CN102793629A - Preparation method of rapidly disintegrating paper type dry paste tablets capable of rapidly disintegrating in oral cavity - Google Patents
Preparation method of rapidly disintegrating paper type dry paste tablets capable of rapidly disintegrating in oral cavity Download PDFInfo
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- CN102793629A CN102793629A CN2012102420287A CN201210242028A CN102793629A CN 102793629 A CN102793629 A CN 102793629A CN 2012102420287 A CN2012102420287 A CN 2012102420287A CN 201210242028 A CN201210242028 A CN 201210242028A CN 102793629 A CN102793629 A CN 102793629A
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Abstract
The invention provides a preparation method of rapidly disintegrating paper type dry paste tablets capable of rapidly disintegrating in a oral cavity, belongs to the technical field of pharmacy, in particular relates to a medicinal preparation, namely a rapidly-disintegrated paper type dry paste tablet, which utilizes rice as an auxiliary material or carrier through emulsifying, paste mixing, film making and other production processes, can be rapidly dissolved in the oral cavity, and can be taken by means of saliva without drinking water. The preparation prepared from rice serving as the auxiliary material has the characteristics of convenient taking, quick response, high bioavailability and the like, and is applicable to patients with difficulty in swallowing, such as the aged, patients lying in beds, infants, psychopath and critically ill patients.
Description
Technical field
The invention belongs to the pharmaceutical technology field, be specifically related to a kind of can be in the oral cavity rapidly the speed of disintegrate collapse dried poultice of paper mold and preparation method thereof.
Background technology
Along with the prolongation and the age growth of human average life, old people, infant, critical patient and aphagia and behind gastrointestinal tract drug effect reduce even the patient's of losing efficacy oral administration mode becomes the problem that people pay close attention to.According to estimates, there is 50% people that swallow tablet and capsule are had any problem approximately, influenced the compliance of Drug therapy.In department of pediatrics and old medicine and pharmacology field; To in water, dissolving or suspend, can chew or can in mouth, dissolve rapidly or the solid preparation of disintegrate having very big demand; Need not the oral quick dispersible preparation that water and swallowing act just can disperse or dissolve rapidly, just can address this problem.This dosage form can be dispersed or dissolved in saliva rapidly after putting into mouth, but the absorption of the mucosa in the medicine oral, and bioavailability is higher than ordinary preparation, proves effective rapidly no liver sausage first pass effect.
And oral cavity disintegration tablet can address the above problem; Oral cavity disintegration tablet is absorbed by the abundant buccal mucosa of blood, is a kind of oral quick dispersible preparation that water and swallowing act just can disperse or dissolve rapidly that need not, and oral cavity disintegration tablet directly gets into systemic circulation without gastrointestinal; Avoided the liver first-pass effect of oral route; Reach and absorb rapidly few side effects, the purpose that application dose is littler than other oral formulations.
The oral cavity disintegration tablet solid preparation came across for 20 beginnings of the century.1908, American Beringer G.M. processed tablet with the material of two or more different solubility, behind the chance water; Tablet ease of solubility composition at first dissolves; Form " honeycomb " effect, make slightly solubility material generation avalanche, thereby make the quick disintegrate of whole tablet become granule.Nineteen twenty-seven, American scholar Rapp B. uses the enamel-cover principle and has processed quinine speed disintegrating tablet, and has applied for patent, and in this period, the fast release solid formulation research emphasis is that the speed of tablet collapses, and makes slow progress.Up to the beginning of the sixties; Solid dispersion technology is applied to pharmaceutical field first; In order to solve problems such as insoluble drug absorption difference, bioavailability are low new approaches are provided, have made with the solid dispersion technology to be that rapid release, the quick-effective preparation on basis obtained development faster.The later stage seventies 20th century; The people such as Gregor of Wyeth (Wryth&Brothere) adopt Freeze Drying Technique to make the pharmaceutical carrier of high porosity; This carrier can dissolve rapidly after the oral cavity runs into saliva; Do not need water delivery service, take medicine to the bad patient of some function of deglutition convenience is provided with water intaking inconvenience.Get into the nineties, people begin to turn to adjuvant to emphasis, in the screening like binding agent, disintegrating agent.Attempt to prepare the disintegrating property fast-release tablet suitable, and obtain certain progress with freeze drying process with common tabletting method.
Oral cavity disintegration tablet is summarized by technology of preparing and is divided three types: solid solution method, direct compression process and freeze-drying.The oral cavity disintegration tablet of freeze-drying and the preparation of solid solution method, general disintegrate or dissolution time in the oral cavity was radix with 10 seconds, can reach 3 to 5 seconds the soonest, generally at 10 to 20 seconds.Direct compression process is the disintegrating agent that adds during through tabletting, and imbibition and capillarity after meeting water cause the rapid entering of moisture and the quick disintegrate of tablet.The general Orally disintegrating or the dissolution time of the oral cavity disintegration tablet of direct compression process preparation were radix with 30 seconds, general 30 to 40 seconds, can reach for 10 seconds the soonest.According to research, the time of staying of general oral foreign body surpasses 15 seconds, and the people just has the trained reflex of chewing foreign body, and disintegration time was a standard within 15 seconds.Obviously, freeze-drying and solid solution method have outstanding advantage.
With abroad compare, what domestic employing was many is wet granulation, and the direct powder compression method used is also arranged.Through wet granule compression tablet prepared oral cavity disintegration tablet, disintegration time was controlled in 30 seconds.Panyathip etc. adopt direct compression and wet granulation process combined, and disintegrating agent adds after adopting wet granulation, help tabletting though the powder compressibility strengthens, and disintegrating property descends thereupon.
Eventually the above, the preparation of oral cavity disintegration tablet, key technology is in the selection of adjuvant or carrier, how to make medicine in a short period of time at intraoral disintegration or dissolve absorption, is the essential condition of selecting adjuvant.
Summary of the invention
The objective of the invention is to select for use a kind of new adjuvant or carrier, it can be dissolved rapidly or disintegrate in the oral cavity, the present invention utilizes the rice powder to be adjuvant; Through emulsifying, mixing batter, copy production process such as film, prepare a kind of can dissolving rapidly in the oral cavity, the patient does not need drinking-water; The pharmaceutical preparation that can take by saliva; According to the manufacturing process of technology, utilize the drug nomenclature of this method preparation to collapse the dried poultice of paper mold for speed, belong to a kind of of oral cavity disintegration tablet.This tablet has taking convenience; Onset is rapid, and characteristics such as bioavailability height are applicable to the patient with dysphagia; Like old man, bed position patient, infant, psychotic, critical patient etc., be the novel solid fast dissolving dosage form that receives much concern in recent years.
Technical scheme of the present invention is following:
1. form:
Medicine rice phospholipid solution correctives
Wherein said medicine can be folk prescription or compound recipe Western medicine raw material, also can be folk prescription or herbal mixture or Chinese medicine extract.
The present invention is model drug with the carbamazepine just, carries out the prepared that speed collapses the dried poultice of paper mold.
2. method for preparing:
2.1 rice powder emulsifying
The rice of getting in the prescription is pulverized, and crosses 100 mesh sieves, adds 2.5～3 times of water gagings, stirring heating down; And make temperature remain on 50～55 ℃, and the rice powder all being dispersed in making it emulsifying in the water, the concentration after the emulsifying is 15～17 Baume degrees; Cross 100 mesh sieves, put in the adjunce copper, subsequent use;
Wherein said rice is through eluriating, dry, shell gained with rice.
2.2 mixing batter
Open the agitator of above-mentioned adjunce copper, add phospholipid solution, medicine (carbamazepine) and correctives in the prescription in order respectively, stirred 30 minutes, be mixed with the phospholipid emulsion, subsequent use;
Wherein said phospholipid solution is prepared by following method: be that 1%～2% sodium hydroxide solution is heated to 85～100 ℃ with concentration earlier, adding phospholipid makes it all to be dissolved in the sodium hydroxide solution under stirring state; Put and be chilled to 30～40 ℃; Making its pH value is 8～9, crosses 100 mesh sieves, both;
Wherein said phospholipid solution is that need to be made into concentration be 1%～2% phospholipid solution, and 1%～2% sodium hydroxide solution consumption is 0.8%～1.8% of a phospholipid.
Wherein said correctives can be one or more mixture in sucrose, lactose, Flos Chrysanthemi Citrus chachiensis Hort., aspartame, simple syrup, Fructus Citri Limoniae, Oleum menthae, apple essence, flavoring orange essence, the flavoring banana essence.
2.3 copy film
Above-mentioned phospholipid emulsion joined copy in the film machine, width and thickness by required specification adjustment slit spread to homogeneous film, under 60 ℃ of temperature, dry, or carry out lyophilization at-20 ℃, and injection molding is in blocks, both.
Beneficial effect
The present invention compares with other corresponding oral formulations, has following useful effect:
1. involved in the present invention a kind of can be in the oral cavity rapidly the speed of disintegrate collapse the dried poultice of paper mold, contact promptly with saliva and dissolve rapidly, and absorb by oral mucosa; Not only rapid-action; And the influence of not taken food, promptly all can containing take after meal ante cibum, local application's onset is faster.
2. this tablet has taking convenience, is applicable to the patient with dysphagia, like old man, bed position patient, infant, psychotic, critical patient etc.
3. production technology is simple, and equipment is simple, and is easy to operate, and labor intensity is low, and production efficiency is high.Workshop does not have dust simultaneously, helps labor protection and environmental protection yet.
The specific embodiment
The present invention is just collapsed the dried poultice of paper mold for receiving test preparation (50mg/ sheet) with the carbamazepine speed for preparing in the above-mentioned method for preparing; The common tablet of carbamazepine is reference preparation (a 100mg/ sheet), it is carried out projects such as disintegration, moistening time, mouthfeel and pharmacokinetics and studies evaluation.
Evaluation index is measured
1.1 disintegration time mensuration
Getting carbamazepine speed by the preparation of above-mentioned method for preparing collapses 6 of the dried poultices of paper mold (hereinafter to be referred as the paper poultice) and { is numbered (1) (2) (3) (4) (5) (6) }; Adopt dispersible tablet disintegration time mensuration method; Temperature is set at (37 ± 1) ℃; Each survey 1, with the powdered record of complete disintegrate disintegration.See table 1
Table 1
1.2 wetting time is measured
With diameter is that the filter paper of 8cm is put into the surface plate that diameter is 10cm, adds 8mL water then, makes it to soak into, subsequent use; Get 6 of paper poultices and { be numbered (1) (2) (3) (4) (5) (6) }, place respectively on the filter paper after above-mentioned the soaking into, measure to complete moistening required time and be the moistening time.See table 2
Table 2
1.3 mouthfeel
Select 6 volunteers { to be numbered (1) (2) (3) (4) (5) (6) }; The paper poultice of buccal a slice after rectifying flavor in every volunteer's mouth is through bitter in the mouth (--), mildly bitter flavor (-), flavor sweet (+), distinguished the flavor of sweet (++), swash (*), have grittiness (=) to estimate the oral cavity spinosity.See table 3
Table 3
Pharmacokinetic studies
2.1 beasle dog body giving drugs into nose is for dynamics research
According to the pharmacokinetic method, to behind beasle dog oral test preparation and the reference preparation, the drug-time curve and the semilog drug-time curve that record carbamazepine are seen Fig. 1 and Fig. 2 respectively respectively, and the pharmacokinetic parameter that the dog single dose is irritated behind 2 kinds of preparations of clothes is seen table 4.With carrying out variance analysis after Cmax that receives test preparation and reference preparation and the conversion of AUC0-t process natural logrithm; Carry out two one-side t checks then; All there were significant differences for Cmax between two preparations and the logarithm value of AUC0-t (P＜0.05); Receive test preparation the AUC0-t logarithm value 90% crediblely be limited to 239.7%～282.0%, drop on outside the equivalent scope (80%～125%), receive test preparation Cmax logarithm value 90% crediblely be limited to 190.5%～282.6%; Drop on outside the equivalent scope (70%～143%); The biological inequivalence of two kinds of preparations is described, is calculated relative bioavailability F=AUC0-t (T)/AUC0-t (the R) * 100%=261.31% that receives test preparation, the result has obviously improved carbamazepine bioavailability in vivo.Two preparation tmax have significant difference (P＜0.05) through non parametric tests, explain that there were significant differences in the absorption rate aspect.
Description of drawings:
Fig. 1: the beasle dog single oral dose receives the carbamazepine drug-time curve behind test preparation and the reference preparation.
Fig. 2: the beasle dog single oral dose receives the carbamazepine semilog drug-time curve behind test preparation and the reference preparation.
Table 4
The beasle dog single oral dose receives the pharmacokinetic parameters behind test preparation and the reference preparation
Experimental result shows: during the beasle dog single dose administration, receives the Cmax of test preparation and AUC0-12h to be higher than reference preparation, explains to receive test preparation to have the effect of rapid release, and fast at the intravital absorptance ordinary tablet of beasle dog, also meet the characteristic of oral rapidly disintegrating paper poultice.Experimental session does not see that obvious adverse reaction takes place, and does not have the animal subject of dropping by the wayside experiment.Receive test preparation no tangible plateau after blood drug level reaches peak value, possibly be because get the blood point near peak value intensive inadequately due to, but this does not influence the embodiment that receives the test preparation characteristic, can replace ordinary tablet clinically.
2.2 bioequivalence Journal of Sex Research
Adopt cross-over experiment method for designing at random, 5 healthy volunteers are divided into 2 groups at random, behind the fasting 12h, adopt vein imbedding needle method, wherein one group of everyone 2 of each oral reference preparation (100mg/ sheet) is drunk 200ml eliminating cold for resuscitation water simultaneously; Another is organized everyone and respectively sucks and receive 4 of test preparations (50mg/ sheet), places the Sublingual face, does not drink water.Extracting vein blood before the administration after the administration, is taked forearm vein blood 3.0ml in different time points, and blood sample is put in the calparine pipe, behind the centrifugal 10min (4000r/min), pipettes blood plasma in another plastics tool plug centrifuge tube, puts in the cold room and preserves.Freely drink water unified dining the behind take medicine back 4h and 8h during the blood sampling.After 13 days, 2 groups of personnel's intersections are taken medicine at interval, in identical time point blood sampling, draw drug-time curve.Adopt 3p97 software match pharmacokinetic parameters, with the best compartment model of goodness of fit value (Goodness offit) minimum, AIC value minimum and correlation coefficient (R square) MAXIMUM SELECTION, Cmax adopts measured value, and AUC, MRT adopt statistical moment parameter wherein.
Behind healthy volunteer's oral test preparation and the reference preparation; Its blood drug level-time graph; Through the 3p97 software processes, when weight coefficient was w=1/cc, fitting effect was best; Reference preparation with receive the pharmacokinetics model of test preparation in human body to meet one compartment model, relative bioavailability is 115.84%.
Evaluation of result: receive test preparation and reference preparation relatively, AUC is greater than 80% of ordinary tablet, and Cmax obviously improves; Tmax obviously shifts to an earlier date, and relative bioavailability shows said preparation tool rapid release dynamic characteristic between 80%～120%; Drug-time curve is through using the 3p97 software processes; Correlation coefficient when weight is w=1/cc (R square) maximum, fitting result is an one compartment model, AUC adopts the statistical moment principle to calculate.The result shows that it is fast absorbed than reference preparation by test preparation, and peak time shifts to an earlier date, and maximum plasma concentration is high, and relative bioavailability is 115.84%.
Claims (6)
1. the ability speed of the disintegrate method for preparing that collapses the dried poultice of paper mold rapidly in the oral cavity, it is characterized in that: be made up of medicine, rice, phospholipid solution, correctives, its concrete method for preparing is following:
1.1 rice powder emulsifying
Get rice and pulverize, cross 100 mesh sieves, add 2.5～3 times of water gagings, stirring heating down; And make temperature remain on 50～55 ℃, and the rice powder all being dispersed in making it emulsifying in the water, the concentration after the emulsifying is 15～17 Baume degrees; Cross 100 mesh sieves, put in the adjunce copper, subsequent use;
1.2 mixing batter
Open the agitator of above-mentioned adjunce copper, add phospholipid solution, medicine and correctives in the prescription in order respectively, stirred 30 minutes, be mixed with the phospholipid emulsion, subsequent use;
1.3 copy film
Above-mentioned phospholipid emulsion joined copy in the film machine, width and thickness by required specification adjustment slit spread to homogeneous film, under 60 ℃ of temperature, dry, or carry out lyophilization at-20 ℃, and injection molding is in blocks, both.
2. according to claim 1 a kind of can be in the oral cavity speed of the disintegrate method for preparing that collapses the dried poultice of paper mold rapidly, it is characterized in that: said medicine can be folk prescription or compound recipe Western medicine raw material, also can be folk prescription or herbal mixture or Chinese medicine extract.
3. according to claim 1 a kind of can be in the oral cavity speed of the disintegrate method for preparing that collapses the dried poultice of paper mold rapidly, it is characterized in that: said correctives can be one or more mixture in sucrose, lactose, Flos Chrysanthemi Citrus chachiensis Hort., aspartame, simple syrup, Fructus Citri Limoniae, Oleum menthae, apple essence, flavoring orange essence, the flavoring banana essence.
4. according to claim 1 a kind of can be in the oral cavity speed of the disintegrate method for preparing that collapses the dried poultice of paper mold rapidly, it is characterized in that: described rice is through eluriating, dry, shell gained with rice.
5. according to claim 1 a kind of can be in the oral cavity speed of the disintegrate method for preparing that collapses the dried poultice of paper mold rapidly; It is characterized in that: described phospholipid solution is prepared by following method: be that 1%～2% sodium hydroxide solution is heated to 85～100 ℃ with concentration earlier, adding phospholipid makes it all to be dissolved in the sodium hydroxide solution under stirring state; Put and be chilled to 30～40 ℃; Making its pH value is 8～9, crosses 100 mesh sieves, both.
6. according to claim 1 a kind of can be in the oral cavity speed of the disintegrate method for preparing that collapses the dried poultice of paper mold rapidly; It is characterized in that: described phospholipid solution is that need to be made into concentration be 1%～2% phospholipid solution, and 1%～2% sodium hydroxide solution consumption is 0.8%～1.8% of a phospholipid.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1714784A (en) * | 2005-04-28 | 2006-01-04 | 美晨集团股份有限公司 | Industrial producing process for breath refreshing tablet |
| CN101868228A (en) * | 2007-11-21 | 2010-10-20 | 大日本住友制药株式会社 | Orally disintegrating tablet |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1714784A (en) * | 2005-04-28 | 2006-01-04 | 美晨集团股份有限公司 | Industrial producing process for breath refreshing tablet |
| CN101868228A (en) * | 2007-11-21 | 2010-10-20 | 大日本住友制药株式会社 | Orally disintegrating tablet |
Non-Patent Citations (1)
| Title |
|---|
| 谢黎虹 等: "稻米中蛋白质对淀粉RVA特征谱的影响", 《中国水稻科学》, vol. 20, no. 5, 31 December 2006 (2006-12-31), pages 524 - 528 * |
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