydroxypropyl cellulose are crossed 80 mesh sieves.
According to aforesaid preparation method, wherein: described system wet granular also comprises mixing.
According to aforesaid preparation method, wherein: described being mixed into done mixed wet mixing more earlier.
According to aforesaid preparation method; wherein: described system wet granular is rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose that takes by weighing recipe quantity; insert in the high-speed mixing granulating machine; the sealing high-speed dry was mixed 5-15 minute; added then an amount of wet mixing 1-5 of ethanol minute, after the wet mixing, wet mixing cutting 1-3 minute; emit granule, obtain wet granular.
According to aforesaid preparation method, wherein: described method comprises the steps:
1) gets the raw materials ready
Rifaximin is pulverized, crossed 100 mesh sieves; With lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, cross 120 mesh sieves; With microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately, cross 80 mesh sieves, obtain standby former, adjuvant;
2) system wet granular
Take by weighing rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose of recipe quantity, insert in the high-speed mixing granulating machine, the sealing high-speed dry was mixed 5-15 minute, added then an amount of wet mixing 1-5 of ethanol minute, after the wet mixing, granule is emitted in wet mixing cutting 1-3 minute, obtains wet granular;
3) make dried granule
The wet granular that the last step was made changes in the ebullated dryer, and temperature is controlled at 60-70 ℃ of baking 15-30 minute, shuts down, clear filter bag, and blowing obtains dried granule;
4) tabletting, packing
To go up prepared dried granule of step and add pelletizing machine, start button carries out granulate; the magnesium stearate that adds the carboxymethyl starch sodium and the recipe quantity of recipe quantity again; add three-dimensional mixer with suction feeding and mix, tabletting, packing promptly gets Rifaximin medicament combination dispersible tablet.
According to aforesaid preparation method, wherein: step 2) described in do to mix and to be under the condition of rotating speed 35～55 commentariess on classics/min, preferred 45 commentariess on classics/min dried mixed 5-15 minute.
According to aforesaid preparation method, wherein: step 2) described in wet mixing be wet mixing 1～5min under the condition of rotating speed 25～35 commentaries on classics/min, preferred 30 commentaries on classics/min.
Below be detailed description of the present invention:
Rifaximin medicament combination dispersible tablet provided by the present invention composed as follows:
Rifaximin 100-200 weight portion
Lactose 50-100 weight portion
Microcrystalline Cellulose 70-140 weight portion
Low-substituted hydroxypropyl cellulose 20-40 weight portion
Acesulfame potassium 5-10 weight portion
Carboxymethyl starch sodium 10-40 weight portion
Magnesium stearate 1-2 weight portion.
" development of rifaximin dispersible tablet and quality control " is (referring to " number reason medicine and pharmacology magazine ", 2007 the 20th the 6th phases of volume) water insoluble at rifaximin, the characteristics that bioavailability is low, its tablet formulation of development is proposed, adopt Orthogonal Method in this method, with the disintegration is index, rifaximin dispersible tablet prescription is screened, the made dispersible tablet of result is disintegrate fully in 60 seconds, granule can be all by No. 2 sieves, meet that " Chinese pharmacopoeia is about the requirement of dispersible tablet, shows that its prescription and preparation technology are feasible.Add the adjuvant sodium lauryl sulphate as cosolvent, to increase its dissolubility at the water-fast characteristics of rifaximin especially in this prescription.
And among the present invention, through a large amount of tests used adjuvant and consumption thereof are screened, to develop and need not add the prescription of sodium lauryl sulphate as cosolvent, its dissolubility is also better, and other performance such as dispersing uniformity etc. are also good.
Rifaximin medicament combination dispersible tablet provided by the present invention, disintegrate fully in 2 minutes and 19 seconds average time, and can cross No. 2 sieves (2000 editions two appendix IA of Chinese Pharmacopoeia), accumulation stripping percentage rate can reach 100% (adopting Chinese Pharmacopoeia appendix XC dissolution determination method second method) in the time of 2 minutes.
In order to be illustrated more clearly in the present invention, below carry out some explanations with regard to thinking of the present invention earlier.
Dispersible tablet of the present invention (dispersible tablets), claim water dispersion tablet (water dis-persibletablets) again, mean a kind of tablet of meeting the even stickiness suspension of water rapid disintegrate formation, dispersible tablet has the advantage of tablet and liquid preparation concurrently, that is: taking convenience, absorb soon, bioavailability height and untoward reaction are little etc.
The active component of dispersible tablet, regulation is generally arranged, therefore, the research that the present invention is carried out to the branch assembly with regard to integral formula to the stripping and the dispersion effect of described dispersible tablet, dispersible tablet of the present invention, require to meet behind the water as soon as possible that disintegrate becomes granule, and form uniform suspension, so design of components is important.
At first, the kind of disintegrating agent and consumption are most important to disintegrate, the result of extraction of dispersible tablet, from composition, the most frequently used have carboxymethyl starch sodium (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC), cross-linked carboxymethyl cellulose sodium (cCMC-Na), a crospolyvinylpyrrolidone (PVPP) etc.
Prior art shows that the difference on the disintegrating agent consumption also may produce diametrically opposite effect to the disintegrate behavior of dispersible tablet.As a kind of quickly disintegrated efficiently CMS-Na, its consumption be 1%～2% o'clock not obvious to the influence of disintegration of tablet; Can obviously accelerate disintegrate at 3%～7% o'clock, 8%～10% has postponed disintegrate on the contrary.
Studies show that several disintegrating agents with different performance are united use, adjust its composition or consumption separately, can reach better disintegrate effect at active component.
It is low that " Chinese pharmaceutic adjuvant " mentions the microcrystalline Cellulose swellbility, is not suitable for using as disintegrating agent.Yet the present invention is unexpected to be found, uses high carboxymethyl starch sodium of swellbility or low-substituted hydroxypropyl cellulose and microcrystalline Cellulose combination collocation to use, and can well improve dispersing uniformity and dissolution rate.
Analysis may be high swelling property materials such as carboxymethyl starch sodium in aqueous solution after the disintegrate, the Colloidal fluid of formation is wrapped in the outside of drug particles, has hindered the further stripping of granule Chinese medicine powder.
And the present invention uses microcrystalline Cellulose and carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose combination collocation, not only the dispersing uniformity time short, and the effective ingredient dissolution rate is fast.
The present invention adopts lactose as filler in dispersible tablet, and the tablet appearance that makes is good, is difficult for dry linting.Effect is significantly better than other filler material.
In addition, note also control microcrystalline Cellulose and low-substituted hydroxypropyl cellulose ratio, when large percentage, can not reach good dispersion effect, jitter time has exceeded the state-promulgated pharmacopoeia standard.
In addition, the suitable composition of binding agent and other inserts and ratio are influential to the disintegrate of dispersible tablet.
Among the present invention, select for use ethanol as binding agent, as long as its consumption can satisfy the amount that supplementary material can reach the system soft material, this point can both be expected for those skilled in the art.According to the used consumption of ethanol of the concrete prescription of Rifaximin medicament combination dispersible tablet of the present invention is 30-60ml.
Based on described consideration, the present invention is in order to obtain the best prescription combination of described dispersible tablet, is kind and best proportioning or the consumption that index adopts quadrature, method for designing screening disintegrating agent such as even with disintegration time, suspension ability or uniformity, stripping.Screening test sees test example 1 for details.Test is found, when the Rifaximin medicament combination dispersible tablet that is provided consist of rifaximin 100-200 weight portion, lactose 50-100 weight portion, microcrystalline Cellulose 70-140 weight portion, low-substituted hydroxypropyl cellulose 20-40 weight portion, acesulfame potassium 5-10 weight portion, carboxymethyl starch sodium 10-40 weight portion and magnesium stearate 1-2 weight portion the time, its substrate's appearance of prepared Rifaximin medicament combination dispersible tablet, hardness and dispersing uniformity are all better.Consist of rifaximin 100 weight portions when the Rifaximin medicament combination dispersible tablet that is provided, lactose 50 weight portions, microcrystalline Cellulose 70 weight portions, low-substituted hydroxypropyl cellulose 20 weight portions, acesulfame potassium 5 weight portions, carboxymethyl starch sodium 20 weight portions and magnesium stearate 1 weight portion or rifaximin 200 weight portions, lactose 100 weight portions, microcrystalline Cellulose 140 weight portions, low-substituted hydroxypropyl cellulose 40 weight portions, acesulfame potassium 10 weight portions, when carboxymethyl starch sodium 40 weight portions and magnesium stearate 2 weight portions, its substrate's appearance of prepared Rifaximin medicament combination dispersible tablet, hardness and dispersing uniformity are all good.
Rifaximin medicament combination dispersible tablet provided by the present invention can be with reference to the preparation method preparation of any dispersible tablet of prior art, those skilled in the art can prepare this Rifaximin medicament combination dispersible tablet by simple experiment in conjunction with the prior art of self grasping after reading the present invention.But in order further to improve the quality of this Rifaximin medicament combination dispersible tablet, further improve and disperse result of extraction, the present invention provides a kind of preferred manufacturing procedure simultaneously:
Method comprises raw material rifaximin and adjuvant lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, sieves, and the system wet granular is made dried granule, tabletting and packing.
Above-mentioned supplementary material is pulverized respectively, is sieved earlier, raw material can be controlled in the certain particle scope, helps mixing in the blend step of back more even like this, and dispersibility is better.Those skilled in the art know described sieving usually cross for how many mesh sieves, and sieving of prior art can be prepared up-to-standard dispersible tablet, but the present invention preferably rifaximin pulverized 100 mesh sieves; Lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately are crossed 120 mesh sieves; Microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately are crossed 80 mesh sieves.
System wet granular described in the preparation method of the present invention also comprises mixing.
Being mixed into described in the preparation method of the present invention done earlier and mixed wet mixing again.
System wet granular described in the preparation method of the present invention is rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose that takes by weighing recipe quantity; insert in the high-speed mixing granulating machine; the sealing high-speed dry was mixed 5-15 minute; added then an amount of wet mixing 1-5 of ethanol minute; after the wet mixing; granule is emitted in wet mixing cutting 1-3 minute, obtains wet granular.
Preferred preparation method of the present invention comprises the steps:
1) gets the raw materials ready
Rifaximin is pulverized, crossed 100 mesh sieves; With lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, cross 120 mesh sieves; With microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately, cross 80 mesh sieves, obtain standby former, adjuvant;
2) system wet granular
Take by weighing rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose of recipe quantity, insert in the high-speed mixing granulating machine, the sealing high-speed dry was mixed 5-15 minute, added then an amount of wet mixing 1-5 of ethanol minute, after the wet mixing, granule is emitted in wet mixing cutting 1-3 minute, obtains wet granular;
3) make dried granule
The wet granular that the last step was made changes in the ebullated dryer, and temperature is controlled at 60-70 ℃ of baking 15-30 minute, shuts down, clear filter bag, and blowing obtains dried granule;
4) tabletting, packing
To go up prepared dried granule of step and add pelletizing machine, start button carries out granulate; the magnesium stearate that adds the carboxymethyl starch sodium and the recipe quantity of recipe quantity again; add three-dimensional mixer with suction feeding and mix, tabletting, packing promptly gets Rifaximin medicament combination dispersible tablet.
Doing wherein: step 2) mixed to doing under the condition of rotating speed 35～55 commentaries on classics/min, preferred 45 commentaries on classics/min and mixed 5-15 minute.
Wet mixing wherein: step 2) is wet mixing 1～5min under the condition of rotating speed 25～35 commentaries on classics/min, preferred 30 commentaries on classics/min.
Wherein, the wet granular described in the step 3) dries by the fire the regular hour in ebullated dryer after, its moisture should be controlled at 2.0-4.0%.
Compared with prior art, the present invention has following beneficial effect:
(1) Rifaximin medicament combination dispersible tablet of the present invention does not need to add sodium lauryl sulphate as cosolvent, and its solubility property is better equally;
(2) dispersing uniformity of Rifaximin medicament combination dispersible tablet of the present invention, dissolution rifaximin dispersible tablet more of the prior art are good;
(3) the preparation method simple possible of Rifaximin medicament combination dispersible tablet of the present invention is fit to large-scale production.
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1
1, prescription
Specification (100mg)
Rifaximin 100g
Lactose 50g
Microcrystalline Cellulose 70g
Low-substituted hydroxypropyl cellulose 20g
Acesulfame potassium 5g
Ethanol 30ml
Carboxymethyl starch sodium 20g
Magnesium stearate 1g
Make 1000
2, preparation technology
1) gets the raw materials ready
Rifaximin is pulverized, crossed 100 mesh sieves; With lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, cross 120 mesh sieves; With microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately, cross 80 mesh sieves, obtain standby former, adjuvant;
2) system wet granular
Take by weighing rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose of recipe quantity, insert in the high-speed mixing granulating machine, the sealing high-speed dry was mixed 5 minutes, add an amount of wet mixing of ethanol 1 minute then, after the wet mixing, wet mixing cutting 1 minute, emit granule, obtain wet granular;
3) make dried granule
The wet granular that the last step was made changes in the ebullated dryer, and temperature is controlled at 60 ℃ of bakings 15 minutes, shuts down, clear filter bag, and blowing obtains dried granule;
4) tabletting, packing
To go up prepared dried granule of step and add pelletizing machine, start button carries out granulate, adds the magnesium stearate of the carboxymethylstach sodium and the recipe quantity of recipe quantity again, and add three-dimensional mixer with suction feeding and mix, tabletting, packing promptly gets the rifaximin dispersible tablet.
Embodiment 2
1, prescription
Specification (200mg)
Rifaximin 200g
Lactose 100g
Microcrystalline Cellulose 140g
Low-substituted hydroxypropyl cellulose 40g
Acesulfame potassium 10g
Ethanol 60ml
Carboxymethyl starch sodium 40g
Magnesium stearate 2g
Make 1000
2, preparation technology
1) gets the raw materials ready
Rifaximin is pulverized, crossed 100 mesh sieves; With lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, cross 120 mesh sieves; With microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately, cross 80 mesh sieves, obtain standby former, adjuvant;
2) system wet granular
Take by weighing rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose of recipe quantity, insert in the high-speed mixing granulating machine, the sealing high-speed dry was mixed 15 minutes, add an amount of wet mixing of ethanol 5 minutes then, after the wet mixing, wet mixing cutting 3 minutes, emit granule, obtain wet granular;
3) make dried granule
The wet granular that the last step was made changes in the ebullated dryer, and temperature is controlled at 70 ℃ of bakings 30 minutes, shuts down, clear filter bag, and blowing obtains dried granule;
4) tabletting, packing
To go up prepared dried granule of step and add pelletizing machine, start button carries out granulate, adds the magnesium stearate of the carboxymethylstach sodium and the recipe quantity of recipe quantity again, and add three-dimensional mixer with suction feeding and mix, tabletting, packing promptly gets the rifaximin dispersible tablet.
Embodiment 3
1, prescription
Specification (120mg)
Rifaximin 120g
Lactose 60g
Microcrystalline Cellulose 80g
Low-substituted hydroxypropyl cellulose 25g
Acesulfame potassium 6g
Ethanol 35ml
Carboxymethyl starch sodium 25g
Magnesium stearate 1.2g
Make 1000
2, preparation technology
1) gets the raw materials ready
Rifaximin is pulverized, crossed 100 mesh sieves; With lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, cross 120 mesh sieves; With microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately, cross 80 mesh sieves, obtain standby former, adjuvant;
2) system wet granular
Take by weighing rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose of recipe quantity, insert in the high-speed mixing granulating machine, being sealed under the condition that rotating speed is 45 commentaries on classics/min high-speed dry mixed 5-15 minute, adding ethanol then is under the condition of 30 commentaries on classics/min wet mixing 1-5 minute at rotating speed in right amount, after the wet mixing, granule is emitted in wet mixing cutting 1-3 minute, obtains wet granular;
3) make dried granule
The wet granular that the last step was made changes in the ebullated dryer, and temperature is controlled at 60-70 ℃ of baking 15-30 minute, shuts down, clear filter bag, and blowing obtains dried granule;
4) tabletting, packing
To go up prepared dried granule of step and add pelletizing machine, start button carries out granulate, adds the magnesium stearate of the carboxymethylstach sodium and the recipe quantity of recipe quantity again, and add three-dimensional mixer with suction feeding and mix, tabletting, packing promptly gets the rifaximin dispersible tablet.
Embodiment 4
1, prescription
Specification (160mg)
Rifaximin 160g
Lactose 75g
Microcrystalline Cellulose 100g
Low-substituted hydroxypropyl cellulose 30g
Acesulfame potassium 7.5g
Ethanol 45ml
Carboxymethyl starch sodium 30g
Magnesium stearate 1.4g
Make 1000
2, preparation technology
1) gets the raw materials ready
Rifaximin is pulverized, crossed 100 mesh sieves; With lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, cross 120 mesh sieves; With microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately, cross 80 mesh sieves, obtain standby former, adjuvant;
2) system wet granular
Take by weighing rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose of recipe quantity, insert in the high-speed mixing granulating machine, being sealed under the condition that rotating speed is 35 commentaries on classics/min high-speed dry mixed 10 minutes, adding ethanol then is wet mixing 3 minutes under the condition of 25 commentaries on classics/min at rotating speed in right amount, after the wet mixing, granule is emitted in wet mixing cutting 2.5 minutes, obtains wet granular;
3) make dried granule
The wet granular that the last step was made changes in the ebullated dryer, and temperature is controlled at 65 ℃ of bakings 25 minutes, shuts down, clear filter bag, and blowing obtains dried granule;
4) tabletting, packing
To go up prepared dried granule of step and add pelletizing machine, start button carries out granulate, adds the magnesium stearate of the carboxymethylstach sodium and the recipe quantity of recipe quantity again, and add three-dimensional mixer with suction feeding and mix, tabletting, packing promptly gets the rifaximin dispersible tablet.
Embodiment 5
1, prescription
Specification (180mg)
Rifaximin 180g
Lactose 85g
Microcrystalline Cellulose 120g
Low-substituted hydroxypropyl cellulose 35g
Acesulfame potassium 8.5g
Ethanol 50ml
Carboxymethyl starch sodium 35g
Magnesium stearate 1.8g
Make 1000
2, preparation technology
1) gets the raw materials ready
Rifaximin is pulverized, crossed 100 mesh sieves; With lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, cross 120 mesh sieves; With microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately, cross 80 mesh sieves, obtain standby former, adjuvant;
2) system wet granular
Take by weighing rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose of recipe quantity, insert in the high-speed mixing granulating machine, being sealed under the condition that rotating speed is 55 commentaries on classics/min high-speed dry mixed 8 minutes, adding ethanol then is wet mixing 2 minutes under the condition of 35 commentaries on classics/min at rotating speed in right amount, after the wet mixing, granule is emitted in wet mixing cutting 2 minutes, obtains wet granular;
3) make dried granule
The wet granular that the last step was made changes in the ebullated dryer, and temperature is controlled at 68 ℃ of bakings 26 minutes, shuts down, clear filter bag, and blowing obtains dried granule;
4) tabletting, packing
To go up prepared dried granule of step and add pelletizing machine, start button carries out granulate, adds the magnesium stearate of the carboxymethylstach sodium and the recipe quantity of recipe quantity again, and add three-dimensional mixer with suction feeding and mix, tabletting, packing promptly gets the rifaximin dispersible tablet.
Embodiment 6
1, prescription
Specification (100mg)
Rifaximin 100g
Lactose 50g
Microcrystalline Cellulose 70g
Low-substituted hydroxypropyl cellulose 20g
Acesulfame potassium 5g
Ethanol 30ml
Carboxymethyl starch sodium 10g
Magnesium stearate 1g
Make 1000
2, preparation technology
1) gets the raw materials ready
Rifaximin is pulverized, crossed 100 mesh sieves; With lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, cross 120 mesh sieves; With microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately, cross 80 mesh sieves, obtain standby former, adjuvant;
2) system wet granular
Take by weighing rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose of recipe quantity, insert in the high-speed mixing granulating machine, the sealing high-speed dry was mixed 13 minutes, add an amount of wet mixing of ethanol 3.5 minutes then, after the wet mixing, wet mixing cutting 2 minutes, emit granule, obtain wet granular;
3) make dried granule
The wet granular that the last step was made changes in the ebullated dryer, and temperature is controlled at 63 ℃ of bakings 28 minutes, shuts down, clear filter bag, and blowing obtains dried granule;
4) tabletting, packing
To go up prepared dried granule of step and add pelletizing machine, start button carries out granulate, adds the magnesium stearate of the carboxymethylstach sodium and the recipe quantity of recipe quantity again, and add three-dimensional mixer with suction feeding and mix, tabletting, packing promptly gets the rifaximin dispersible tablet.
Embodiment 7
1, prescription
Specification (200mg)
Rifaximin 200g
Lactose 100g
Microcrystalline Cellulose 140g
Low-substituted hydroxypropyl cellulose 40g
Acesulfame potassium 10g
Ethanol 60ml
Carboxymethyl starch sodium 20g
Magnesium stearate 2g
Make 1000
2, preparation technology
With raw material rifaximin and adjuvant lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, acesulfame potassium and carboxymethyl starch sodium according to the method pulverize separately of routine, sieve, add the method system wet granular of ethanol 60ml according to routine, the system drying obtains dried granule, and tabletting, packing are promptly then.
Test example 1
This test example is screened the prescription of rifaximin dispersible tablet of the present invention.
The characteristics that the inventor is water insoluble at rifaximin, bioavailability is low, preliminary definite microcrystalline Cellulose is binding agent and disintegrating agent, low-substituted hydroxypropyl cellulose promotes stripping, ethanol is binding agent, and carboxymethyl starch sodium is a disintegrating agent, plays disintegration, magnesium stearate is a lubricant, increase flowability, lactose is correctives and filler, and acesulfame potassium is a correctives.
Below be the detailed process of prescription screening:
Prescription 1, the rifaximin of recipe quantity, ethanol is made wetting agent, adds lactose, microcrystalline Cellulose, acesulfame potassium, the lubricant magnesium stearate.As a result, the outward appearance of slice, thin piece can, the dispersibility of slice, thin piece is undesirable.
Prescription 2, the amount of minimizing microcrystalline Cellulose, other adds low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium, makees wetting agent with ethanol, and other are constant.As a result, the outward appearance of slice, thin piece, hardness can, dispersibility increases.
Prescription 3 in order further to ensure the quality of products, increases adding carboxymethyl starch sodium, and other are constant.As a result, the outward appearance of slice, thin piece, hardness, dispersibility is all fine.
Prescription 4 prescriptions 7, to the adjustment that the consumption of supplementary material suits, the result, the outward appearance of slice, thin piece, hardness and dispersibility are all better; When the consumption of supplementary material is the twice of consumption of prescription 3 (writing out a prescription 7), the outward appearance of slice, thin piece, hardness, dispersibility is all fine.
The selection result sees Table 1:
Table 1
| Composition and inspection item | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 | Prescription 7 |
| Rifaximin | 100g | 100g | 100g | 120g | 160g | 180g | 200g |
| Lactose | 50g | 50g | 50g | 60g | 75g | 85g | 100g |
| Microcrystalline Cellulose | 90g | 70g | 70g | 80g | 100g | 120g | 140g |
| Low-substituted hydroxypropyl cellulose | Zhao | 20g | 20g | 25g | 30g | 35g | 40g |
| Acesulfame potassium | 5g | 5g | 5g | 6g | 7.5g | 8.5g | 10g |
| Ethanol | 30ml | 30ml | 30ml | 35ml | 45ml | 50ml | 60ml |
| Carboxymethyl starch sodium | Grab | 10g | 20g | 25g | 30g | 35g | 40g |
| Magnesium stearate | 1g | 1g | 1g | 1.2g | 1.4g | 1.8g | 2g |
| Substrate's appearance | Better | Better | Better | Better | Better | Better | Better |
| Hardness | Better | Better | Better | Better | Better | Better | Better |
| Dispersing uniformity | Difference | Better | Well | Better | Better | Better | Well |
According to table 1, that determines Rifaximin medicament combination dispersible tablet provided by the present invention consists of rifaximin 100-200 weight portion, lactose 50-100 weight portion, microcrystalline Cellulose 70-140 weight portion, low-substituted hydroxypropyl cellulose 20-40 weight portion, acesulfame potassium 5-10 weight portion, carboxymethyl starch sodium 10-40 weight portion and magnesium stearate 1-2 weight portion, and with write out a prescription 3 and prescription 7 be the best prescription of Rifaximin medicament combination dispersible tablet of the present invention.
Test example 2
This test example is to carry out the quality control of rifaximin dispersible tablet.
(1) dispersing uniformity
About the dispersible tablet inspection, get 2 of the prepared dispersible tablets of embodiment 1 with reference to " The People's Republic of China's pharmacopeia " version in 2005 two appendix, put in the 100ml water of (20 ± 1) ℃, jolting 3min, make the dispersible tablet homodisperse, all disintegrate also by No. 2 sieves, meets the requirements.
(2) suspension stability experiment
Get 1 of dispersible tablet, add (20 ± 1) ℃ water 50ml.Fully stir, measure the light transmittance (T in its zero moment immediately in the 700nm place
0), and write down 3,6,912,15, the light transmittance (T of 18min
t), survey 6 altogether, get arithmetic mean of instantaneous value.Make Y=(T
t-T
0)/T
0, with the Y time t is carried out linear regression and gets equation: Y=0.0735t+0.4049, r=0.9996.The slope k value is littler, illustrates that the suspension sedimentation is slower, and is more stable.
(3) dissolution determination
Test (slurry method) according to 2005 editions Pharmacopoeia of the People's Republic of China appendix (XC) employing method 2.Add 0.1mol/L hydrochloric acid (containing 0.1% sodium lauryl sulphate) solution 1000ml in 6 stripping rotors, temperature is controlled at (37.5 ± 0.5) ℃, regulates rotating speed to 100r/min.Get 3ml in the 10ml measuring bottle respectively at 5,10,20,30,45,60, replenish 3ml isothermal dissolution medium to stripping rotor simultaneously, after standardize solution shakes up, filter.Measure trap at 416nm wavelength place, calculate stripping accumulative total percentage rate, the results are shown in Table 2.
Table 2. rifaximin dispersible tablet cumulative leaching rate
| Time (min) | 5 | 10 | 20 | 30 | 45 | 60 |
| Cumulative leaching rate (%) | 79.6 | 86.7 | 93.0 | 96.9 | 97.6 | 97.8 |
(4) assay
Get 20 of rifaximin dispersible tablets, porphyrize, precision takes by weighing in right amount (being equivalent to rifaximin 100mg), put in the 100ml volumetric flask, add the stripping medium dissolves and be diluted to scale, shake up, filter, precision is measured subsequent filtrate 5ml, place another 100ml measuring bottle, add above-mentioned solvent dilution, shake up to scale, measure trap and calculate content at the 416nm wavelength, the results are shown in Table 3.
Table 3. rifaximin dispersible tablet assay result (n=3)
| Lot number | Content (labelled amount %) | ?RSD(％) |
| 20080508 | 104.2 | 0.50 |
| 20080509 | 104.3 | 0.49 |
| 20080510 | 104.1 | 0.52 |
(5) stability experiment
Get need testing solution (dissolution medium and rifaximin solution), at room temperature place 8h respectively 0,2,4,6, the 8h sampling and measuring, its trap is no change almost, shows that this product is stable in 0.1mol/L (containing 0.1% sodium lauryl sulphate) solution.
(6) hardness measurement
Get 5 of rifaximin dispersible tablets, the hardness that records with hardness tester is 3.02-6.11kg, and its arithmetic mean of instantaneous value is 3.62kg.
Test example 3
This test example is to investigate the stability of Rifaximin medicament combination dispersible tablet of the present invention.
(1) accelerated test
According to 2005 editions Pharmacopoeia of the People's Republic of China appendix XIX C medicine stability test guidelines, get three batches in the sample of embodiment 1, press commercially available back, under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%, placed 6 months.Take a sample respectively once 1st month, 2 months, 3 months, 6 the end of month at duration of test, detect by stable high spot reviews project.The results are shown in Table 4.
Table 4. accelerated test result
| Time (moon) | Character | Content (%) | Related substance (%) | Dissolution (%) |
| 0 | Orange color chips | 104.1 | 0.97 | 97.8 |
| 1 | Orange color chips | 104.2 | 0.98 | 97.6 |
| 2 | Orange color chips | 103.9 | 0.98 | 97.5 |
| 3 | Orange color chips | 103.0 | 0.99 | 96.5 |
| 6 | Orange color chips | 100.9 | 1.02 | 95.5 |
(2) long term test
According to 2005 editions Pharmacopoeia of the People's Republic of China appendix XIX C medicine stability test guidelines, get three batches in the sample of embodiment 1, press commercially available back, under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%, placed 12 months.Sampling in per 3 months once respectively at sampling in 0 month, 3 months, 6 months, 9 months, 12 months, detects by stable high spot reviews project.The results are shown in Table 5.
Table 5. long-term test results
Above-mentioned experiment shows, the having good stability of the Rifaximin medicament combination dispersible tablet that the embodiment of the invention 1 is prepared.
The rifaximin dispersible tablet prepared to other embodiment of the present invention also carried out identical test, and its result is similar.
Comparative example 1
Compare to the prepared rifaximin compositions dispersible tablet of the embodiment of the invention 1 with according to the accumulation dissolution of the rifaximin dispersible tablet (title reference substance) of the method preparation of " development of rifaximin dispersible tablet and quality control " (referring to " number reason medicine and pharmacology magazine ", 2007 the 20th the 6th phases of volume).
Method: test (slurry method) according to 2005 editions Pharmacopoeia of the People's Republic of China appendix (XC) employing method 2.Add 0.1mol/L hydrochloric acid (containing 0.1% sodium lauryl sulphate) solution 1000ml in 6 stripping rotors, temperature is controlled at (37.5 ± 0.5) ℃, regulates rotating speed to 100r/min.Get 3ml in the 10ml measuring bottle respectively at 5,10,20,30,45,60, replenish 3ml isothermal dissolution medium to stripping rotor simultaneously, after standardize solution shakes up, filter.Measure trap at 416nm wavelength place, calculate stripping accumulative total percentage rate, the results are shown in Table 6.
Table 6. rifaximin dispersible tablet cumulative leaching rate
| Time (min) | Sample | 5 | 10 | 20 | 30 | 45 | 60 |
| Cumulative leaching rate (%) | The present invention | 79.6 | 86.7 | 93.0 | 96.9 | 97.6 | 97.8 |
| Reference substance | 78.5 | 85.6 | 91.9 | 95.8 | 97.2 | 97.3 |
Claims (13)
1. Rifaximin medicament combination dispersible tablet is characterized in that: described medicament combination dispersible tablet composed as follows:
The preparation method of described rifaximin compositions dispersible tablet comprises the steps:
Described method comprises raw material rifaximin and adjuvant lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, sieves, and the system wet granular is made dried granule, tabletting and packing.
2. Rifaximin medicament combination dispersible tablet according to claim 1 is characterized in that: described medicament combination dispersible tablet composed as follows:
3. Rifaximin medicament combination dispersible tablet according to claim 1 is characterized in that: described medicament combination dispersible tablet composed as follows:
4. the preparation method of claim 1 or 2 or 3 described Rifaximin medicament combination dispersible tablets, it is characterized in that: this method comprises the steps:
Described method comprises raw material rifaximin and adjuvant lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, sieves, and the system wet granular is made dried granule, tabletting and packing.
5. method according to claim 4 is characterized in that: described rifaximin is crossed 100 mesh sieves, and described lactose, acesulfame potassium and carboxymethyl starch sodium are crossed 120 mesh sieves respectively, and microcrystalline Cellulose and low-substituted hydroxypropyl cellulose are crossed 80 mesh sieves.
6. method according to claim 4 is characterized in that: described system wet granular also comprises mixing.
7. method according to claim 6 is characterized in that: described being mixed into done mixed wet mixing more earlier.
8. method according to claim 7; it is characterized in that: described system wet granular is rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose that takes by weighing recipe quantity; insert in the high-speed mixing granulating machine; the sealing high-speed dry was mixed 5-15 minute; added then an amount of wet mixing 1-5 of ethanol minute, after the wet mixing, wet mixing cutting 1-3 minute; emit granule, obtain wet granular.
9. method according to claim 8 is characterized in that: described method comprises the steps:
1) gets the raw materials ready
Rifaximin is pulverized, crossed 100 mesh sieves; With lactose, acesulfame potassium and carboxymethyl starch sodium pulverize separately, cross 120 mesh sieves; With microcrystalline Cellulose and low-substituted hydroxypropyl cellulose pulverize separately, cross 80 mesh sieves, obtain standby former, adjuvant;
2) system wet granular
Take by weighing rifaximin, lactose, microcrystalline Cellulose, acesulfame potassium and the low-substituted hydroxypropyl cellulose of recipe quantity, insert in the high-speed mixing granulating machine, the sealing high-speed dry was mixed 5-15 minute, added then an amount of wet mixing 1-5 of ethanol minute, after the wet mixing, granule is emitted in wet mixing cutting 1-3 minute, obtains wet granular;
3) make dried granule
The wet granular that the last step was made changes in the ebullated dryer, and temperature is controlled at 60-70 ℃ of baking 15-30 minute, shuts down, clear filter bag, and blowing obtains dried granule;
4) tabletting, packing
To go up prepared dried granule of step and add pelletizing machine, start button carries out granulate; the magnesium stearate that adds the carboxymethyl starch sodium and the recipe quantity of recipe quantity again; add three-dimensional mixer with suction feeding and mix, tabletting, packing promptly gets Rifaximin medicament combination dispersible tablet.
10. method according to claim 9 is characterized in that: step 2) described in do to mix under the condition of rotating speed 35～55 commentariess on classics/min, doing mixed 5-15 minute.
11. method according to claim 10 is characterized in that: step 2) described in do to mix under the condition of rotating speed 45 commentariess on classics/min, doing mixed 5-15 minute.
12. method according to claim 9 is characterized in that: step 2) described in wet mixing under the condition of rotating speed 25～35 commentaries on classics/min wet mixing 1～5min.
13. method according to claim 12 is characterized in that: step 2) described in wet mixing under the condition of rotating speed 30 commentaries on classics/min wet mixing 1～5min.
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| Title |
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| 张秋荣登.粉末直接压片法制备氢氯噻嗪分散片.《郑州大学学报（医学版）》.2008,第43卷(第1期),第162-164页. * |
| 徐蓓婷等.利福昔明分散片的研制及质量控制.《数理医药学杂志》.2007,第20卷(第6期),第843-844页. * |
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