CN102793629B - Preparation method of rapidly disintegrating paper type dry paste tablets capable of rapidly disintegrating in oral cavity - Google Patents

Abstract

The invention provides a preparation method of rapidly disintegrating paper type dry paste tablets capable of rapidly disintegrating in a oral cavity, 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

A kind of can be in the oral cavity the rapid speed of the disintegrate preparation method that collapses the dried poultice of paper mold

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 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 becomes the problem that people pay close attention to.According to estimates, approximately there is 50% people that the Tablet and Capsula of swallowing is had any problem, affected 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 large demand, need not the oral rapid dispersion 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 rapidly saliva after putting into mouth, and medicine can absorb by intraoral mucosa, and bioavailability is higher than ordinary preparation, proves effective rapidly, without the 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, it is a kind of oral rapid dispersion preparation that water and swallowing act just can disperse or dissolve rapidly that need not, oral cavity disintegration tablet directly enters 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 less than other oral formulations.

The oral cavity disintegration tablet solid preparation came across for 20 beginnings of the century.1908, American Beringer G.M. made 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 made 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.Until the beginning of the sixties, solid dispersion technology is applied to pharmaceutical field first, new approaches are provided in order to solve the problems such as insoluble drug absorption difference, bioavailability are low, so that rapid release, quick-effective preparation take solid dispersion technology as the basis have obtained faster development.20 century 70 later stages, (the Wryth﹠amp of Wyeth; The people such as Gregor 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 some function of deglutition patient bad and water intaking inconvenience convenience is provided.Enter the nineties, people begin emphasis is turned to adjuvant, in the screening such as binding agent, disintegrating agent.Attempt to prepare the disintegrating property fast-release tablet suitable with freeze drying process with common tabletting method, and obtain certain progress.

Oral cavity disintegration tablet sums up minute three classes by technology of preparing: solid solution method, direct compression process and freeze-drying.Freeze-drying and the standby oral cavity disintegration tablet of solid solution legal system, generally the disintegrate in oral cavity or dissolution time take 10 seconds as radix, reach 3 to 5 seconds the soonest, generally at 10 to 20 seconds.Direct compression process is the disintegrating agent that adds during by tabletting, imbibition and capillarity after meeting water, and what cause moisture enters rapidly quick disintegrate with tablet.The general Orally disintegrating of the oral cavity disintegration tablet of direct compression process preparation or dissolution time take 30 seconds as radix, general 30 to 40 seconds, reached 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.Prepare oral cavity disintegration tablet by wet granule compression tablet technique, disintegration time was controlled in 30 seconds.The technique that the employing direct compression such as Panyathip and wet granulation combine, disintegrating agent adds after adopting wet granulation, is conducive to 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 object of the invention is to select 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, by emulsifying, mixing batter, copy the production process such as film, prepare a kind of can rapidly dissolving 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 technique, utilize the drug nomenclature of the 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, bioavailability high, the patient who is applicable to have dysphagia, such as old man, bed position patient, infant, psychotic, critical patient etc., it is the novel solid fast dissolving dosage form that receives much concern in recent years.

Technical scheme of the present invention is as follows:

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 carries out the technique preparation that speed collapses the dried poultice of paper mold just take carbamazepine as model drug.

2. preparation method:

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, heats under the stirring, 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, for 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 respectively in order phospholipid solution, medicine (carbamazepine) and correctives in the prescription, stirred 30 minutes, be mixed with the phospholipid emulsion, for subsequent use;

Wherein said phospholipid solution is prepared by following method: be first that 1%～2% sodium hydroxide solution is heated to 85～100 ℃ with concentration, add phospholipid under stirring state, make it all to be dissolved in the sodium hydroxide solution, let cool 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 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, adjust width and the thickness of slit by required specification, spread to homogeneous film, dry under 60 ℃ of temperature, or carry out lyophilization at-20 ℃, injection molding is in blocks, both.

Beneficial effect

The present invention compares with other corresponding oral formulations, has following useful effect:

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 namely with saliva and dissolve rapidly, and by buccal absorption, not only rapid-action, and the impact of not taken food, namely before or after meals all can containing be taken, and local application's onset is faster.

2. this tablet has taking convenience, is applicable to have the patient of dysphagia, such as 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 also is conducive to labor protection and environmental protection without dust simultaneously.

The specific embodiment

The present invention is just collapsed the dried poultice of paper mold for being subjected to test preparation (50mg/ sheet) with the carbamazepine speed for preparing in the above-mentioned preparation method, the common tablet of carbamazepine is reference preparation (100mg/ sheet), it is carried out the 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 preparation method 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 Setting is (37 ± 1) ℃, each survey 1, with the powdered record of complete disintegrate disintegration.See Table 1

Table 1

1.2 wetting time is measured

Be that the filter paper of 8cm is put into the surface plate that diameter is 10cm with diameter, then add 8mL water, make it to soak into, for 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 behind taste masking in every volunteer's mouth is by 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 pharmacokinetic methods, 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 respectively Fig. 1 and Fig. 2 respectively, and the dog single dose gavages 2 kinds of pharmacokinetic parameters behind the preparation and sees Table 4.After being subjected to the Cmax of test preparation and reference preparation and AUC0-t through the natural logrithm conversion, carry out variance analysis, then carry out two one-side t checks, all there were significant differences for Cmax between two preparations and the logarithm value of AUC0-t (P＜0.05), be subjected to test preparation the AUC0-t logarithm value 90% crediblely be limited to 239.7%～282.0%, drop on outside the equivalent scope (80%～125%), be subjected to 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, calculate the relative bioavailability F=AUC0-t (T) that is subjected to test preparation/AUC0-t (R) * 100%=261.31%, the result has obviously improved carbamazepine bioavailability in vivo.Two preparation tmax have significant difference (P＜0.05) through non parametric tests, illustrate that there were significant differences in the absorption rate aspect.

Description of drawings:

Fig. 1: the beasle dog single oral dose is subjected to the carbamazepine drug-time curve behind test preparation and the reference preparation.

Fig. 2: the beasle dog single oral dose is subjected to the carbamazepine semilog drug-time curve behind test preparation and the reference preparation.

Table 4

The beasle dog single oral dose is subjected to the pharmacokinetic parameters behind test preparation and the reference preparation

Experimental result shows: during the beasle dog single dose administration, be subjected to the Cmax of test preparation and AUC0-12h to be higher than reference preparation, illustrate to be subjected to test preparation to have the effect of rapid release, the absorptance ordinary tablet in the beasle dog body is fast, also meets the feature of oral rapidly disintegrating paper poultice.Experimental session has no obvious adverse reaction and occurs, without the animal subject of dropping by the wayside experiment.Be subjected to test preparation after blood drug level reaches peak value without obvious plateau, may be because get the blood point intensive not near peak value due to, but this does not affect the embodiment of tested formulation characteristics, can replace ordinary tablet clinically.

2.2 bioequivalence Journal of Sex Research

Adopt random cross-over experiment method for designing, 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 the 200ml warm water simultaneously; Another is organized everyone and respectively sucks and be subjected to 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 4h and the 8h after taking medicine during the blood sampling.Behind the interval 13 days, 2 groups of personnel's intersections are taken medicine, and 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 is w=1/cc, fitting effect is best, reference preparation and be subjected to the pharmacokinetics model of test preparation in human body to meet one compartment model, relative bioavailability is 115.84%.

Evaluation of result: be subjected to 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 one compartment model, AUC adopts the statistical moment principle to calculate.The result shows, absorbed than reference preparation by test preparation fast, and peak time shifts to an earlier date, and maximum plasma concentration is high, and relative bioavailability is 115.84%.

Claims (5)

1. an energy rapid speed of the disintegrate preparation method that collapses the dried poultice of paper mold in the oral cavity, it is characterized in that: be to be prepared from by medicine, rice, phospholipid solution and correctives, its concrete preparation method is as follows:

1.1 rice powder emulsifying

Get rice and pulverize, cross 100 mesh sieves, add 2.5～3 times of water gagings, heat under the stirring, 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, for subsequent use;

1.2 mixing batter

Open the agitator of above-mentioned adjunce copper, add respectively in order phospholipid solution, medicine and correctives in the prescription, stirred 30 minutes, be mixed with the phospholipid emulsion, for subsequent use;

1.3 copy film

Above-mentioned phospholipid emulsion joined copy in the film machine, adjust width and the thickness of slit by required specification, spread to homogeneous film, dry under 60 ℃ of temperature, or carry out lyophilization at-20 ℃, injection molding is in blocks, and get final product.

According to claim 1 a kind of can be in the oral cavity the rapid speed of the disintegrate preparation method that collapses the dried poultice of paper mold, it is characterized in that: described medicine is folk prescription or compound recipe Western medicine raw material, or folk prescription or compound Chinese medicine extract.

According to claim 1 a kind of can be in the oral cavity the rapid speed of the disintegrate preparation method that collapses the dried poultice of paper mold, it is characterized in that: described correctives is one or more mixture in sucrose, lactose, stevioside, aspartame, simple syrup, Oleum menthae, apple essence, flavoring orange essence, the flavoring banana essence.

According to claim 1 a kind of can be in the oral cavity the rapid speed of the disintegrate preparation method that collapses the dried poultice of paper mold, it is characterized in that: described rice is through eluriating, dry, shell gained with rice.

According to claim 1 a kind of can be in the oral cavity the rapid speed of the disintegrate preparation method that collapses the dried poultice of paper mold, it is characterized in that: described phospholipid solution is prepared by following method: be first that 1%～2% sodium hydroxide solution is heated to 85～100 ℃ with concentration, under stirring state, add phospholipid, make it all to be dissolved in the sodium hydroxide solution, let cool to 30～40 ℃, making its pH value is 8～9, crosses 100 mesh sieves, and get final product.

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