CN102716099A - Levocetirizine hydrochloride chewable tablet and preparation method thereof - Google Patents
Levocetirizine hydrochloride chewable tablet and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a levocetirizine hydrochloride chewable tablet for relieving hypersensitivity caused by allergy diseases and the preparation technology thereof. Levocetirizine hydrochloride has stronger bitterness, in the invention, by adopting the composite of Beta-cyclodextrin and microcrystalline cellulose, the medicine is prepared to be inclusion compound so as to cover up the bitterness of the medicine, the prepared medicine is better in mouth-feel and is convenient to take, the process operability in preparing the inclusion compound and the stability of the levocetirizine hydrochloride chewable tablet are enhanced at the same time, the levocetirizine hydrochloride chewable tablet is particularly suitable for old and child patients having difficulty in swallowing, enhances the compliance of the patients and has a better marketable value.
Description
Technical field
The present invention relates to a kind of allergic symptom that causes by allergic disease that is used to alleviate; As: the levo-cetirizine hydrochloride chewable tablet of Mucocutaneous anaphylactic diseases such as allergic rhinitis (allergic symptom that comprises eyes), urticaria, vasodilation, contact dermatitis, insect bite dermatitis belongs to field of pharmaceutical preparations.
Background technology
The levo-cetirizine hydrochloride oral absorption is rapid, and bioavailability is higher, and the protein binding rate of these article is 96%; Concentration in brain is lower than 1/10 of PC; These article were eliminated half-life 7-8 hour without liver metabolism, most with the original shape medicament forms through RE; Excretion accounts for 85% in the urine, accounts for 13% in the feces.
At present, levo-cetirizine hydrochloride is a line medication of treating anaphylactic disease clinically, and antiinflammatory and anti-allergic effects are preferably arranged, and effect is strong and lasting, and curative effect is better than existing all antihistaminics, has obtained extensive use clinically.But because mostly dosage form commonly used clinically is conventional tablet or capsule, gerontal patient or child for a lot of dysphagias take inconvenience, and compliance is relatively poor; For anhydrous special circumstances, like what need take medicine immediately, it is very difficult taking conventional tablet or capsule in addition.Therefore be necessary to develop a kind of gerontal patient of being suitable for and children taking, the while does not need water delivery service and dosage form easy to carry.
At present, levo-cetirizine hydrochloride gone on the market both at home and abroad conventional tablet, dispersible tablet, capsule and oral administration solution still do not have the chewable tablet listing.Because the levo-cetirizine hydrochloride crude drug has serious pained mouthfeel, the oral cavity chewable tablet of therefore taking like a shot for a kind of patient of exploitation, the disagreeable taste of covering medicine becomes a key problem in technology link.The Chinese patent ZL03807044.8 of Pfizer discloses a kind of delicious chewing tablet of cetirizine agent; Wherein adopt cyclodextrin as inclusion agents; Covered bitterness to a certain extent although utilize the clathration of cyclodextrin; But heavier bitter plucked instrument sense is still arranged when chewing, and ill effect such as cause vomiting still is difficult to accepted by child or gerontal patient.
Summary of the invention
The object of the present invention is to provide a kind of oral levo-cetirizine hydrochloride chewable tablet that supplies; Through in said preparation, adding pharmaceutical fields such as enclose material, flavoring agent, filler, disintegrating agent and lubricant adjuvant commonly used; Prepared a kind of taste, mouthfeel is levo-cetirizine hydrochloride chewable tablet preferably all.Wherein beta-schardinger dextrin-and particle mean size between the 15-50 micron (preferably between the 10-45 micron; More preferably between the 15-42 micron; More preferably between the 20-40 micron; Between the 25-35 micron) first kind of microcrystalline Cellulose (in this application sometimes be called for short " microcrystalline Cellulose ") combine and carry out preparatory enclose for levo-cetirizine hydrochloride as enclose material (inclusion agents), significantly improve the effect that comprises to the levo-cetirizine hydrochloride of serious bitter taste, optimize the auxiliary agent of medicated layer simultaneously and select and consumption; Improve processability and disintegrative; Can make things convenient for the old man and the child of dysphagia to take medicine, increase patient's compliance, have market value preferably.Simultaneously, also to consider the influence of the selection of various components and amounts of components for chewable tablet stability.
The present invention also provides a kind of preparation technology of levo-cetirizine hydrochloride chewable tablet, at first through research, confirms to adopt β-cyclodextrin that medicine is carried out enclose; In research process, find; The consumption influence of β-cyclodextrin can't be accomplished complete enclose medicine very little, and the taste masking effect is bad; Consumption is too many, because β-cyclodextrin is poor slightly with drug compatibility under super-humid conditions, is prone to cause the medicine small amount of degradation.The ratio of final definite medicine and β-cyclodextrin is 1:5～1:10, and it can cover the disagreeable taste of medicine, simultaneously the long-term stability of placing of medicine is not had influence.
Because the water solublity of β-cyclodextrin is relatively poor, must under hot conditions, could dissolve, to put and be chilled to room temperature and separate out again, therefore independent employing β-cyclodextrin is to the medicine enclose, the technology more complicated.The chewing tablet of cetirizine hydrochloride patent of Nanjing Golden Eagle Pharmaceutical Technology Development Co., Ltd's application; The patent No. is in 200510040439.8 the patent cetirizine and other adjuvant to be mixed together granulation, and β-cyclodextrin can not be with the medicine enclose, shown in accompanying drawing 4 like this; The particulate DSC collection of illustrative plates of simple mixing granulation shows; Medicine fusion endothermic peak still exists, and proves that this technology is not the β-cyclodextrin clathrate of preparation medicine, just simple physics mixed process.We find through experimentation, the levo-cetirizine hydrochloride aqueous solution are added in the mixture of β-cyclodextrin and first kind of microcrystalline Cellulose the clathrate that is mixed with through simple physics; The bitter taste of medicine is covered fully, and first kind of microcrystalline Cellulose not only do not influence the enclose of β-cyclodextrin to medicine, simultaneously because the water-insoluble of first kind of microcrystalline Cellulose; It is wet moderate that the clathrate that makes is done; Can directly granulate, the technical process for preparing clathrate has been simplified in oven dry.Shown in accompanying drawing 5; Use β-cyclodextrin and first kind of microcrystalline cellulose mixt that drug solution is carried out the clathrate DSC collection of illustrative plates that enclose obtains and show that the fusion endothermic peak of medicine and beta-schardinger dextrin-disappears basically; The fusion endothermic peak of first kind of microcrystalline Cellulose remains unchanged, and explains that first kind of microcrystalline Cellulose can not disturb the enclose of β-cyclodextrin to medicine.First kind of microcrystalline Cellulose provides the technology operability in technical process, medicine stability difference and the very few problem that can't carry out the enclose operation of consumption of avoiding the beta-schardinger dextrin-consumption too much to bring.
Next is levo-cetirizine hydrochloride chewable tablet preparation technology's screening, through the investigation to the medicine long-time stability, after discovery is prepared into single-layer sheet with it; Stability of drug is relatively poor, through experimentation, the adjuvant that influences medicine stability is placed on another layer; After it was prepared into double-layer tablet, stability of drug obviously improved, so the levo-cetirizine hydrochloride chewable tablet finally is prepared into double-layer tablet; One deck is a medicated layer, and one deck is an auxiliary layer.
Particle mean size is at (preferably between the 63-76 micron) and bulk density g/cm between the 60-80 micron
3The use of water-insoluble second kind of microcrystalline Cellulose (for example microcrystalline Cellulose PH102) in medicated layer between the 0.28-0.33 also can bring outstanding effect; On the one hand; Cause processing, the forming property improved because of good flowability and cohesive; On the other hand, with the for example polyvinylpolypyrrolidone combination use of other disintegrating agent, further improve disintegrative.
The design of auxiliary layer: through adjuvant compatibility result, find mannitol in the prescription, sucralose and hami melon essence are bigger to the medicine stability influence; Therefore consider it is prepared one deck separately; With the contact area of minimizing with medicine, increase stability of drug, in auxiliary layer, add a certain amount of color indigo simultaneously; Both well distinguish medicated layer and auxiliary layer, increased the attractive in appearance of label again.
Summarize as follows according to technical scheme of the present invention:
1. levo-cetirizine hydrochloride chewable tablet is characterized in that said preparation prepares through following process:
A) the particulate preparation of medicated layer: levo-cetirizine hydrochloride is soluble in water; Then with pharmaceutically acceptable enclose material mixing formation clathrate; Granulate and oven dry acquisition particulate matter; In particulate matter, add vertical compression lactose as filler, particle mean size then at (preferably between the 62-86 micron, more preferably between the 64-80 micron) and bulk density g/cm between the 60-90 micron
3Water-insoluble second kind of microcrystalline Cellulose (for example microcrystalline Cellulose PH102) between 0.28-0.33 adds disintegrating agent (for example polyvinylpolypyrrolidone) and mix homogeneously, adds the magnesium stearate as lubricant then, and mix homogeneously promptly gets the medicated layer granule; Preferably; Wherein the enclose material be β-cyclodextrin and particle mean size between the 15-50 micron (preferably between the 10-45 micron; More preferably between the 15-42 micron; More preferably between the 20-40 micron, between the 25-35 micron) both enclose material blends of forming of first kind of microcrystalline Cellulose, the part by weight of this mixture and medicine levo-cetirizine hydrochloride is 3:1～7:1;
B) the particulate preparation of auxiliary layer: with mannitol, first kind of microcrystalline Cellulose, color indigo (for example lemon yellow) mix homogeneously adds suitable quantity of water system soft material, granulates and oven dry; Add sucralose and essence (for example hami melon essence), mix homogeneously; Add magnesium stearate then, mix homogeneously promptly gets the auxiliary layer granule;
C) tabletting: place tablet machine to carry out tabletting according to certain part by weight medicated layer granule and auxiliary layer granule, obtain the levo-cetirizine hydrochloride chewable tablet.
2. according to above 1 chewable tablet, wherein the part by weight of enclose material blends and medicine levo-cetirizine hydrochloride is 4:1～6:1, preferred 4.5:1～5.5:1.
3. according to above 1 or 2 described levo-cetirizine hydrochloride chewable tablet, it is a double-layer tablet, and one deck is a medicated layer; Another layer is an auxiliary layer, and the weight ratio of medicated layer and auxiliary layer is 2:1-1:2, preferably 1.5:1-1:1.5; More preferably 1.3:1-1:1.3, further preferred 1.1:1-1:1.1.
4. according to above 2 or 3 described chewable tablet, wherein in steps A) in the part by weight of beta-schardinger dextrin-and first kind of microcrystalline Cellulose be 3:1～1:3, preferred 2:1～1:2, more preferably 1.5:1～1:1.5.
5. according to above 3 or 4 described chewable tablet, wherein the disintegrating agent in the medicated layer is selected from one or more in carboxymethylstach sodium, polyvinylpolypyrrolidone or the cross-linking sodium carboxymethyl cellulose, preferred polyvinylpolypyrrolidone; The color indigo is selected from one or more in lemon yellow, iron oxide red or the sapphirine indigo, preferred lemon yellow.
6. according to above 3 or 4 described chewable tablet, wherein the essence in the auxiliary layer is selected from peach flavor essence, hami melon essence, one or more in apple essence or the Fructus Citri tangerinae essence, preferred hami melon essence.
7. according to any one chewable tablet in the above 1-6 item, wherein for the particulate preparation of medicated layer, the amount ratio of levo-cetirizine hydrochloride and filler is 1:50-1:120; Preferred 1:60-1:100; More preferably 1:70-1:90, preferred especially 1:80 is according to the weight meter.
8. according to any one chewable tablet in the above 1-7 item, wherein for the particulate preparation of medicated layer, the amount ratio of levo-cetirizine hydrochloride and disintegrating agent is 1:2-1:6, preferred 1:3-1:5, and more preferably 1:3.5-1:4.5,1:4 most preferably is according to the weight meter.
9. according to any one chewable tablet in the above 1-8 item, wherein for the particulate preparation of medicated layer, the amount ratio of levo-cetirizine hydrochloride and lubricant is 1:2-2:1; Preferred 1:1.7-1.7:1; More preferably 1:1.5-1.5:1, further preferred 1:1.3-1.3:1 is according to the weight meter.
10. according to any one chewable tablet in the above 1-9 item; Wherein for the particulate preparation of medicated layer; As the vertical compression lactose of filler and the weight ratio of second kind of microcrystalline Cellulose (for example microcrystalline Cellulose PH102) is 3.8:1-2.2:1, preferred 3.5:1-2.5:1, more preferably 3.2:1-2.8:1.
11. according to any one chewable tablet in the above 1-10 item, wherein for the particulate preparation of auxiliary layer, the weight ratio of mannitol and first kind of microcrystalline Cellulose is 3.8:1-2.2:1, preferred 3.5:1-2.5:1, more preferably 3.2:1-2.8:1.
12. according to any one chewable tablet in the above 1-11 item, wherein for the particulate preparation of auxiliary layer, the weight sum of mannitol and first kind of microcrystalline Cellulose is 90-98wt% with respect to the percentage ratio of the particulate gross weight of auxiliary layer, preferred 93-96wt%.
13. according to any one chewable tablet in the above 1-12 item; Wherein for the particulate preparation of auxiliary layer; The color indigo is 0.01-0.5wt%, preferred 0.05-0.4wt%, more preferably 0.1-0.3wt% with respect to the percentage ratio of the particulate gross weight of auxiliary layer, and sucralose is 1-4wt%, preferred 1.5-3.5wt%, more preferably 1.8-3wt%, further preferred 2.0-2.5wt% with respect to the percentage ratio of the particulate gross weight of auxiliary layer; Or essence is 1.5-4.5wt%, preferred 2-4wt%, more preferably 2.5-3.5wt%, further preferred 2.8-3.2wt% with respect to the percentage ratio of the particulate gross weight of auxiliary layer; Or magnesium stearate is 0.5-1.5wt%, 0.8-1.2wt% preferably with respect to the percentage ratio of the particulate gross weight of auxiliary layer.
14. prepare the method for the chewable tablet of any one in the above 1-13 item, this method may further comprise the steps:
A) the particulate preparation of medicated layer: levo-cetirizine hydrochloride is soluble in water; Then with pharmaceutically acceptable enclose material mixing formation clathrate; Granulate and oven dry acquisition particulate matter; In particulate matter, add vertical compression lactose as filler, particle mean size then at (preferably between the 62-86 micron, more preferably between the 64-80 micron) and bulk density g/cm between the 60-90 micron
3Water-insoluble second kind of microcrystalline Cellulose (preferably microcrystalline cellulose PH102) between 0.28-0.33 adds disintegrating agent (for example polyvinylpolypyrrolidone) and mix homogeneously, adds the magnesium stearate as lubricant then, and mix homogeneously promptly gets the medicated layer granule; Preferably; Wherein the enclose material be beta-schardinger dextrin-and particle mean size between the 15-50 micron (preferably between the 10-45 micron; More preferably between the 15-42 micron; More preferably between the 20-40 micron, between the 25-35 micron) both enclose material blends of forming of first kind of microcrystalline Cellulose, the part by weight of this mixture and medicine levo-cetirizine hydrochloride is 3:1～7:1;
B) the particulate preparation of auxiliary layer: with mannitol, first kind of microcrystalline Cellulose, color indigo (for example lemon yellow) mix homogeneously adds suitable quantity of water system soft material, granulates and oven dry; Add sucralose and essence (for example hami melon essence), mix homogeneously; Add magnesium stearate then, mix homogeneously promptly gets the auxiliary layer granule;
C) tabletting: place tablet machine to carry out tabletting according to certain part by weight medicated layer granule and auxiliary layer granule, obtain the levo-cetirizine hydrochloride chewable tablet.
15. according to above 14 described methods, wherein the part by weight of enclose material blends and medicine levo-cetirizine hydrochloride is 4:1～6:1, preferred 4.5:1～5.5:1.
16. according to above 14 or 15 described methods, it is a double-layer tablet, one deck is a medicated layer; Another layer is an auxiliary layer, and the weight ratio of medicated layer and auxiliary layer is 2:1-1:2, preferably 1.5:1-1:1.5; More preferably 1.3:1-1:1.3, further preferred 1.1:1-1:1.1.
17. according to above 15 or 16 described methods, wherein in steps A) in the part by weight of beta-schardinger dextrin-and first kind of microcrystalline Cellulose be 3:1～1:3, preferred 2:1～1:2, more preferably 1.5:1～1:1.5.
18. according to above 16 or 17 described methods, wherein the disintegrating agent in the medicated layer is selected from one or more in carboxymethylstach sodium, polyvinylpolypyrrolidone or the cross-linking sodium carboxymethyl cellulose, preferred polyvinylpolypyrrolidone; The color indigo is selected from one or more in lemon yellow, iron oxide red or the sapphirine indigo, preferred lemon yellow.
19. according to above 16 or 17 described methods, wherein the essence in the auxiliary layer is selected from peach flavor essence, hami melon essence, one or more in apple essence or the Fructus Citri tangerinae essence, preferred hami melon essence.
20. according to any one method in the above 14-19 item, wherein for the particulate preparation of medicated layer, the amount ratio of levo-cetirizine hydrochloride and filler is 1:50-1:120; Preferred 1:60-1:100; More preferably 1:70-1:90, preferred especially 1:80 is according to the weight meter.
21. according to any one method in the above 14-20 item, wherein for the particulate preparation of medicated layer, the amount ratio of levo-cetirizine hydrochloride and disintegrating agent is 1:2-1:6, preferred 1:3-1:5, and more preferably 1:3.5-1:4.5,1:4 most preferably is according to the weight meter.
22. according to any one method in the above 14-21 item, wherein for the particulate preparation of medicated layer, the amount ratio of levo-cetirizine hydrochloride and lubricant is 1:2-2:1; Preferred 1:1.7-1.7:1; More preferably 1:1.5-1.5:1, further preferred 1:1.3-1.3:1 is according to the weight meter.
23. according to any one method in the above 14-22 item; Wherein for the particulate preparation of medicated layer; As the vertical compression lactose of filler and the weight ratio of second kind of microcrystalline Cellulose (for example microcrystalline Cellulose PH102) is 3.8:1-2.2:1, preferred 3.5:1-2.5:1, more preferably 3.2:1-2.8:1.
24. according to any one method in the above 14-23 item, wherein for the particulate preparation of auxiliary layer, the weight ratio of mannitol and first kind of microcrystalline Cellulose is 3.8:1-2.2:1, preferred 3.5:1-2.5:1, more preferably 3.2:1-2.8:1.
25. according to any one method in the above 14-24 item, wherein for the particulate preparation of auxiliary layer, the weight sum of mannitol and first kind of microcrystalline Cellulose is 90-98wt% with respect to the percentage ratio of the particulate gross weight of auxiliary layer, preferred 93-96wt%.
26. according to any one method in the above 14-25 item; Wherein for the particulate preparation of auxiliary layer; The color indigo is 0.01-0.5wt%, preferred 0.05-0.4wt%, more preferably 0.1-0.3wt%, or sucralose with respect to the percentage ratio of the particulate gross weight of auxiliary layer with respect to the percentage ratio of the particulate gross weight of auxiliary layer is 1-4wt%, preferred 1.5-3.5wt%, more preferably 1.8-3wt%, further preferred 2.0-2.5wt%; Or essence is 1.5-4.5wt%, preferred 2-4wt%, more preferably 2.5-3.5wt%, further preferred 2.8-3.2wt% with respect to the percentage ratio of the particulate gross weight of auxiliary layer; Or magnesium stearate is 0.5-1.5wt%, 0.8-1.2wt% preferably with respect to the percentage ratio of the particulate gross weight of auxiliary layer.
27. according in the above 1-13 item any one chewable tablet or according to any one method among the above 14-26, wherein
The levo-cetirizine hydrochloride chewable tablet can prepare by following formulation and technology:
Prescription:
Medicated layer:
Auxiliary layer:
Preparation technology:
The particulate preparation of medicated layer:
(1) levo-cetirizine hydrochloride that takes by weighing recipe quantity is put in the suitable quantity of water, stirs to make its dissolving.
(2) take by weighing β-cyclodextrin and first kind of microcrystalline Cellulose of recipe quantity, put mix homogeneously in the wet granulator, the levo-cetirizine hydrochloride aqueous solution is added wherein, mix homogeneously, 30 mesh sieves are granulated, 50 ℃ of oven dry, 30 mesh sieve granulate.
(3) take by weighing the vertical compression lactose of recipe quantity, the granule mix homogeneously of second kind of microcrystalline Cellulose (for example microcrystalline Cellulose PH102), polyvinylpolypyrrolidone and above-mentioned preparation.
(4) magnesium stearate of adding recipe quantity, mix homogeneously promptly gets the medicated layer granule.
The particulate preparation of auxiliary layer:
(1) mannitol is crossed 60 mesh sieves, subsequent use.
(2) take by weighing the mannitol of recipe quantity, first kind of microcrystalline Cellulose, the lemon yellow mix homogeneously adds suitable quantity of water system soft material, the granulation of 24 mesh sieves, 50 ℃ of oven dry, 24 mesh sieve granulate.
(3), add the sucralose and the hami melon essence of prescription proportional quantities, mix homogeneously according to the particulate amount of preparation.
(4) magnesium stearate of adding prescription proportional quantities, mix homogeneously promptly gets the auxiliary layer granule.
Tabletting
With the medicated layer and the auxiliary layer granule of above-mentioned preparation, put the scrobicula stamping of rotary tablet machine with diameter 11mm, promptly get.
The invention still further relates to by above any one the levo-cetirizine hydrochloride chewable tablet that method obtained.
The average dissolution of the chewable tablet that the present invention obtains is between 95-104%, preferably between 96-102%.
Description of drawings
Accompanying drawing 1 levo-cetirizine hydrochloride crude drug DSC collection of illustrative plates
The DSC collection of illustrative plates of accompanying drawing 2 microcrystalline Cellulose PH101
The DSC collection of illustrative plates of accompanying drawing 3 beta-schardinger dextrin-s
The DSC collection of illustrative plates of accompanying drawing 4 levo-cetirizine hydrochloride physical mixtures
The DSC collection of illustrative plates of accompanying drawing 5 levo-cetirizine hydrochloride clathrates
The explanation of term:
For " particle mean size is at first kind of microcrystalline Cellulose of (preferably between the 10-50 micron; more preferably between the 15-45 micron; more preferably between the 20-40 micron; between the 25-35 micron) between the 10-45 micron ", generally can use be generally used for preparing tablet, any conventional microcrystalline Cellulose of particle mean size in said scope.
For express phrase " particle mean size between the 60-90 micron with bulk density g/cm
3Water-insoluble second kind of microcrystalline Cellulose (for example microcrystalline Cellulose PH102) between 0.28-0.33 " in " water-insoluble " be meant that the dissolubility in 25 ℃ distilled water is lower than 0.25wt%.
The pH value of preferred second kind of microcrystalline Cellulose is at 5-7, more preferably from about 6.
Particle mean size described here is meant number average particle size.
For the physico-chemical parameter of microcrystalline Cellulose PH102, referring to Zhang Nan etc., " principal component analysis and clustering methodology are used for the microcrystalline Cellulose classification ", Chinese experimental pharmacology of Chinese medical formulae magazine, the 17th the 19th phase of volume, in October, 2011.
Advantage of the present invention:
The present invention comprises for levo-cetirizine hydrochloride through the mixture that utilizes beta-schardinger dextrin-and microcrystalline Cellulose in advance, obtains unforeseeable enclose effect, has covered the bitter taste of medicine fully.
The present invention utilizes the use that combines with other disintegrating agent of second kind of microcrystalline Cellulose (for example microcrystalline Cellulose PH102) of coarsegrain, good fluidity; Cause processing, the forming property improved because of the good flowability of second kind of microcrystalline cellulose and cohesive; On the other hand; With the for example polyvinylpolypyrrolidone combination use of other disintegrating agent, further improve disintegrative.
First kind of microcrystalline Cellulose provides the technology operability in technical process, medicine stability difference and the very few problem that can't carry out the enclose operation of consumption of avoiding the beta-schardinger dextrin-consumption too much to bring.
The specific embodiment
The granularity of microcrystalline Cellulose PH-102: get the about 10.0g of PH-102, place on the 200LS-N aerojet sieve, transferring timer is 3 minutes (75 microns screen clothes are 6 minutes); Adjust blood pressure power is 1500-2500Pa.S (40 microns and 32 microns screen clothes; Adjust blood pressure power is at 2500-4000Pa.s), begin to sieve, sieve is finished; Weighing remains in the weight of the test sample on the sieve, calculates the percentage rate of residue.Granularity must not be less than 45 greater than the residue percentage rate of 75 microns (200 orders), and granularity must not surpass 8% greater than the residue percentage rate of 250 microns (60 orders).Preferably, fineness: (aerojet sieve) 60 screen residues≤8%, preferred≤1%; 200 screen residues>=45%, preferred>=62%.Bulk density g/cm
3=0.28-0.33.
Microcrystalline Cellulose PH-102: 62 microns of particle mean sizes, bulk density g/cm
3=0.28-0.33, U.S. FMC BioPolymer company produces,
Particle size distribution LD, micron, d10 (European Pharmacopoeia)=34, d50 (European Pharmacopoeia)=105, d90 (European Pharmacopoeia)=220.
In an embodiment, for beta-schardinger dextrin-, adopt Yunan County, the Guangdong Province product of ring of light shape dextrin company limited forever, name of product is " betacyclodextrin "; For levo-cetirizine hydrochloride, use the product of Hunan Jiudian Pharmaceutical Co., Ltd.For sucralose, use the product of the Hubei Yitai Pharmaceutical Co., Ltd. in Hubei Province.For mannitol, use the product of Nanning chemical pharmacy company limited.For vertical compression lactose (direct compression lactose), adopt the Kang Fu board product (or also can adopt German BASF
LCE) of the Kang Fu of Zhengjiang City, Jiangsu Province biological engineering company limited.
For with cyclodextrin jointly as the microcrystalline Cellulose (as first kind of microcrystalline Cellulose) of inclusion agents, the microcrystalline Cellulose that the medicament tabletting is used, for example microcrystalline Cellulose (its bulk density g/cm of particle mean size between the 10-45 micron
3Preferably between 0.34-0.45), like the microcrystalline Cellulose (or also can use east, Beijing China to make every effort to open up the microcrystalline Cellulose of development in science and technology company limited) of Shanghai De Mo Pharmaceutical Technology Co., Ltd sale.
Be used to estimate the test of the effect of covering bitter taste
Totally 20 experimenters' that are made up of 10 7-9 year children and 10 60-80 year old peoples evaluation group estimates; The standard of estimating is: everyone chews 1 tablet to be tested above-mentioned 20 people for a certain chewable tablet; If nobody is felt slightly significantly bitter taste, then this chewable tablet is be evaluated as " covering fully " grade.If have and feel slightly significantly bitter taste more than 1 people, then this chewable tablet is be evaluated as " do not reach fully and cover " grade.
Embodiment 1 (reference)
Prescription:
| The supplementary material title | Recipe quantity (1000) |
| Levo-cetirizine hydrochloride | 2.5g |
| β-cyclodextrin | 5g |
| Microcrystalline Cellulose (the Shanghai moral is silent) | 15g |
| Water | In right amount |
| Mannitol | 100g |
| The vertical compression lactose | 50g |
| Microcrystalline Cellulose PH102 | 50g |
| Polyvinylpolypyrrolidone | 10g |
| Sucralose | 4g |
| Hami melon essence | 5g |
| Magnesium stearate | 3g |
Preparation technology:
1. the levo-cetirizine hydrochloride that takes by weighing recipe quantity is put in the suitable quantity of water, and stirring and dissolving is subsequent use.
2. take by weighing the microcrystalline Cellulose (the Shanghai moral is silent) of 42 microns of beta-schardinger dextrin-and the particle mean sizes of recipe quantity, mix homogeneously adds the levo-cetirizine hydrochloride aqueous solution wherein, stirs, and 30 mesh sieves are granulated, 50 ℃ of oven dry, 30 mesh sieve granulate.
3. according to the amount of the clathrate for preparing, add mannitol, vertical compression lactose, microcrystalline Cellulose PH102, polyvinylpolypyrrolidone, sucralose and the hami melon essence of recipe quantity, mix homogeneously.
4. add the magnesium stearate of recipe quantity, mix homogeneously is put the scrobicula stamping of rotary tablet machine with diameter 9mm, promptly gets.
Brief summary: the levo-cetirizine hydrochloride clathrate of this formulation and technology preparation, taste are bitter, are evaluated as " do not reach fully and cover " grade, explain that the consumption of β-cyclodextrin is less, fail the complete enclose of medicine, therefore consider to increase the amount of β-cyclodextrin in the prescription.
With the levo-cetirizine hydrochloride chewable tablet setting-out of embodiment 1 preparation, carry out study on the stability, concrete outcome is seen table 1.
Table 1 embodiment 1 stability experiment result
Can find out that from above-mentioned experimental result in the long-term put procedure of medicine, therefore less stable is considered to carry out adjuvant compatibility experiment, filters out the adjuvant that influences medicine stability.
With reference to the conventional amount used of adjuvant in the prescription, crude drug is mixed with certain proportion with adjuvant, tabletting carries out the adjuvant compatibility and investigates, and concrete outcome is seen table 2.
Table 2 adjuvant compatibility experimental result
From above-mentioned experimental result, can find out; The compatibility of medicine and mannitol, sucralose and hami melon essence is relatively poor; In order to guarantee the long-term shelf-stability of medicine, consideration will be placed on another layer with the adjuvant of drug compatibility difference, promptly be prepared into double-layer tablet; Reduce the contact area of itself and medicine, guarantee stability of drug.
Embodiment 2 (the present invention)
Prescription:
Medicated layer:
Auxiliary layer:
Preparation technology:
One, particulate preparation
The preparation of medicated layer:
1. the levo-cetirizine hydrochloride that takes by weighing recipe quantity is put in the suitable quantity of water, and stirring and dissolving is subsequent use.
2. take by weighing the beta-schardinger dextrin-and the microcrystalline Cellulose of recipe quantity, mix homogeneously adds the levo-cetirizine hydrochloride aqueous solution wherein, stirs, and 30 mesh sieves are granulated, 50 ℃ of oven dry, 30 mesh sieve granulate.
3. according to the amount of the clathrate for preparing, add vertical compression lactose, the microcrystalline Cellulose PH102 of recipe quantity, polyvinylpolypyrrolidone, mix homogeneously.
4. add the magnesium stearate mix homogeneously of recipe quantity, promptly get the medicated layer granule.
The preparation of auxiliary layer:
1. mannitol is crossed 60 mesh sieves, subsequent use.
2. take by weighing the mannitol of recipe quantity, microcrystalline Cellulose, the lemon yellow mix homogeneously adds suitable quantity of water system soft material, and 24 mesh sieves are granulated, 50 ℃ of oven dry, 24 mesh sieve granulate.
3. according to the particulate amount of preparation, add the sucralose and the hami melon essence of prescription proportional quantities, mix homogeneously.
4. add the magnesium stearate of prescription proportional quantities, mix homogeneously promptly gets the auxiliary layer granule, and is subsequent use.
Two, tabletting
With the medicated layer and the auxiliary layer granule of above-mentioned preparation, put the scrobicula stamping of rotary tablet machine with diameter 11mm, promptly get.
The DSC figure of the medicated layer of tabletting is referring to accompanying drawing 5.
Brief summary: the levo-cetirizine hydrochloride clathrate of this formulation and technology preparation, covered the bitter taste of medicine fully, reach " covering fully " grade.The levo-cetirizine hydrochloride chewable tablet of this formulation and technology preparation is carried out study on the stability, and concrete outcome is seen table 3.
Table 3 embodiment 2 stability experiment results
Can find that from the stability experiment result related substance has the trend of increase with prolonging standing time; Especially under the 40 ℃/RH75% acceleration environment; The adjuvant compatibility result of reference drug and beta-schardinger dextrin-simultaneously, medicine and β-cyclodextrin under super-humid conditions, less stable; Therefore consider on the basis that can cover the medicine bitter taste, to reduce the consumption of β-cyclodextrin in the prescription as far as possible.
The average dissolution of chewable tablet: 97%.
Embodiment 3 (the preferred embodiments of the invention)
Prescription:
Medicated layer:
| The supplementary material title | Recipe quantity (1000) |
| Levo-cetirizine hydrochloride | 2.5g |
| β-cyclodextrin | 15g |
| Microcrystalline Cellulose (the Shanghai moral is silent) | 15g |
| Water | In right amount |
| The vertical compression lactose | 150g |
| Microcrystalline Cellulose PH102 | 50g |
| Polyvinylpolypyrrolidone | 10g |
| Magnesium stearate | 3g |
Auxiliary layer:
| The supplementary material title | Recipe quantity (1000) |
| Mannitol | 150g |
| Microcrystalline Cellulose (the Shanghai moral is silent) | 50g |
| Lemon yellow | 0.5g |
| Water | In right amount |
| Sucralose | 4g |
| Hami melon essence | 5g |
| Magnesium stearate | 2g |
Preparation technology:
One, particulate preparation
The preparation of medicated layer:
1. the levo-cetirizine hydrochloride that takes by weighing recipe quantity is put in the suitable quantity of water, stirs to make its dissolving.
2. take by weighing the β-cyclodextrin and the microcrystalline Cellulose of recipe quantity, put mix homogeneously in the wet granulator, the levo-cetirizine hydrochloride aqueous solution is added wherein, mix homogeneously, 30 mesh sieves are granulated, 50 ℃ of oven dry, 30 mesh sieve granulate.
3. take by weighing the vertical compression lactose of recipe quantity, the granule mix homogeneously of microcrystalline Cellulose PH102, polyvinylpolypyrrolidone and above-mentioned preparation.
4. add the magnesium stearate of recipe quantity, mix homogeneously promptly gets the medicated layer granule.
The preparation of auxiliary layer:
1. mannitol is crossed 60 mesh sieves, subsequent use.
2. take by weighing the mannitol of recipe quantity, microcrystalline Cellulose, the lemon yellow mix homogeneously adds suitable quantity of water system soft material, and 24 mesh sieves are granulated, 50 ℃ of oven dry, 24 mesh sieve granulate.
3. according to the particulate amount of preparation, add the sucralose and the hami melon essence of prescription proportional quantities, mix homogeneously.
4. add the magnesium stearate of prescription proportional quantities, mix homogeneously promptly gets the auxiliary layer granule.
Two, tabletting
With the medicated layer and the auxiliary layer granule of above-mentioned preparation, put the scrobicula stamping of rotary tablet machine with diameter 11mm, promptly get.
Brief summary: the levo-cetirizine hydrochloride clathrate of this formulation and technology preparation, covered the bitter taste of medicine equally, reach " covering fully " grade.The levo-cetirizine hydrochloride chewable tablet of this formulation and technology preparation is carried out study on the stability, and concrete outcome is seen table 4.
Table 4 embodiment 3 stability experiment results
Can find from the stability experiment result, the levo-cetirizine hydrochloride chewable tablet of embodiment 3 preparation at ambient temperature, related substance is with prolonging no significant change standing time; Under 40 ℃/RH75% acceleration environment, related substance has increase slightly, compares with embodiment 2, and stability better.
Average dissolution: 102%.
Embodiment 4 (the present invention)
Prescription:
Medicated layer:
| The supplementary material title | Recipe quantity (1000) |
| Levo-cetirizine hydrochloride | 2.5g |
| β-cyclodextrin | 10g |
| Microcrystalline Cellulose | 15g |
| Water | In right amount |
| The vertical compression lactose | 150g |
| Microcrystalline Cellulose PH102 | 50g |
| Polyvinylpolypyrrolidone | 10g |
| Magnesium stearate | 3g |
Auxiliary layer:
| The supplementary material title | Recipe quantity (1000) |
| Mannitol | 150g |
| Microcrystalline Cellulose | 50g |
| Lemon yellow | 0.5g |
| Water | In right amount |
| Sucralose | 4g |
| Hami melon essence | 5g |
| Magnesium stearate | 2g |
Preparation technology:
One, particulate preparation
The preparation of medicated layer:
1. the levo-cetirizine hydrochloride that takes by weighing recipe quantity is put in the suitable quantity of water, stirs to make its dissolving.
2. take by weighing the β-cyclodextrin and the microcrystalline Cellulose of recipe quantity, put mix homogeneously in the wet granulator, the levo-cetirizine hydrochloride aqueous solution is added wherein, mix homogeneously, 30 mesh sieves are granulated, 50 ℃ of oven dry, 30 mesh sieve granulate.
3. take by weighing the vertical compression lactose of recipe quantity, the granule mix homogeneously of microcrystalline Cellulose PH102, polyvinylpolypyrrolidone and above-mentioned preparation.
4. add the magnesium stearate of recipe quantity, mix homogeneously promptly gets the medicated layer granule.
The preparation of auxiliary layer:
1. mannitol is crossed 60 mesh sieves, subsequent use.
2. take by weighing the mannitol of recipe quantity, microcrystalline Cellulose, the lemon yellow mix homogeneously adds suitable quantity of water system soft material, and 24 mesh sieves are granulated, 50 ℃ of oven dry, 24 mesh sieve granulate.
3. according to the particulate amount of preparation, add the sucralose and the hami melon essence of prescription proportional quantities, mix homogeneously.
4. add the magnesium stearate of prescription proportional quantities, mix homogeneously promptly gets the auxiliary layer granule.
Two, tabletting
With the medicated layer and the auxiliary layer granule of above-mentioned preparation, put the scrobicula stamping of rotary tablet machine with diameter 11mm, promptly get.
Brief summary: the levo-cetirizine hydrochloride clathrate of this formulation and technology preparation, covered the bitter taste of medicine equally, reach " covering fully " grade.The levo-cetirizine hydrochloride chewable tablet of this formulation and technology preparation is carried out study on the stability, and concrete outcome is seen table 5.
Table 5 embodiment 4 stability experiment results
Can find that from the stability experiment result when levo-cetirizine hydrochloride chewable tablet of embodiment 4 preparations was placed under room temperature and 40 ℃/RH75% acceleration environment for a long time, related substance had increase slightly, compares with embodiment 3, related substance is low slightly.But both do not have significant difference, and the enclose ratio of therefore preferred medicine beta-schardinger dextrin-and medicine is 4:1～6:1.
Simultaneously with in the prescription every contain beta-schardinger dextrin-10mg, investigate the proper ratio of itself and microcrystalline Cellulose.
The average dissolution of chewable tablet: 98%.
Embodiment 5 (contrast)
Prescription:
Medicated layer:
| The supplementary material title | Recipe quantity (1000) |
| Levo-cetirizine hydrochloride | 2.5g |
| β-cyclodextrin | 10g |
| Microcrystalline Cellulose | 30g |
| Water | In right amount |
| The vertical compression lactose | 150g |
| Microcrystalline Cellulose PH102 | 50g |
| Polyvinylpolypyrrolidone | 10g |
| Magnesium stearate | 3g |
Auxiliary layer:
| The supplementary material title | Recipe quantity (1000) |
| Mannitol | 150g |
| Microcrystalline Cellulose | 50g |
| Lemon yellow | 0.5g |
| Water | In right amount |
| Sucralose | 4g |
| Hami melon essence | 5g |
| Magnesium stearate | 2g |
Preparation technology:
One, particulate preparation
The preparation of medicated layer:
1. the levo-cetirizine hydrochloride that takes by weighing recipe quantity is put in the suitable quantity of water, stirs to make its dissolving.
2. take by weighing the β-cyclodextrin and the microcrystalline Cellulose of recipe quantity, put mix homogeneously in the wet granulator, the levo-cetirizine hydrochloride aqueous solution is added wherein, mix homogeneously, 30 mesh sieves are granulated, 50 ℃ of oven dry, 30 mesh sieve granulate.
3. take by weighing the vertical compression lactose of recipe quantity, the granule mix homogeneously of microcrystalline Cellulose PH102, polyvinylpolypyrrolidone and above-mentioned preparation.
4. add the magnesium stearate of recipe quantity, mix homogeneously promptly gets the medicated layer granule.
The preparation of auxiliary layer:
1. mannitol is crossed 60 mesh sieves, subsequent use.
2. take by weighing the mannitol of recipe quantity, microcrystalline Cellulose, the lemon yellow mix homogeneously adds suitable quantity of water system soft material, and 24 mesh sieves are granulated, 50 ℃ of oven dry, 24 mesh sieve granulate.
3. according to the particulate amount of preparation, add the sucralose and the hami melon essence of prescription proportional quantities, mix homogeneously.
4. add the magnesium stearate of prescription proportional quantities, mix homogeneously promptly gets the auxiliary layer granule.
Two, tabletting
With the medicated layer and the auxiliary layer granule of above-mentioned preparation, put the scrobicula stamping of rotary tablet machine with diameter 11mm, promptly get.
Brief summary: this formulation and technology is when the preparation clathrate; Increased the consumption of microcrystalline Cellulose, the result does not cover the bitter taste of medicine fully, possibly be because the consumption of microcrystalline Cellulose is too big; Reduced the contact area of medicine and β-cyclodextrin; Therefore, in order to guarantee the enclose effect, must reduce the consumption of microcrystalline Cellulose.
Embodiment 6 (the present invention)
Prescription:
Medicated layer:
| The supplementary material title | Recipe quantity (1000) |
| Levo-cetirizine hydrochloride | 2.5g |
| β-cyclodextrin | 10g |
| Microcrystalline Cellulose | 20g |
| Water | In right amount |
| The vertical compression lactose | 150g |
| Microcrystalline Cellulose PH102 | 50g |
| Polyvinylpolypyrrolidone | 10g |
| Magnesium stearate | 3g |
Auxiliary layer:
| The supplementary material title | Recipe quantity (1000) |
| Mannitol | 150g |
| Microcrystalline Cellulose | 50g |
| Lemon yellow | 0.5g |
| Water | In right amount |
| Sucralose | 4g |
| Hami melon essence | 5g |
| Magnesium stearate | 2g |
Preparation technology:
One, particulate preparation
The preparation of medicated layer:
1. the levo-cetirizine hydrochloride that takes by weighing recipe quantity is put in the suitable quantity of water, stirs to make its dissolving.
2. take by weighing the β-cyclodextrin and the microcrystalline Cellulose of recipe quantity, put mix homogeneously in the wet granulator, the levo-cetirizine hydrochloride aqueous solution is added wherein, mix homogeneously, 30 mesh sieves are granulated, 50 ℃ of oven dry, 30 mesh sieve granulate.
3. take by weighing the vertical compression lactose of recipe quantity, the granule mix homogeneously of microcrystalline Cellulose PH102, polyvinylpolypyrrolidone and above-mentioned preparation.
4. add the magnesium stearate of recipe quantity, mix homogeneously promptly gets the medicated layer granule.
The preparation of auxiliary layer:
1. mannitol is crossed 60 mesh sieves, subsequent use.
2. take by weighing the mannitol of recipe quantity, microcrystalline Cellulose, the lemon yellow mix homogeneously adds suitable quantity of water system soft material, and 24 mesh sieves are granulated, 50 ℃ of oven dry, 24 mesh sieve granulate.
3. according to the particulate amount of preparation, add the sucralose and the hami melon essence of prescription proportional quantities, mix homogeneously.
4. add the magnesium stearate of prescription proportional quantities, mix homogeneously promptly gets the auxiliary layer granule.
Two, tabletting
With the medicated layer and the auxiliary layer granule of above-mentioned preparation, put the scrobicula stamping of rotary tablet machine with diameter 11mm, promptly get.
Brief summary: this formulation and technology is when the preparation clathrate, and the whole operation process is smooth, and the bitter taste of medicine is covered, and reaches " covering fully " grade, therefore shows that the ratio of β-cyclodextrin and microcrystalline Cellulose is that 1:2 is suitable.
Embodiment 7 (the present invention)
Prescription:
Medicated layer:
| The supplementary material title | Recipe quantity (1000) |
| Levo-cetirizine hydrochloride | 2.5g |
| β-cyclodextrin | 10g |
| Microcrystalline Cellulose | 5g |
| Water | In right amount |
| The vertical compression lactose | 150g |
| Microcrystalline Cellulose PH102 | 50g |
| Polyvinylpolypyrrolidone | 10g |
| Magnesium stearate | 3g |
Auxiliary layer:
| The supplementary material title | Recipe quantity (1000) |
| Mannitol | 150g |
| Microcrystalline Cellulose | 50g |
| Lemon yellow | 0.5g |
| Water | In right amount |
| Sucralose | 4g |
| Hami melon essence | 5g |
| Magnesium stearate | 2g |
Preparation technology:
One, particulate preparation
The preparation of medicated layer:
1. the levo-cetirizine hydrochloride that takes by weighing recipe quantity is put in the suitable quantity of water, stirs to make its dissolving.
2. take by weighing the β-cyclodextrin and the microcrystalline Cellulose of recipe quantity, put mix homogeneously in the wet granulator, the levo-cetirizine hydrochloride aqueous solution is added wherein, mix homogeneously, 30 mesh sieves are granulated, 50 ℃ of oven dry, 30 mesh sieve granulate.
3. take by weighing the vertical compression lactose of recipe quantity, the granule mix homogeneously of microcrystalline Cellulose PH102, polyvinylpolypyrrolidone and above-mentioned preparation.
4. add the magnesium stearate of recipe quantity, mix homogeneously promptly gets the medicated layer granule.
The preparation of auxiliary layer:
1. mannitol is crossed 60 mesh sieves, subsequent use.
2. take by weighing the mannitol of recipe quantity, microcrystalline Cellulose, the lemon yellow mix homogeneously adds suitable quantity of water system soft material, and 24 mesh sieves are granulated, 50 ℃ of oven dry, 24 mesh sieve granulate.
3. according to the particulate amount of preparation, add the sucralose and the hami melon essence of prescription proportional quantities, mix homogeneously.
4. add the magnesium stearate of prescription proportional quantities, mix homogeneously promptly gets the auxiliary layer granule.
Two, tabletting
With the medicated layer and the auxiliary layer granule of above-mentioned preparation, put the scrobicula stamping of rotary tablet machine with diameter 11mm, promptly get.
Brief summary: during clathrate, covered by the bitter taste of medicine in preparation for this formulation and technology, but when in pharmaceutical aqueous solution is added to the mixture of beta-schardinger dextrin-and microcrystalline Cellulose, preparing clathrate, material is wet slightly, but does not influence the carrying out of operating process.
According to embodiment 5～embodiment 7, the optimal proportion of β-cyclodextrin and microcrystalline Cellulose is 2:1～1:2 when showing the preparation clathrate.
Embodiment 8 (preferred version of the present invention)
According to embodiment 1～embodiment 7 experimental results, confirm the formulation and technology that the levo-cetirizine hydrochloride chewable tablet is optimum, specific as follows:
Prescription:
Medicated layer:
| The supplementary material title | Recipe quantity (1000) |
| Levo-cetirizine hydrochloride | 2.5g |
| β-cyclodextrin | 10g |
| Microcrystalline Cellulose | 10g |
| Water | In right amount |
| The vertical compression lactose | 150g |
| Microcrystalline Cellulose PH102 | 50g |
| Polyvinylpolypyrrolidone | 10g |
| Magnesium stearate | 3g |
Auxiliary layer:
| The supplementary material title | Recipe quantity (1000) |
| Mannitol | 150g |
| Microcrystalline Cellulose | 50g |
| Lemon yellow | 0.5g |
| Water | In right amount |
| Sucralose | 4g |
| Hami melon essence | 5g |
| Magnesium stearate | 2g |
Preparation technology:
One, particulate preparation
The preparation of medicated layer:
1. the levo-cetirizine hydrochloride that takes by weighing recipe quantity is put in the suitable quantity of water, stirs to make its dissolving.
2. take by weighing the beta-schardinger dextrin-and the microcrystalline Cellulose of recipe quantity, put mix homogeneously in the wet granulator, the levo-cetirizine hydrochloride aqueous solution is added wherein, mix homogeneously, 30 mesh sieves are granulated, 50 ℃ of oven dry, 30 mesh sieve granulate.
3. take by weighing the vertical compression lactose of recipe quantity, the granule mix homogeneously of microcrystalline Cellulose PH102, polyvinylpolypyrrolidone and above-mentioned preparation.
4. add the magnesium stearate of recipe quantity, mix homogeneously promptly gets the medicated layer granule.
The preparation of auxiliary layer:
1. mannitol is crossed 60 mesh sieves, subsequent use.
2. take by weighing the mannitol of recipe quantity, microcrystalline Cellulose, the lemon yellow mix homogeneously adds suitable quantity of water system soft material, and 24 mesh sieves are granulated, 50 ℃ of oven dry, 24 mesh sieve granulate.
3. according to the particulate amount of preparation, add the sucralose and the hami melon essence of prescription proportional quantities, mix homogeneously.
4. add the magnesium stearate of prescription proportional quantities, mix homogeneously promptly gets the auxiliary layer granule.
Two, tabletting
With the medicated layer and the auxiliary layer granule of above-mentioned preparation, put the scrobicula stamping of rotary tablet machine with diameter 11mm, promptly get.
With the levo-cetirizine hydrochloride chewable tablet setting-out of embodiment 8 preparations, carry out study on the stability, concrete outcome is seen table 6:
Table 6 embodiment 8 stability experiment results
Claims (14)
1. the method for preparing the levo-cetirizine hydrochloride chewable tablet, this method may further comprise the steps:
A) the particulate preparation of medicated layer: levo-cetirizine hydrochloride is soluble in water; Then with pharmaceutically acceptable enclose material mixing formation clathrate; Granulate and oven dry obtains particulate matter, in particulate matter, add vertical compression lactose as filler, particle mean size then between the 60-90 micron and bulk density g/cm
3Water-insoluble second kind of microcrystalline Cellulose (preferably microcrystalline cellulose PH102) between 0.28-0.33 adds disintegrating agent (for example polyvinylpolypyrrolidone) and mix homogeneously, adds the magnesium stearate as lubricant then, and mix homogeneously promptly gets the medicated layer granule; Preferably, wherein the enclose material is the enclose material blends that beta-schardinger dextrin-and the first kind microcrystalline Cellulose of particle mean size between the 15-50 micron form, and the part by weight of this mixture and medicine levo-cetirizine hydrochloride is 3:1～7:1;
B) the particulate preparation of auxiliary layer: with mannitol, first kind of microcrystalline Cellulose, color indigo (for example lemon yellow) mix homogeneously adds suitable quantity of water system soft material, granulates and oven dry; Add sucralose and essence (for example hami melon essence), mix homogeneously; Add magnesium stearate then, mix homogeneously promptly gets the auxiliary layer granule;
C) tabletting: place tablet machine to carry out tabletting according to certain part by weight medicated layer granule and auxiliary layer granule, obtain the levo-cetirizine hydrochloride chewable tablet.
2. method according to claim 1, wherein the part by weight of enclose material blends and medicine levo-cetirizine hydrochloride is 4:1～6:1, preferably 4.5:1～5.5:1.
3. method according to claim 1 and 2, it is a double-layer tablet, one deck is a medicated layer; Another layer is an auxiliary layer, and the weight ratio of medicated layer and auxiliary layer is 2:1-1:2, preferably 1.5:1-1:1.5; More preferably 1.3:1-1:1.3, further preferred 1.1:1-1:1.1.
4. according to claim 2 or 3 described methods, wherein in steps A) in the part by weight of beta-schardinger dextrin-and first kind of microcrystalline Cellulose be 2:1～1:2.
5. according to claim 3 or 4 described methods, wherein the disintegrating agent in the medicated layer is selected from one or more in carboxymethylstach sodium, polyvinylpolypyrrolidone or the cross-linking sodium carboxymethyl cellulose, preferred polyvinylpolypyrrolidone; The color indigo is selected from one or more in lemon yellow, iron oxide red or the sapphirine indigo, preferred lemon yellow.
6. according to claim 3 or 4 described methods, wherein the essence in the auxiliary layer is selected from peach flavor essence, hami melon essence, one or more in apple essence or the Fructus Citri tangerinae essence, preferred hami melon essence.
7. according to any one method among the claim 1-6, wherein for the particulate preparation of medicated layer, the amount ratio of levo-cetirizine hydrochloride and filler is 1:50-1:120; Preferred 1:60-1:100; More preferably 1:70-1:90, preferred especially 1:80 is according to the weight meter.
8. according to any one method among the claim 1-7, wherein for the particulate preparation of medicated layer, the amount ratio of levo-cetirizine hydrochloride and disintegrating agent is 1:2-1:6, preferred 1:3-1:5, and more preferably 1:3.5-1:4.5,1:4 most preferably is according to the weight meter.
9. according to any one method among the claim 1-8, wherein for the particulate preparation of medicated layer, the amount ratio of levo-cetirizine hydrochloride and lubricant is 1:2-2:1; Preferred 1:1.7-1.7:1; More preferably 1:1.5-1.5:1, further preferred 1:1.3-1.3:1 is according to the weight meter.
10. according to any one method among the claim 1-9; Wherein for the particulate preparation of medicated layer; As the vertical compression lactose of filler and the weight ratio of second kind of microcrystalline Cellulose (for example microcrystalline Cellulose PH102) is 3.8:1-2.2:1, preferred 3.5:1-2.5:1, more preferably 3.2:1-2.8:1.
11. according to any one method among the claim 1-10, wherein for the particulate preparation of auxiliary layer, the weight ratio of mannitol and first kind of microcrystalline Cellulose is 3.8:1-2.2:1, preferred 3.5:1-2.5:1, more preferably 3.2:1-2.8:1.
12. according to any one method among the claim 1-11, wherein for the particulate preparation of auxiliary layer, the weight sum of mannitol and first kind of microcrystalline Cellulose is 90-98wt% with respect to the percentage ratio of the particulate gross weight of auxiliary layer, preferred 93-96wt%.
13. according to any one method among the claim 1-12; Wherein for the particulate preparation of auxiliary layer; The color indigo is 0.01-0.5wt%, preferred 0.05-0.4wt%, more preferably 0.1-0.3wt%, or sucralose with respect to the percentage ratio of the particulate gross weight of auxiliary layer with respect to the percentage ratio of the particulate gross weight of auxiliary layer is 1-4wt%, preferred 1.5-3.5wt%, more preferably 1.8-3wt%, further preferred 2.0-2.5wt%; Or essence is 1.5-4.5wt%, preferred 2-4wt%, more preferably 2.5-3.5wt%, further preferred 2.8-3.2wt% with respect to the percentage ratio of the particulate gross weight of auxiliary layer; Or magnesium stearate is 0.5-1.5wt%, 0.8-1.2wt% preferably with respect to the percentage ratio of the particulate gross weight of auxiliary layer.
14. by according to any one the levo-cetirizine hydrochloride chewable tablet that method obtained in the above claim 1-13 item.
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| CN103652558A (en) * | 2013-12-11 | 2014-03-26 | 罗永祺 | Chewable tablet containing guangsan seven-white and Chinese yam and preparation method thereof |
| CN103652558B (en) * | 2013-12-11 | 2015-09-30 | 罗永祺 | A kind of GUANG Radix Notoginseng bletilla Chinese yam chewable tablet and preparation method |
| CN109481409A (en) * | 2018-12-29 | 2019-03-19 | 江苏优仿医药科技有限公司 | A kind of Cetirizine hydrochloride Tablets and preparation method thereof |
| CN109481409B (en) * | 2018-12-29 | 2022-02-15 | 微研优仿医药科技(江苏)有限公司 | Cetirizine hydrochloride tablet and preparation method thereof |
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