CN105560199B - A kind of children's domperidone oral disintegrating tablet and preparation method thereof - Google Patents
A kind of children's domperidone oral disintegrating tablet and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
Abstract
The invention discloses a kind of children's domperidone oral disintegrating tablets and preparation method thereof.The oral disintegrating tablet is made of following raw material by mass parts：10~30 parts of domperidone, 10~30 parts of fatty glyceride, 5~10 parts of Tween 80,900~2700 parts of white sugar, 2~5 parts of crospovidone, 10~30 parts of mannitol, 0.01~0.05 part of essence, 0.2~0.5 part of magnesium stearate, 0.2~0.5 part of superfine silica gel powder.Oral disintegrating tablet medicament is made using domperidone as effective ingredient, by the technique of innovation in the present invention.Domperidone oral disintegrating tablet prepared by the present invention successfully solves the problems such as low drug dissolution and drug bitterness sense, has good effect for children's functional dyspepsia.
Description
Technical field
The present invention relates to a kind of drugs of stomach and intestine motivator, and in particular to a kind of children's domperidone oral cavity disintegration tablet and its system
Preparation Method belongs to pharmaceutical technology field.
Background technology
Domperidone is a kind of benzimidazole analog derivative of synthesis, it be a kind of dopamine with emesis effect by
Body antagonist not easily passs through blood-brain barrier and into National People's Congress's brain.Domperidone acts on the chemoreceptor trigger zone outside blood-brain barrier,
Therefore central nervous system is hardly acted on；Domperidone selective exclusion dopamine 2 (DA2) receptor, mainly acts on week
Enclose nervous system.Since DA2 receptors are similarly the major receptors of gastrointestinal tract, DA2 receptor antagonists can reduce dopamine
The pipe smooth muscle relaxation of mediation.In the gastrointestinal tract, domperidone can increase gastral power as a kind of dynamics-promoting medicine.
Apositia caused by children's gastric dynamic dysfunction is also known as children's functional dyspepsia, refers to that children move due to a lack of stomach
Symptom caused by power based on long period anorexia or anorexia, there is morbidity throughout the year.Apositia is to children
Growth and development, nutrition condition, intellectual development have an impact.Long-term apocleisis can lead to malnutritional anemia, rickets and exempt from
Epidemic disease power is low, repeated respiratory infections etc. occurs.In recent years, with many factors such as the change of society, school, family and environment
Effect, the incidence of functional dyspepsia of children in apparent ascendant trend, seriously affect the general level of the health of infant, study into
Achievement and quality of life bring larger psychological pressure and mental burden to parent.Therefore, cost-effective dyskinesis is found
The drug of type functional dyspepsia FD is of great significance to the researcher in terms of base's paediatrics.
Chinese patent document CN102125528A discloses domperidone oral disintegrating tablet, selected in preparation method pharmaceutically to fit
Excipient is selected from the several of filler, odor mask, disintegrant, surfactant, adhesive, lubricant and glidant and mixes
Close object.More than patent is disadvantageous in that, odor mask aspartame, stevioside, fructose, grape are added in the preparation method
Sugar, syrup, honey, xylitol, mannitol, lactose, sorbierite, maltitol, glycyrrhizin.The patent not to domperidone into
The effective processing of row, only adds in odor mask, is that can not solve domperidone bitterness sense.
Chinese patent document CN101804036A discloses domperidone orally disintegrating tablet and preparation method thereof, formula
It is：Domperidone, lactose, erythrose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, saccharin sodium, magnesium stearate.Its preparation side
Method is：Domperidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, erythrose, magnesium stearate are handled, mixing, ethyl alcohol system
Grain, whole grain, tabletting.More than patent is disadvantageous in that erythrose, saccharin sodium are corrigent and nothing in selected auxiliary material
Method solves domperidone bitterness sense.
Chinese patent document CN101394850A discloses a kind of Orodispersible domperidone tablets；The patent is by following component
Composition：Domperidone, mannitol, maltodextrin, croscarmellose sodium, microcrystalline cellulose, acesulfame potassium,
Fragrance, ammonium glycyrrhetate, magnesium stearate.More than patent preferably resolves domperidone bitterness sense, but is disadvantageous in that, institute
The auxiliary material and preparation process of choosing influence the mobile performance of mixture in tableting processes, and tablet can be caused piece weight shakiness etc. occur
Problem.
Due to domperidone experiment proves that no matter shared recipe quantity number, can all leave uncomfortable bitterness in the oral cavity
Sense, children often can generate gastric disorder causing nausea phenomenon when taking tablet, suspension, so as to cause medication in children difficult.Develop dopan
Vertical ketone novel formulation, particularly domperidone oral cavity disintegration tablet be solve children at present there is an urgent need for clinical problem.Using routine prescription and
Conventional fabrication process, it is difficult to solve drug dissolution and bitterness sense technical barrier and according to domestic existing auxiliary material and life
Production condition, preparation process are difficult to ensure that with the trouble under relatively low production cost and convenient for children, dysphagia or particular surroundings
Person's medication, at present oral drugs flavoring and taste masking are an urgent demands of pediatric drugs.
Invention content
In view of the deficiencies of the prior art, the present invention provides a kind of children's domperidone oral disintegrating tablet and preparation method thereof, passes through
The auxiliary material selection of innovation and the auxiliary material proportion of optimization and the preparation process of innovation, successfully solve that drug dissolution is low and medicine
The problems such as object bitterness sense.
Technical solution of the present invention is as follows：
A kind of children's domperidone oral disintegrating tablet, is made of following raw material by mass parts：
, according to the invention it is preferred to：
A kind of children's domperidone oral disintegrating tablet, is made of following raw material by mass parts：
According to the present invention, further preferred：
A kind of children's domperidone oral disintegrating tablet, is made of following raw material by mass parts：
Alternatively, a kind of children's domperidone oral disintegrating tablet, is made of following raw material by mass parts：
Alternatively, a kind of children's domperidone oral disintegrating tablet, is made of following raw material by mass parts：
Children's domperidone oral disintegrating tablet of the present invention, used raw material it is not specified be conventional production purchased in market
Product.
A kind of preparation method of children's domperidone oral disintegrating tablet, includes the following steps：
(1) domperidone is crushed, crosses 140~160 mesh sieve, obtain the particle that average grain diameter is 21~45 μm, it is standby
With；
(2) white sugar of proportional quantity, crospovidone are crushed, crosses 100~120 mesh sieve, it is spare；
(3) fatty glyceride at 60 DEG C~80 DEG C is melted, after adding in the Tween 80 mixing of proportional quantity, weighs proportional quantity
Domperidone, add 1/3 (W/W) white sugar of proportional quantity, after room temperature cooling and solidifying, crushed 10~20 mesh sieve；
(4) mannitol is dissolved in the mixed solution that 50~60% (W/W) are configured in deionized water, then adds in step
(3) material after abundant mixing, is put into freeze drying box；Freeze dryer is opened, freeze-drying shelf is down to -40 DEG C~-50 DEG C, waits to mix
It closes solution temperature and is down to -30 DEG C~-40 DEG C, pre-freeze keeps the temperature 2~3 hours；Start to vacuumize, then gradually raise the temperature to -10
DEG C~-15 DEG C, it is dried in vacuo 15~20 hours；Shelf temperature is improved again to 30 DEG C~40 DEG C, is kept for 1~2 hour, vacuum degree
Maintain 0~10Pa, until product moisture terminates in 2~6% (W/W) freeze-dryings, outlet to obtain the final product；
(5) by the crospovidone of proportional quantity and deionized water mixing, remaining 2/3 white sugar, heating 60~80 are added in
After DEG C, room temperature is down to, is pelletized；Then it is dried for 50~60 DEG C, until moisture is 2%~6% (W/W)；
(6) by step (4) and (5) particle and essence, magnesium stearate, superfine silica gel powder mixing, tabletting to get.
According to currently preferred, the domperidone described in step (1) crushes, and crosses 150~160 mesh sieve, uses laser
Granulometry obtains average grain diameter at 21~32 μm.
According to currently preferred, the product moisture described in step (4) is controlled in 2%~5% (W/W).
According to the present invention it is further preferred that a kind of preparation method of children's domperidone oral disintegrating tablet, includes the following steps：
(1) domperidone is crushed, crosses 150 mesh sieve, it is 28~32 μm to obtain average grain diameter, spare；
(2) white sugar of proportional quantity, crospovidone are crushed, crosses 110 mesh sieve, it is spare；
(3) fatty glyceride is weighed into proportional quantity after 60 DEG C~80 DEG C meltings, addition proportional quantity Tween 80 mixing
Domperidone adds 1/3 (W/W) white sugar of proportional quantity, after room temperature cools and solidifies, crushed 15 mesh sieve；
(4) mannitol is dissolved in the mixed solution that 55% (W/W) is configured in deionized water, then adds in step (3)
Material after abundant mixing, is put into freeze drying box.Freeze dryer is opened, freeze-drying shelf is down to -40 DEG C~-50 DEG C, solution to be mixed
Temperature is down to -30 DEG C~-40 DEG C, and pre-freeze keeps the temperature 2~3 hours；Start to vacuumize, then gradually raise the temperature to -10 DEG C~-15
DEG C, it is dried in vacuo 15~20 hours；Shelf temperature is improved again to 30 DEG C~40 DEG C, is kept for 1~2 hour, vacuum degree maintains 0
~10Pa, until product moisture terminates in 2~5% (W/W) freeze-dryings, outlet to obtain the final product；
(5) by the crospovidone of proportional quantity and deionized water mixing, remaining 2/3 white sugar is added in, 60 DEG C of heating~
After 80 DEG C, room temperature is down to, is pelletized；It is dried at 50 DEG C~60 DEG C, until moisture is 2%~6% (W/W)；
(6) by step (4) and (5) particle and essence, magnesium stearate, superfine silica gel powder mixing, tabletting to get.
Room temperature of the present invention means 10~30 DEG C.
With reference to experimental example, the present invention is described further, but not limited to this.
Experimental example 1：The determination experiment of domperidone grain size and particle diameter distribution
Domperidone is a kind of benzimidazole analog derivative synthesized more, almost insoluble in water, in order to make it in sweet dew
Uniformly disperse in alcohol, the sedimentation volume ratio for reaching qualified is the technological difficulties in dry suspensoid agent preparation process, and raw material granularity is
One important influence factor first has to determine the granularity of raw material in dry suspensoid agent production.Therefore domperidone is selected through ultra micro
It crushes.
1st, domperidone grain size and particle diameter distribution
The particle diameter distribution of domperidone is measured using sieve analysis method, every batch of is measured 50g domperidone particles.Make
It is measured with pulp classifier and standard testing sieve, amplitude 1.5mm, time of vibration 20min.The specification of sieve is 110 mesh, 120
Mesh, 130 mesh, 140 mesh, 150 mesh and 160 mesh.It is stood using purchased from the Laser diffraction particle size analysis-e/or determining dopan of Marlven2000
Average grain diameter under ketone particle screening, the average grain diameter and particle diameter distribution of domperidone are as shown in table 1.
Determination of particle size distribution (D50):Malvern2000 or the comparable laser particle size analyzer of performance, take this product about
0.12g makes detector shading rate add water 800mL in 8~20% ranges, stirred 15 minutes with 3000 turns per minute of rotating speed or
It is stirred with 3000 turns per minute of rotating speed, and ultrasonic 2~3 minutes (ultrasonic power 16W, 3 μm of amplitude) simultaneously, checks, take in accordance with the law
The continuous average value for measuring 3 times should meet following table regulation.
The average grain diameter and particle diameter distribution of 1 domperidone of table
Interpretation of result：With the increase of mesh number, domperidone grain amount also increases as, the particle under sieving, average grain
Diameter constantly reduces.
2nd, granularity is observed
It is prepared by 2.1 domperidone mixtures
Sample preparation sample 1：The domperidone of 130 mesh is prepared according to (3) method the step of embodiment 1；Sample 2：It will
The domperidone of 140 mesh is prepared according to (3) method the step of embodiment 1.
Granularity is lyophilized in 2.2 domperidone mixture crystallites
The drop respectively of obtained sample 1, sample 2 is taken to cover coverslip on glass slide, observe microcrystal grain under the microscope
Degree (amplification l0 × 10 or 10 × 40 times).The uniformity coefficient of the smaller object lens observation particle distribution of selection amplification factor first.So
After representational position is selected to take pictures, shooting photo should be no less than 15, more than 50 observation crystallite crystal form total number of particles.Crystallite
Crystal particle counts and the calculating Image-pro calculation procedures of particle size.The distributed data of every photo particle is concentrated whole
Reason, so as to obtain crystallite crystal particle size distribution ratio.
3rd, result
The result is shown in Figure 1 (sample 1) and Fig. 2 (sample 2)；It can be seen that by Fig. 1,2,2 gained crystallite crystal particle of sample is apparent
Less than normal, 38 μm of crystallite crystal particle proportions of grain size ＜ are up to 93%, 2 47 μm of gained grain size ＞ of sample less than 7%, grain size
52 μm of ＞'s only accounts for 0.3%.In contrast, sample 1 38 μm of gained grain size ＞ accounts for 55%, and 52 μm of grain size ＞'s accounts for 19%.System
Meter, which is learned, to be examined, two kinds of significant differences of crystallite crystal particle grain size (P ＜ 0.01).
Evaluation of result：Crystallite crystal particle is white powder, and feel is moist.It is observed with light microscope, it is seen that micro-
Brilliant particle also there are no domperidone granule medicament without phenomenon is adhered.The crystallite granularity that the domperidone of 130 mesh is formed compared with
Greatly, therefore particles more than 140 mesh is selected.
Experimental example 2：The research experiment of odor mask in domperidone oral cavity disintegration tablet
Taste bud is gustatory receptor, is mainly distributed in back and the lingual papilla of lingual margin, is also dispersed in pars oralis pharyngis mucous membrane.Taste
Flower bud is in cepaeform structure, containing 50~100 gustatories.The surface protein of taste receptors or the hole sample with being referred to as ion channel
Protein-interacting causes intracellular current potential to change, and triggers it and sends chemical signal, which is reconverted into neurotransmitter and is passed to brain
It is defeated.
This experiment uses lipid microsphere technology, reduces drug and dissolves and discharge in saliva, reduces drug molecule and taste bud
Combination, cover bitter taste of drug.
This product is oral cavity disintegration tablet, and according to the property of domperidone oral cavity disintegration tablet, therefore, our Formulation is tentatively selected
Common fatty glyceride and Tween 80 etc. are aided with other auxiliary materials, to carry out the screening of prescription and optimization, with without bitter, delicious
Can mouthfeel be inspection target, carry out the screening of prescription.The prescription of design is as follows：It is shown in Table 2, table 3；
2 supplementary material of table forms table
| Name of material | Purposes |
| Domperidone | Raw material |
| Fatty glyceride | Odor mask |
| Tween 80 | Surfactant |
| Mannitol | Diluent, skeleton agent |
| White sugar | Corrigent, adhesive |
| Essence | Corrigent |
| Crospovidone | Disintegrant |
| Superfine silica gel powder | Glidant |
| Magnesium stearate | Lubricant |
3 each supplementary material dosage the selection result (mass ratio) of table
| Material | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 |
| Domperidone | 10 | 10 | 10 | 10 | 10 |
| Fatty glyceride | 5 | 10 | 15 | 20 | 25 |
| Tween 80 | 4 | 5 | 6 | 8 | 10 |
| Mannitol | 10 | 10 | 10 | 10 | 10 |
| White sugar | 900 | 900 | 900 | 900 | 900 |
| Essence | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 |
| Crospovidone | 2 | 2 | 2 | 2 | 2 |
| Superfine silica gel powder | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
| Magnesium stearate | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
Prescription evaluation and result：
Prescription 1：Tablet uniform color, smooth appearance, no grittiness have stronger bitterness sense；
Prescription 2：Tablet uniform color, smooth appearance, no grittiness, no bitterness sense；
Prescription 3：Tablet uniform color, smooth appearance, no grittiness, no bitterness sense；
Prescription 4：Tablet uniform color, smooth appearance, no grittiness, no bitterness sense；
Prescription 5：Tablet uniform color, smooth appearance, no grittiness, no bitterness sense.
As a result：Learnt by more than Prescription evaluation, prescription 1 has a stronger bitterness sense, optimizing prescriptions 2,3,4,5 without bitterness sense,
Determine the dosage of fatty glyceride in prescription 2,3,4,5, the prescription preferable amount as this preparation odor mask.
Experimental example 3：Prescription screening is tested
The auxiliary material of oral disintegrating tablet institute of the present invention plan is pharmaceutic adjuvant grade, for this preparation characteristic, Design Fundamentals screening
Prescription.Dissolution rate is investigated respectively, and pays attention to observing preparation process phenomenon.It is shown in Table 4：
4 domperidone oral cavity disintegration tablet prescription screening (unit of table：g)
| Component | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 |
| Domperidone | 5 | 10 | 15 | 20 | 25 | 25 |
| Fatty glyceride | 4 | 10 | 15 | 20 | 25 | 25 |
| Tween 80 | 2 | 5 | 6 | 7 | 8 | 8 |
| Mannitol | 4 | 10 | 15 | 20 | 25 | 25 |
| White sugar | 400 | 900 | 1300 | 1600 | 2000 | 2400 |
| Essence | 0.01 | 0.01 | 0.02 | 0.02 | 0.03 | 0.04 |
| Crospovidone | 1 | 2 | 3 | 4 | 4 | 4 |
| Superfine silica gel powder | 0.1 | 0.2 | 0.3 | 0.4 | 0.4 | 0.4 |
| Magnesium stearate | 0.1 | 0.2 | 0.3 | 0.4 | 0.4 | 0.4 |
Due to easy to absorb moisture of the raw material used in domperidone oral cavity disintegration tablet itself, the distinctive physics such as mobility is bad are special
Property, it is pelletized using conventional solid pharmaceutical preparation auxiliary material, main problem present in preparation process is that mobility is bad, when leading to tabletting
Piece weight is unstable, differs greatly, and secondly the present invention is due to domperidone drug bitterness, using odor mask is added in, due to odor mask
It adds in, influences the dissolution of drug.In order to solve this problem, the present invention studies the prescription and technique of the product, with sucrose
For major auxiliary burden, the mobility of particle can be obviously improved with the made particle of certain density proportioning.The quality of mobility of particle
It determines domperidone oral cavity disintegration tablet content uniformity important indicator, turnover rate is commonly used in pharmacy and angle of repose represents that angle of repose is got over
Small, mobility of particle is better.
It tests to each prescription, as a result see the table below 5：
5 domperidone oral cavity disintegration tablet prescription screening experimental examination result of table
Interpretation of result：1 dissolution rate of prescription is preferable, but angle of repose is larger, and the mobility of particle is poor, domperidone oral disintegrating tablet
Tablet weight variation is larger during tabletting.2~6 dissolution rate of prescription is preferable, angle of repose is smaller, and the mobility of particle is preferable, and tablet weight variation is equal
In limit, gained domperidone oral disintegrating tablet indices are good.So determine the optimal prescription that prescription 2~6 is this preparation.
Experimental example 4：Domperidone orally disintegrating tablet disintegration time limited checking experiment
Oral disnitegration tablet is a kind of innovation dosage form developed in recent years, and oral disintegrating tablet is not need to water in oral cavity to be disintegrated
Or the tablet of dissolving, facilitate old man, infant, dysphagia or patient takes in special circumstances.It is put in human mouth, absorbs water
Point, it is rapid to be disintegrated, into the fine powder of no sand type, enter alimentary canal with swallowing act, generation system acts on after absorption.
For oral disnitegration tablet disintegration time within 1 minute, medium first choice water, dosage should be less than 2mL, water bath with thermostatic control pot temperature
For (37 ± 0.5) DEG C, using static method, 710 μm of ＜ is answered in the granularity control of stainless steel basket used.
1st, material and instrument
Prepared by domperidone orally disintegrating tablet Samples EXAMPLE 1, embodiment 2, embodiment 3, lift disintegration tester；Glass tries
Pipe (long (95 ± 2.5) mm, internal diameter 11.5mm, wall thickness 1.3mm；Standard screen；Intelligent disintegration tester；Oral disnitegration tablet special stainless steel
Basket.
2nd, method and result
2.1《Chinese Pharmacopoeia》Method checks that sample disintegration time limited presses《The bottom sheet of annex XA of China's coastal port two
Agent disintegration time limited inspection method.
Test tube equipped with 2mL water is vertically put into the water bath with thermostatic control of (37 ± 0.5) DEG C, makes the 1/3 of test tube to be submerged in water
Under bath foam face, stainless steel basket is put into test tube, treats that water temperature balances inside and outside test tube, takes each 6 of 3 batch samples, is placed in respectively
In stainless steel basket, 1 is put every time, the timing since tablet contacts the water surface, the continuous disintegration of tablet, when tablet shows without disintegration in water
As when stop timing, at once quickly by the stainless steel basket lift-off water surface, should be retained on sieve without apparent bulky grain, if there is foam-like
Emplastic attaches to screen surface, should be regarded as being disintegrated, measurement result is shown in Table 6.
6 device of table checks sample disintegration time limited result
The correlation experiment that 2.2 sample inside and outside disintegration time limiteds checked
Using the sample that lot number is 20041001 as trial target, ifs vitro disintegration overtime check is using method under item；It collapses in vivo
Solution overtime check carries out in 6 volunteers, and 1 sample is placed on tongue by everyone, immediately with manual time-keeping, until sample is in mouth
Until intracavitary disintegration completely, its disintegration time is measured.The result shows that the good relationship that inside and outside disintegration time limited checks (is shown in Table
7)。
7 inside and outside disintegration time limited inspection result of table
It discusses：This experimental result is shown, the disintegration time limited of oral disnitegration tablet, is met related request, can more accurately be examined
Measure whether sample can completely be disintegrated in 1 minute in 2mL water and be checked by 710 μm of sieves, and with internal disintegration time limited
Has good correlation.
Experimental example 5：Domperidone orally disintegrating tablet dissolution in vitro is tested
1st, instrument and drug：Ultraviolet-uisible spectrophotometer, dissolution tester；Domperidone orally disintegrating tablet (is implemented
Prepared by example 1)；Control sample (ordinary tablet, Xian-Janssen Pharmaceutical Ltd.'s production Domperidone Tablets).
2nd, experimental method
The preparation of In vitro dissolution rate bioassay standard curve：Domperidone reference substance about 15mg is taken, it is accurately weighed, it puts
In 100mL measuring bottles, proper amount of methanol is added to dissolve, then scale is diluted to dissolution medium (determination condition for referring to dissolution rate), shaken
Even, accurate measurement 0.5,1,2,3,4mL, put in 25mL measuring bottles, are diluted to scale with dissolution medium, shake up respectively, according to light splitting light
Degree method measures trap A at 284nm wavelength, and A is returned with concentration C (μ g/mL)；
It obtains normal equation C=34.7A+6.53 × 10 (r=0.9999).
The determination condition paddle method of dissolution rate is carried out by Chinese Pharmacopoeia version prescriptive procedure in 2010.Measuring wavelength is
284nm；Dissolution medium is to take sodium chloride 2g, and appropriate amount of water is added to make dissolving, adds hydrochloric acid 7mL, adds water and be diluted to 1000mL, shake up,
It is dissolution medium to take 500mL；Rotating speed (100 ± 1) r/min；Temperature (37 ± 0.5) DEG C.Respectively at 2,5,10,20,30 and 45min
5mL is sampled, while supplements synthermal same volume dissolution medium, crosses 0.8 μm of miillpore filter, subsequent filtrate is taken to measure A, by standard curve
Drug concentration is obtained in equation, and calculates cumulative defaultlogic.
Both embodiment 1 and commercially available dissolution determination carry out dissolution rate measure under these conditions respectively, and compare
The cumulative defaultlogic of the two, is as a result shown in Fig. 3.
This experiment shows domperidone orally disintegrating tablet dissolution rate far faster than ordinary tablet, and the preparation of oral disnitegration tablet
Technique, by low temperature freeze drying process, makes its oral disnitegration tablet become a kind of ideal quick-release using mannitol and odor mask is added in
Mouth collapses agent, and there is sale in the country to auxiliary material used at present.
Experimental example 6：Supplementary material compatibility experiments
The supplementary material compatibility test selected during domperidone oral cavity disintegration tablet drug research of the present invention is as follows；
By raw material and selected auxiliary material physical mixed by a certain percentage, according to Chinese Pharmacopoeia 2010 editions two (annex XIXC) original
Medicine and the experimental method of influence factor in pharmaceutical preparation stability test guideline are expected, respectively in 60 DEG C ± 2 DEG C of high temperature, humidity
90% ± 5%, it is placed 10 days under conditions of strong 4500 ± 500lx of light, checks and place front and rear change.Result of the test is as follows：
1st, hot conditions supplementary material compatibility experiments
Supplementary material is mixed according to a certain percentage, exposure was put under the conditions of 60 DEG C ± 2 DEG C of high temperature 10 days, respectively at 0,5,10 day
Sampling, inspection result see below 8 tables.
8 supplementary material compatibility test high temperature of table (60 DEG C ± 2 DEG C) 10 days
| Project name | Ratio | Character | Related substance (%) | Content (%) |
| Domperidone | — | It is white powder, odorless | 0.19 | 99.61 |
| Domperidone+fatty glyceride | 1：5 | It is off-white powder, odorless | 0.20 | 99.57 |
| Domperidone+Tween 80 | 1：5 | It is white powder, odorless | 0.20 | 99.49 |
| Domperidone+mannitol | 1：5 | It is white powder, odorless | 0.19 | 99.63 |
| Domperidone+white sugar | 1：5 | It is white powder, odorless | 0.19 | 99.52 |
| Domperidone+essence | 1：5 | It is white powder, odorless | 0.19 | 99.54 |
| Domperidone+crospovidone | 1：5 | It is white powder, odorless | 0.20 | 99.36 |
| Domperidone+superfine silica gel powder | 20：1 | It is white powder, odorless | 0.19 | 99.51 |
| Domperidone+magnesium stearate | 20：1 | It is white powder, odorless | 0.19 | 99.61 |
Through 10 days compatibility tests under the conditions of 60 DEG C ± 2 DEG C of high temperature, each auxiliary material character, related substance, content are as a result shown
It is unchanged.
The above result shows that domperidone is good with auxiliary material compatibility under the conditions of 60 DEG C ± 2 DEG C of high temperature.
2nd, super-humid conditions supplementary material compatibility experiments
Supplementary material is mixed according to a certain percentage, exposure is put under the conditions of high humidity (90% ± 5%) 10 days, respectively at 0,5,10
Its sampling, measures indices, as a result sees 9 tables.
Sample is divides equally three parts of progress, three condition tests after weighing, therefore 10 days results of high humidity were the same as high temperature 10 days.
9 supplementary material compatibility test high humidity (90% ± 5%) of table 10 days
| Project name | Ratio | Character | Related substance (%) | Content (%) |
| Domperidone | — | It is white powder, odorless | 0.19 | 99.56 |
| Domperidone+fatty glyceride | 1：5 | It is off-white powder, odorless | 0.20 | 99.36 |
| Domperidone+Tween 80 | 1：5 | It is white powder, odorless | 0.20 | 99.51 |
| Domperidone+mannitol | 1：5 | It is white powder, odorless | 0.19 | 99.63 |
| Domperidone+white sugar | 1：5 | It is white powder, odorless | 0.19 | 99.45 |
| Domperidone+essence | 1：5 | It is white powder, odorless | 0.19 | 99.52 |
| Domperidone+crospovidone | 1：5 | It is white powder, odorless | 0.20 | 99.42 |
| Domperidone+superfine silica gel powder | 20：1 | It is white powder, odorless | 0.19 | 99.58 |
| Domperidone+magnesium stearate | 20：1 | It is white powder, odorless | 0.19 | 99.53 |
Through 10 days compatibility tests under the conditions of high humidity 90% ± 5%, each auxiliary material character, related substance, content are as a result shown
It is unchanged.
The above result shows that domperidone is good with auxiliary material compatibility under the conditions of high humidity 90% ± 5%.Compbined test knot
Fruit shows that preparation should be sealed.
3rd, illumination condition supplementary material compatibility test
Supplementary material is mixed according to a certain percentage, exposure is put under the conditions of illumination (4500 ± 500lx) 10 days, respectively at 0,5,
It samples within 10 days, measures domperidone content compared with 0 day, the results are shown in Table 10.0 day result of illumination was the same as high temperature 0 day.
10 supplementary material compatibility test illumination (4500 ± 500lx) of table 10 days
Through 10 days compatibility tests under the conditions of illumination (4500 ± 500lx), as a result show each auxiliary material character, related substance,
Content is unchanged,
The above result shows that domperidone oral disintegrating tablet is good with auxiliary material compatibility under the conditions of illumination (4500 ± 500lx).
It is shown under three kinds of experimental conditions through supplementary material compatibility test, all samples items leading indicator relatively becomes with raw material without apparent
Change, show that domperidone is respectively provided with preferable compatibility with above-mentioned auxiliary material, selected auxiliary material is reasonable.
Experimental example 7：The human pharmacokinetics of domperidone oral cavity disintegration tablet and bioequivalence research experiment
In recent years, domestic and international drug research person in taste masking technology, reduce the Formulation of disagreeable taste in terms of carried out it is wide
General research.Wherein, solid dispersions are most direct, simple masking methods, and a physical barriers are provided for drug granule,
So as to reduce the contact between drug and taste bud, in addition some insoluble drugs may also function as with the effect for increasing dissolution.It is more
Pan Li ketone tastes are extremely bitter, influence patient medication, carry out taste masking processing using solid dispersion technology, can effectively cover bitter taste, add in
Appropriate corrigent further improves mouthfeel, substantially increases the compliance of patient's especially children.Mouth made from this experiment
Disintegrating tablet is in good taste, for this purpose, this experiment to the relative bioavailability of domperidone orally disintegrating tablet agent and domperidone tablet into
Row research, bioequivalence of the 2 kinds of preparations of evaluation in healthy human body, foundation is provided for clinical practice.
1st, materials and methods
1.1 drugs and instrument：Domperidone oral cavity disintegration tablet is by test preparation (embodiment 1, specification 10mg), Domperidone Tablets ginseng
Than preparation (Xi'an Yang Sen pharmaceutical Co. Ltds, 10mg/ pieces).Domperidone standard items (content 100%)；Acetonitrile (level-one chromatography
It is pure)；Sodium hydroxide, ether and potassium dihydrogen phosphate are that domestic analysis is pure.High performance liquid chromatograph, mobile phase：Acetonitrile：Phosphate
Buffer solution (O.02mol/L, potassium dihydrogen phosphate)=25：75(V：V).Flow velocity 1.0ml/min.4O DEG C of column temperature, excitation wavelength
For 285nm, launch wavelength 325nm.
1.2 subjects select
22 healthy male volunteers, average age for (33.9 ± 3.8) year, average weight is (64.4 ± 5.5) kg；
Subject's electrocardiogram, blood pressure, blood urine are conventional, hepatic and renal function inspection is normal；Without smoking, history of drinking history, tested first 2 weeks, do not take
Other used any drugs.Sign informed consent form.
3 groupings, administration and blood specimen collection
With random own control cross matching.It is empty after fasting to the 2nd day morning, acquisition blank blood after preceding 1 day supper
Abdomen takes orally domperidone orally disintegrating tablet 20mg, and drug is placed in lingual surface, is swallowed after rapid disintegration, not handy water delivery service；Or with temperature
Boiling water 200mL takes orally Domperidone Tablets 20mg；After medication in 2h, water restriction, after 2h, drinking-water is random；It takes medicine after 4h, provides
Unified standard meal.After 1st off-test 1 week, start the 2nd administration.
During experiment, no smoking, drink and drinks spirituosity, caffeine class beverage, forbids aggravating activities.Before administration
And administration after 0.08,0.25,0.5,0.75,1,1.5,2,3,4,6,8,12,24,30,36h extract veins of upper extremity blood 5mL, put liver
In test tube after plain anti-freezing, 3000r/min centrifugation 10min, separated plasma, blood plasma is preserved in -20 DEG C, spare.
4 determination of plasma concentration
4.1 chromatographic condition:Mobile phase is 0.02mol/L dipotassium hydrogen phosphates-acetonitrile (volume ratio 75:25, pH3.5)；Flow
For 1.0mL/min；Column temperature：40℃；Excitation wavelength：285nm；Launch wavelength 325nm.
The processing of 4.2 plasma samples
Precision measures plasma sample 1.0mL, 10mL tool plug glass of the merging containing internal standard (50ng/mL propranolols) 0.1mL
In glass test tube, 1.0mol/L sodium hydroxide 0.1mL are added in, mixing adds in dichloromethane 3mL；Vortex oscillation 3min, 4000r/
Min centrifuges 10min, draws lower floor's organic phase；Dichloromethane 3mL is added in, then is extracted 1 time, merges organic phase, in 40 DEG C of water-baths
In, it is dried up with nitrogen；Residue is dissolved with 200 μ l of 0.1mol/L hydrochloric acid, and 4000r/min centrifugation 10min take 8 μ l sample introductions.5 sides
The science of law is evaluated
It is prepared by 5.1 standard curves
It is accurate to add in domperidone titer in blank plasma 1.0mL, its concentration is made to be respectively 1,2,5,10,20,
30th, 40,50 μ g, internal standard (50ng/mL propranolols) 0.1mL, by being operated under plasma sample processing item in accordance with the law, 80 μ l of sample introduction, with
Testing concentration is abscissa, and the peak area ratio of determinand and internal standard compound is ordinate, is returned with weighted least-squares method
Return operation；
Regression equation：Y=0.023x+0.008, γ2=0.9992.
The range of linearity of domperidone is 1.0~50.0 μ g/L；It is minimum to be quantitatively limited to 1.0 μ g/L.
5.2 specificities are under this chromatographic condition, and the retention time of domperidone is 6.60min, the guarantor of internal standard propranolol
The time is stayed as 8.64min, disturbed specimen does not measure endogenous impurity in blood plasma.
The in a few days relative standard deviation RSD of 5.3 precision, 3 concentration (2,20,50 μ g/mL) basic, normal, high with the rate of recovery is
6.26%th, 4.68%, 2.96%；In the daytime relative standard deviation RSD is 3.95%, 4.03%, 2.63%.The rate of recovery of 3 concentration
Respectively 89.83%, 98.24% and 96.47%.
6 data processing variance analyses and Doubled haploid population
As a result it is as follows：
6.1 blood concentration-time curves
After 22 healthy volunteers take orally domperidone orally disintegrating tablet and ordinary tablet 20mg respectively, blood concentration-when
Half interval contour is shown in Fig. 4.
6.2 pharmacokinetic parameter
Its main pharmacokinetic parameter is shown in Table 11.The result shows that domperidone orally disintegrating tablet agent and Domperidone Tablets
The physiological disposition of agent is basically identical.
11 domperidone orally disintegrating tablet agent of table and the control of domperidone tablet
| Index | By test preparation | Reference preparation |
| t1/2(ke)(h) | 11.22±5.5 | 10.13±4.01 |
| tmax(h) | 0.83±0.28 | 0.91±0.47 |
| Cmax(μg/mL) | 40.43±12.88 | 42.31±20.31 |
| AUC0-t(μg.h/mL) | 187.61±81.20 | 189.07±97.68 |
| AUC0-∞(μg.h/mL) | 220.18±106.93 | 215.57±102.12 |
7 relative bioavailabilities
It is utilized with Relative biological of the trapezoidal faces area method estimation domperidone orally disintegrating tablet agent compared with domperidone tablet
It spends for (101.96 ± 16.06) %；By the AUC of 2 kinds of preparations0-1, cmax value after Logarithm conversion, carry out variance analysis show,
2 kinds of preparations ask that there was no significant difference (P ＞ 0.05)；It carries out Doubled haploid population and shows that 2 difference are not statistically significant.Prompting 2
Kind preparation bioequivalence in human body.
8 safety evaluatios
During experiment, after subject takes oral disnitegration tablet, no oral cavity grittiness, when average disintegration, asks about
0.5min.Subject occurs without any adverse drug reaction；Through laboratory examination, index is showed no exception.Show trial drug
Under test dose, there is preferable safety.
Beneficial effects of the present invention are as follows：
1st, the auxiliary material proportion and the system of innovation that domperidone oral disintegrating tablet of the present invention is selected and optimized by the auxiliary material of innovation
Standby technique solves patient's especially infant to the compliance of drug.The oral disintegrating tablet is and in good taste rapidly in intraoral disintegration,
Drug is i.e. into human body when not feeling its bitter taste, remaining only fragranced, the distinctive bitter taste of domperidone to overcoming and
It masks, this considerably increases the compliances of medication.
2nd, because present invention process operating process is extremely easy so that operation and process conditions are easy to grasp and implement, this
On the one hand sample improves yield rate, on the other hand solve the disadvantage that granulation destroys its raw material crystal form and causes poor taste；More
It is important to avoid that content caused by damp and hot factor declines, impurity increases, quality is more stablized, and is also easier to control, very
Suitable for industrialized big production.
3rd, domperidone oral disintegrating tablet of the invention successfully solves the problems, such as that drug dissolution is low, and drug dissolution is high,
Conducive to absorption, there is good effect for children's functional dyspepsia.
The above result shows that using the prescription and technique of innovation, the indices such as yield rate, mouthfeel of oral disintegrating tablet are apparent,
This absolutely proves that the prescription of innovation and technique are practicable.
Description of the drawings
Fig. 1 is domperidone and mannitol mixture freeze-dried powder (sample 1) microscope photo in experimental example 1；
Fig. 2 is domperidone and mannitol mixture freeze-dried powder (sample 2) microscope photo in experimental example 1；
Fig. 3 is domperidone orally disintegrating tablet and ordinary tablet dissolution in vitro empirical curve in experimental example 5, and ordinate is tired
Dissolution rate is counted, abscissa is the time；
Fig. 4 is domperidone orally disintegrating tablet and ordinary tablet in experimental example 7, and blood concentration-time curve, ordinate is blood
Concentration, abscissa are the time.
Specific embodiment
Below by specific embodiment and with reference to attached drawing, the present invention will be further described, but not limited to this.
Supplementary material explanation in embodiment：
| Supplementary material title | Manufacturing enterprise | Execution standard |
| Domperidone | Jiangsu Haosen Pharmaceutical Co., Ltd | 2010 editions two addendums of Chinese Pharmacopoeia |
| Fatty glyceride | Hunan Er-kang Pharmaceutical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
| Tween 80 | Hunan Er-kang Pharmaceutical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
| Mannitol | Hunan Er-kang Pharmaceutical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
| White sugar | Hunan Er-kang Pharmaceutical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
| Essence | Beijing Powdery Food Co., Ltd. | Meet national standard (GB2760-2007) |
| Crospovidone | Hunan Er-kang Pharmaceutical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
| Superfine silica gel powder | Hunan Er-kang Pharmaceutical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
| Magnesium stearate | Hunan Er-kang Pharmaceutical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
Involved device and equipment are solid pharmaceutical preparation production common apparatus in embodiment, and market is commercially available, is described as follows:
Universal high-efficiency pulverizer (model 30B), rectangular shaking screen (model FS-0.5M2-X), high-speed mixing granulating machine (type
Number GHL200), rotary granulator (model ZLB series 300D), three-dimensional motion mixer (model SYH-800) more than equipment：
Changzhou Teng Longyaohua equipment Co., Ltd is on sale.Laser particle size analyzer (model Mastersizer3000) (Britain).Freeze-drying
Machine (model LGJ-200F) Beijing development in science and technology Co., Ltd of Song Yuan Huaxing is on sale.Particle packaging machine (model YO-F100) Shanghai
Yu Ou particles packing machines factory is on sale.Full-automatic double charging high speed tablet presses (model GZPS-49)：Beijing member of Imperial Academy's space flight development in science and technology
Joint-stock company is on sale.
Below in conjunction with specific embodiment, the present invention will be further described.It should be understood that following embodiment is merely to illustrate this
Invention, not for restriction the scope of the present invention.
Embodiment 1, a kind of preparation method of children's domperidone oral cavity disintegration tablet
1st, a kind of children's domperidone oral cavity disintegration tablet, is made of following raw material by mass parts：
2nd, preparation method is as follows：
(1) domperidone is crushed, crosses 150 mesh sieve, it is 28~32 μm to obtain average grain diameter, spare；
(2) white sugar of proportional quantity, crospovidone are crushed, crosses 110 mesh sieve, it is spare；
(3) fatty glyceride is weighed into the more of proportional quantity after 60~80 DEG C of meltings, addition proportional quantity Tween 80 mixing
Pan Li ketone adds 1/3 (W/W) white sugar of proportional quantity, after room temperature cools and solidifies, crushed 15 mesh sieve；
(4) mannitol is dissolved in the mixed solution that 55% (W/W) is configured in deionized water, then adds in step (3)
Material after abundant mixing, is put into freeze drying box.Freeze dryer is opened, freeze-drying shelf is down to -40 DEG C~-50 DEG C, solution to be mixed
Temperature is down to -30 DEG C~-40 DEG C, and pre-freeze keeps the temperature 2~3 hours；Start to vacuumize, then gradually raise the temperature to -10 DEG C~-15
DEG C, slowly heating vacuum drying 15~20 hours；Shelf temperature is improved again to 30 DEG C~40 DEG C, is kept for 1~2 hour, vacuum
Degree maintains 0~10Pa, until product moisture terminates in 2~5% (W/W) freeze-dryings, outlet to obtain the final product；
(5) by the crospovidone of proportional quantity and deionized water mixing, remaining 2/3 white sugar, heating 60~80 are added in
After DEG C, room temperature is down to, is pelletized；It is dried at 50~60 DEG C, until moisture is 2~6% (W/W)；
(6) by step (4) and (5) particle and essence, magnesium stearate, superfine silica gel powder mixing, tabletting to get.
Embodiment 2, a kind of preparation method of children's domperidone oral cavity disintegration tablet
1st, a kind of children's domperidone oral cavity disintegration tablet, is made of following raw material by mass parts：
2nd, preparation method is as follows：
(1) domperidone is crushed, crosses 160 mesh sieve, obtain the particle that average grain diameter is 21~24 μm, it is spare；
(2) white sugar of proportional quantity, crospovidone are crushed, sieved with 100 mesh sieve, it is spare；
(3) fatty glyceride at 60~80 DEG C is melted, after adding in the Tween 80 mixing of proportional quantity, weighs proportional quantity
Domperidone adds 1/3 (W/W) white sugar of proportional quantity, after room temperature cools and solidifies, crushed 20 mesh sieve；
(4) mannitol is dissolved in the mixed solution that 60% (W/W) is configured in deionized water, then adds in step (3)
Material after abundant mixing, is put into freeze drying box；Freeze dryer is opened, freeze-drying shelf is down to -40 DEG C~-50 DEG C, solution to be mixed
Temperature is down to -30 DEG C~-40 DEG C, and pre-freeze keeps the temperature 2~3 hours；Start to vacuumize, then gradually raise the temperature to -10 DEG C~-15
DEG C, slowly heating vacuum drying 15~20 hours；Shelf temperature is improved again to 30 DEG C~40 DEG C, is kept for 1~2 hour, vacuum
Degree maintains 0~10Pa, until product moisture terminates in 2~5% (W/W) freeze-dryings, outlet to obtain the final product；
(5) by the crospovidone of proportional quantity and deionized water mixing, remaining 2/3 white sugar, heating 60~80 are added in
After DEG C, room temperature is down to, is pelletized；Then it is dried for 50~60 DEG C, until moisture is 2~6% (W/W)；
(6) by step (4) and (5) particle and essence, magnesium stearate, superfine silica gel powder mixing, tabletting to get.
Embodiment 3, a kind of preparation method of children's domperidone oral cavity disintegration tablet
1st, a kind of children's domperidone oral cavity disintegration tablet, is made of following raw material by mass parts：
2nd, preparation method is as follows：
(1) domperidone is crushed, crosses 155 mesh sieve, obtain the particle that average grain diameter is 24~28 μm, it is spare；
(2) white sugar of proportional quantity, crospovidone are crushed, crosses 120 mesh sieve, it is spare；
(3) fatty glyceride at 60~80 DEG C is melted, after adding in the Tween 80 mixing of proportional quantity, weighs proportional quantity
Domperidone adds 1/3 (W/W) white sugar of proportional quantity, after room temperature cools and solidifies, crushed 10 mesh sieve；
(4) mannitol is dissolved in the mixed solution that 50% (W/W) is configured in deionized water, then adds in step (3)
Material after abundant mixing, is put into freeze drying box；Freeze dryer is opened, freeze-drying shelf is down to -40 DEG C~-50 DEG C, solution to be mixed
Temperature is down to -30 DEG C~-40 DEG C, and pre-freeze keeps the temperature 2~3 hours；Start to vacuumize, then gradually raise the temperature to -10 DEG C~-15
DEG C, slowly heating vacuum drying 15~20 hours；Shelf temperature is improved again to 30 DEG C~40 DEG C, is kept for 1~2 hour, vacuum
Degree maintains 0~10Pa, until product moisture terminates in 2~5% (W/W) freeze-dryings, outlet to obtain the final product；
(5) by the crospovidone of proportional quantity and deionized water mixing, remaining 2/3 white sugar, heating 60~80 are added in
After DEG C, room temperature is down to, is pelletized；Then it is dried for 50~60 DEG C, until moisture is 2~6% (W/W)；
(6) by step (4) and (5) particle and essence, magnesium stearate, superfine silica gel powder mixing, tabletting to get.
Claims (9)
1. a kind of children's domperidone oral disintegrating tablet, which is characterized in that be made of following raw material by mass parts：
It is prepared by the following method：
(1) domperidone is crushed, crosses 140~160 mesh sieve, obtain the particle that average grain diameter is 21~45 μm, it is spare；
(2) white sugar of proportional quantity, crospovidone are crushed, crosses 100~120 mesh sieve, it is spare；
(3) fatty glyceride at 60~80 DEG C is melted, after adding in the Tween 80 mixing of proportional quantity, weighs the dopan of proportional quantity
Vertical ketone adds 1/3 (W/W) white sugar of proportional quantity, after room temperature cools and solidifies, crushed 10~20 mesh sieve；
(4) mannitol is dissolved in the mixed solution that 50~60% (W/W) are configured in deionized water, then adds in step (3)
Material after abundant mixing, is put into freeze drying box；Freeze dryer is opened, freeze-drying shelf is down to -40 DEG C~-50 DEG C, solution to be mixed
Temperature is down to -30 DEG C~-40 DEG C, and pre-freeze keeps the temperature 2~3 hours；Start to vacuumize, then gradually raise the temperature to -10 DEG C~-15
DEG C, it is dried in vacuo 15~20 hours；Shelf temperature is improved again to 30 DEG C~40 DEG C, is kept for 1~2 hour, vacuum degree maintains 0
~10Pa, until product moisture terminates in 2~6% (W/W) freeze-dryings, outlet to obtain the final product；
(5) by the crospovidone of proportional quantity and deionized water mixing, remaining 2/3 white sugar is added in, after 60~80 DEG C of heating,
Room temperature is down to, is pelletized；Then it is dried for 50~60 DEG C, until moisture is 2~6% (W/W)；
(6) by step (4) and (5) particle and essence, magnesium stearate, superfine silica gel powder mixing, tabletting to get.
2. children's domperidone oral disintegrating tablet as described in claim 1, which is characterized in that be made of following raw material by mass parts：
3. children's domperidone oral disintegrating tablet as claimed in claim 2, which is characterized in that be made of following raw material by mass parts：
4. children's domperidone oral disintegrating tablet as claimed in claim 2, which is characterized in that be made of following raw material by mass parts：
5. children's domperidone oral disintegrating tablet as claimed in claim 2, which is characterized in that be made of following raw material by mass parts：
6. the preparation method of children's domperidone oral disintegrating tablet as described in Claims 1 to 5 is any, includes the following steps：
(1) domperidone is crushed, crosses 140~160 mesh sieve, obtain the particle that average grain diameter is 21~45 μm, it is spare；
(2) white sugar of proportional quantity, crospovidone are crushed, crosses 100~120 mesh sieve, it is spare；
(3) fatty glyceride at 60~80 DEG C is melted, after adding in the Tween 80 mixing of proportional quantity, weighs the dopan of proportional quantity
Vertical ketone adds 1/3 (W/W) white sugar of proportional quantity, after room temperature cools and solidifies, crushed 10~20 mesh sieve；
(4) mannitol is dissolved in the mixed solution that 50~60% (W/W) are configured in deionized water, then adds in step (3)
Material after abundant mixing, is put into freeze drying box；Freeze dryer is opened, freeze-drying shelf is down to -40 DEG C~-50 DEG C, solution to be mixed
Temperature is down to -30 DEG C~-40 DEG C, and pre-freeze keeps the temperature 2~3 hours；Start to vacuumize, then gradually raise the temperature to -10 DEG C~-15
DEG C, it is dried in vacuo 15~20 hours；Shelf temperature is improved again to 30 DEG C~40 DEG C, is kept for 1~2 hour, vacuum degree maintains 0
~10Pa, until product moisture terminates in 2~6% (W/W) freeze-dryings, outlet to obtain the final product；
(5) by the crospovidone of proportional quantity and deionized water mixing, remaining 2/3 white sugar is added in, after 60~80 DEG C of heating,
Room temperature is down to, is pelletized；Then it is dried for 50~60 DEG C, until moisture is 2~6% (W/W)；
(6) by step (4) and (5) particle and essence, magnesium stearate, superfine silica gel powder mixing, tabletting to get.
7. the preparation method of children's domperidone oral disintegrating tablet as claimed in claim 6, which is characterized in that described in step (1)
Domperidone crushes, and crosses 150~160 mesh sieve.
8. the preparation method of children's domperidone oral disintegrating tablet as claimed in claim 6, which is characterized in that described in step (4)
Product moisture is controlled in 2~5% (W/W).
9. the preparation method of children's domperidone oral disintegrating tablet as claimed in claim 6, which is characterized in that include the following steps：
(1) domperidone is crushed, crosses 150 mesh sieve, it is 28~32 μm to obtain average grain diameter, spare；
(2) white sugar of proportional quantity, crospovidone are crushed, crosses 110 mesh sieve, it is spare；
(3) by fatty glyceride after 60~80 DEG C of meltings, addition proportional quantity Tween 80 mixing, the dopan for weighing proportional quantity is stood
Ketone adds 1/3 (W/W) white sugar of proportional quantity, after room temperature cools and solidifies, crushed 15 mesh sieve；
(4) mannitol is dissolved in the mixed solution that 55% (W/W) is configured in deionized water, then adds in the material of step (3),
After abundant mixing, it is put into freeze drying box；Freeze dryer is opened, freeze-drying shelf is down to -40 DEG C~-50 DEG C, solution temperature to be mixed
- 30 DEG C~-40 DEG C are down to, pre-freeze keeps the temperature 2~3 hours；Start to vacuumize, then gradually raise the temperature to -10 DEG C~-15 DEG C,
Vacuum drying 15~20 hours；Shelf temperature is improved again to 30 DEG C~40 DEG C, is kept for 1~2 hour, vacuum degree maintains 0~
10Pa, until product moisture terminates in 2~5% (W/W) freeze-dryings, outlet to obtain the final product；
(5) by the crospovidone of proportional quantity and deionized water mixing, remaining 2/3 white sugar is added in, after 60~80 DEG C of heating,
Room temperature is down to, is pelletized；It is dried at 50~60 DEG C, until moisture is 2~6% (W/W)；
(6) by step (4) and (5) particle and essence, magnesium stearate, superfine silica gel powder mixing, tabletting to get.
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| CN106176647A (en) * | 2016-08-30 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of fertile for western spit of fland oral cavity disintegration tablet and preparation method thereof |
| CN106265569A (en) * | 2016-08-31 | 2017-01-04 | 佛山市弘泰药物研发有限公司 | A kind of everolimus oral cavity disintegration tablet and preparation method thereof |
| CN106236723A (en) * | 2016-09-17 | 2016-12-21 | 佛山市弘泰药物研发有限公司 | A kind of roflumilast oral cavity disintegration tablet and preparation method thereof |
| CN110151711B (en) * | 2019-04-25 | 2021-06-15 | 广东人人康药业有限公司 | Domperidone orally disintegrating tablet and preparation method thereof |
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