CN100536845C - Loratadine paster of penetrating skin - Google Patents
Loratadine paster of penetrating skin Download PDFInfo
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- CN100536845C CN100536845C CNB031346510A CN03134651A CN100536845C CN 100536845 C CN100536845 C CN 100536845C CN B031346510 A CNB031346510 A CN B031346510A CN 03134651 A CN03134651 A CN 03134651A CN 100536845 C CN100536845 C CN 100536845C
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- loratadine
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Abstract
A transdermal disk of loratadine for treating allergic disease is prepared from loratadine, adhesive aggregate, cross-linking agent, plasticizer, solvent and smosis promoter through proportionally mixing.
Description
Technical field
The present invention relates to loratadine percutaneous plaster and preparation method thereof and its application in the medicine of preparation treatment allergic disease.The present invention also further comprises short saturating technology, and adding penetration enhancer such as oleic acid, menthol, azone or phospholipid etc. can significantly improve the loratadine percutaneous rate in prescription.
Background of invention
Allergic disease is a kind of commonly encountered diseases and frequently-occurring disease, and according to estimates, the crowd who accounts for world population 10-25% suffers from allergic rhinitis.Antihistaminic can prevent combining of histamine and blood vessel and peripheral nerve-cell, and symptoms such as rhinitis, sneeze, watery nasal discharge are removed in the amelioration of inflammation reaction, are the most effective class medicines that is applicable to allergic diseases such as allergic rhinitis at present.
Loratadine is to be developed by Schering-plough company, and in the tricyclic antidepressants antihistaminic in Belgium's listing in 1988, compares with other antihistaminics such as diphenhydramine, chlorphenamine, teldane and A Simi azoles, loratadine antagonism periphery H
1The effect of receptor has stronger selectivity, and therefore, curative effect is more remarkable, and does not have side effect such as drowsiness.This medicine is preceding 4 of best-selling drugs in 1998 and 1999 continuous 2 years rank worlds, predicts that 2002 annual sales amounts can reach more than 40 hundred million dollars, is world's sales volume maximum, the Claritin that welcome by doctor and patient up to now.
As Claritin, route of administration generally adopts oral or transdermal administration, and the loratadine of listing is oral formulations both at home and abroad at present.The pharmacokinetic data shows that food produces a very large impact the absorption metabolism meeting of medicine.Relevant loratadine transdermal Study on Technology is not domesticly seen bibliographical information as yet, in vitro study (United States Patent (USP) 4910205) report of loratadine gel transdermal technology is abroad only arranged, and have absorption result body in.Loratadine is fat-soluble compound, and is water insoluble, and molecular weight is 382.89, through physicochemical constant being measured and the infiltration coefficient prediction, shows that the permeance property of loratadine own can not satisfy the treatment requirement fully.
Summary of the invention
In order to overcome deficiency of the prior art, the invention provides and to satisfy a kind of loratadine percutaneous plaster that treatment requires fully
The present invention also provides a kind of loratadine percutaneous plaster preparation method
The present invention further provides a kind of purposes of loratadine percutaneous plaster treatment allergic disease.
In order to realize purpose of the present invention, the present invention adopts following technical scheme.
Percutaneous plaster of the present invention is as active component with loratadine.Loratadine paster of the present invention comprises the sticking matrix-type transdermal paster that contains gluing framework material, or contains the compound percutaneous plaster of adhesive and controlled-release material.
In the prescription of the present invention fixedly EUDRAGIT E 100 consumptions be 1.8g, the calculating of dibutyl sebacate and succinic acid consumption is benchmark with EUDRAGIT E 100, calculates the percentage ratio that the two accounts for EUDRAGIT E 100 respectively.
The sticking matrix-type transdermal paster of loratadine of the present invention comprises adhesive, cross-linking agent, plasticizer, solvent.
The compound loratadine paster of the present invention preferably uses polysiloxane-based or polyisobutylene class pressure sensitive adhesive adds controlled-release material and is prepared from.
Adhesive of the present invention comprises polyacrylate macromolecular material, polysiloxane-based and polyisobutylene class.The preferred polyacrylate macromolecular material that uses.Preferred polyacrylate macromolecular material comprises Eudragit E100.The preferred range of Eudragit E100 consumption is 45%～90% (g/ml); The preferred scope of Eudragit E100 consumption is 55-65% (g/ml).
Cross-linking agent of the present invention is succinic acid preferably, and the effective range of succinic acid is 2 ~ 18%.
Plasticizer of the present invention is dibutyl sebacate preferably, and the effective range of dibutyl sebacate is 20 ~ 70%.
What the solvent that the present invention uses used is organic solvent, and preferred solvent is an alcohols; Preferred solvent is a lower alcohol; Most preferred solvent is an ethanol.
In embodiment preferred of the present invention, percutaneous plaster comprises loratadine, EUDRAGITE100, succinic acid, dibutyl sebacate and ethanol.With EUDRAGIT E 100 is benchmark, per 1.8 gram EUDRAGIT E 100, and corresponding succinic acid 4.4-7.5%, dibutyl sebacate 40-50%, ethanol 3ml, the drug loading of loratadine are 0.65-0.75mg/cm
2
According to the present invention, in optimized technical scheme, percutaneous plaster of the present invention also comprises acceptable penetration enhancer on the pharmacodynamics.Preferred penetration enhancer comprises oleic acid, menthol, azone, phospholipid.The preferred amount ranges of oleic acid is 10% ~ 15% (ml/ml), and preferred amount ranges is 10%.The preferred amount ranges of menthol is 1%-2%.The preferred amount ranges of azone is 3%-10%.The preferred amount ranges of phospholipid is 1%-2%.
The preparation method of the percutaneous plaster that also comprises according to the present invention is characterized in that, comprises the steps:
(A) take by weighing loratadine, adhesive, cross-linking agent, plasticizer, solvent;
(B) adhesive, cross-linking agent, plasticizer mix, and add solvent, leave standstill 24 hours, make the abundant swelling of adhesive;
(C) add loratadine, selectable adding penetration enhancer leaves standstill a few hours; Fully mix and make into pastille glue, ultrasonic degas;
(D) coat on the separate paper, add backing layer, add adherent layer, drying.
By Orthogonal Experiment and Design, optimize the prescription proportioning.In the effective range of succinic acid and dibutyl sebacate, select orthogonal table L for use
9(3
4), the contrived experiment scheme, and, investigate transdermal test in vitro speed, solution viscosity and peel adhesion respectively by the gluing skeleton paster of orthogonal table prescription preparation.The result shows: when dibutyl sebacate and succinic acid large usage quantity, it is big to prepare dried paster peel adhesion, has residual on skin.Particularly work as dibutyl sebacate more than or equal to 60%, the succinic acid consumption was more than or equal to 15% o'clock, and the adhesion of paster is excessive, and is residual too much on skin.Drug loading is more than or equal to 0.88mg/Gm
2The time, after the paster drying, medicine can slowly be separated out from paster, and standing time is long more, separates out seriously more, is unfavorable for preserving.The ethanol consumption increases, and solution viscosity reduces, and in being coated with the shop process, is difficult for being attached on backing layer.
The every index index of comprehensive various investigation, EUDRAGIT E 100 consumptions of promptly writing out a prescription are 1.8g, succinic acid 6.5%, dibutyl sebacate 45%, drug loading are 0.71mg/cm
2, ethanol 3ml is preferred plan.
The present invention is further on the gluing skeleton paster prescription research basis to loratadine, by short infiltration technology research, improve loratadine releasing medicine through skin penetration speed, and by determination of plasma concentration in the body, investigate the inside and outside dependency, estimate release effect in the preparation capable of permeating skin body.
Specifically, the present invention is 1.8g with prescription EUDRAGIT E 100 consumptions, succinic acid 6.5%, and dibutyl sebacate 45%, drug loading are 0.71mg/cm
2Ethanol 3ml is the basis prescription, add penetration enhancer oleic acid, menthol, azone and phospholipid again respectively, by gluing matrix-type transdermal paster preparation method, preparation contains the loratadine paster of different penetration enhancer, measures different time accumulation transit dose Q (μ g), is abscissa with drug release time t, release amount Q is a vertical coordinate, draws the release curve.Result of the test shows that penetration enhancer oleic acid (10%), menthol (1%), azone (5%) and phospholipid (2%) can reach good short effect.The results are shown in accompanying drawing 1.
T returns Q with the time, calculates release equations, and the result is as follows:
Do not contain penetration enhancer: Q=1.4431t-3.9594, r=0.987
10% oleic acid: Q=4.3965t-1.8478, r=0.9979
1% menthol: Q=3.6529t-5.4468, r=0.9974
5% azone: Q=3.7101t-0.5709, r=0.9968
2% phospholipid: Q=3.1285t-7.1914, r=0.9964
The slope of release equations is percutaneous rate, The above results shows, adds an amount of penetration enhancer, can significantly increase loratadine body outer osmotic speed, urge to ooze effect and be followed successively by oleic acid menthol Azone phospholipid, oleic acid can make the loratadine infiltration rate by 1.44 μ g/cm
2.h be increased to 4.4 μ g/cm
2.h, and lag time shorter.
Loratadine paster of the present invention agent has overcome the loratadine oral formulations when taking, and food is to the influence of the absorption metabolism generation of medicine.Preparation of the present invention is compared with oral formulations, not influenced by gastrointestinal factors and other metabolic factors, and is only relevant with skin factors.In addition, anaphylaxis all can be fallen ill whenever and wherever possible, and preparation capable of permeating skin uses more convenient, can realize flexible and changeable individual administration.The gluing skeleton paster skin irritation that contains loratadine is little, has vivo transdermal speed preferably, and blood drug level is steady, and the length of holding time can be used for the treatment of anaphylactic disease better.
Description of drawings
Fig. 1: the loratadine paster body outer osmotic curve that contains different penetration enhancer
Fig. 2: the different proportion oleic acid external release curve of writing out a prescription
Fig. 3: the different proportion menthol external release curve of writing out a prescription
Fig. 4: the different proportion azone external release curve of writing out a prescription
Fig. 5: the different proportion phospholipid external release curve of writing out a prescription
Fig. 6: curve when containing 10% oleic loratadine paster rabbit body giving drugs into nose
The specific embodiment
The following examples are used for further specifying the present invention, but this and do not mean that any limitation of the invention.
The selection of embodiment 1 basis prescription
According to adopting polyacrylate macromolecular material Eudragit E100 to make skeleton and adhesive, make cross-linking agent with succinic acid, dibutyl sebacate is a plasticizer, ethanol is solvent.
In the prescription of the present invention fixedly EUDRAGIT E 100 consumptions be 1.8g, the calculating of dibutyl sebacate and succinic acid consumption is benchmark with EUDRAGIT E 100, calculates the percentage ratio that the two accounts for EUDRAGIT E 100 respectively.Cross-linking agent and plasticizer consumption level are selected according to the description of product of succinic acid, dibutyl sebacate, macromolecular material Eudragit E100, and the effective range of succinic acid is 2 ~ 18%, and the effective range of dibutyl sebacate is 20 ~ 70%.
By Orthogonal Experiment and Design optimization prescription.Determine each factor level thus, see Table 1.
Table 1 orthogonal test factor level table
Select orthogonal table L for use
9(3
4), design following experimental program:
The design of table 2 orthogonal table
By the gluing skeleton paster of orthogonal table prescription preparation, investigate respectively transdermal test in vitro speed, solution viscosity and peel adhesion and, the results are shown in Table 3.
Table 3 orthogonal experiments
Annotate: H, M, L represent high, medium and low respectively.
Result of the test shows that the ethanol consumption increases, and solution viscosity reduces, and in being coated with the shop process, is difficult for being attached on backing layer.And when dibutyl sebacate and succinic acid large usage quantity, it is big to prepare dried paster peel adhesion, has residual on skin.Particularly working as dibutyl sebacate is 60%, and the succinic acid consumption is 15% o'clock, and the adhesion maximum of paster is residual maximum on skin.Drug loading is 0.88mg/cm
2The time, after the paster drying, medicine can slowly be separated out from paster, and standing time is long more, separates out serious more.
Comprehensive various investigation index shows that No. 2 experimental programs are A
1B
2C
2D
2Be optimal case, promptly EUDRAGIT E 100 consumptions are 1.8g, succinic acid 6.5%, and dibutyl sebacate 45%, ethanol 3ml, drug loading are 0.71mg/cm
2
Embodiment 2: the prescription research of loratadine percutaneous plaster basis
Prescription is formed: prescription 1
Loratadine 36mg
Eudragit E100：1800mg
Succinic acid: 120mg
Dibutyl sebacate: 0.85ml
Ethanol: 3ml
Take by weighing Eudragit E 100 in the prescription ratio, succinic acid, dibutyl sebacate adds ethanol, leaves standstill 24 hours, makes Eudragit E 100 abundant swellings, accurately adds loratadine in the prescription ratio, leaves standstill a few hours; Fully mix and make into the pastille glue, ultrasonic degas is coated on the separate paper, and thickness is 0.1mm, adds backing layer, and drying forms.
Paster is cut into the circular shaped patches that diameter is 1.9cm, place on the transdermal diffusion experiment instrument, carry out the Transdermal absorption test, measure different time accumulation transdermal amount Q (μ g), with time t infiltration capacity Q is carried out linear regression, get linear equation: Q=1.4431t-3.9594, r=0.987.
The equation slope is percutaneous rate J.J＝1.4431μg/cm
2.h。
T maps to Q with the time, gets the releasing medicine through skin penetration curve, the results are shown in accompanying drawing 1.
Embodiment 3: oleic acid is to the transdermal enhancing effect research of loratadine
Take by weighing Eudragit E 100 in the prescription ratio, succinic acid, dibutyl sebacate adds ethanol, leaves standstill 24 hours, makes Eudragit E 100 abundant swellings, accurately adds loratadine in the prescription ratio, adds the oleic acid of different proportion respectively, leaves standstill a few hours; Fully mix and make into the pastille glue, ultrasonic degas is coated on the separate paper, and thickness is 0.1mm, adds backing layer, and drying forms.
Paster is cut into the circular shaped patches that diameter is 1.9cm, place on the transdermal diffusion experiment instrument, carry out Transdermal absorption, test determination different time accumulation transdermal amount Q (μ g) carries out linearity with time t to infiltration capacity Q and returns
Return, get linear equation:
0.15ml oleic acid: Q=1.1113t-2.1851r=0.9772
0.30ml oleic acid: Q=4.3965t-1.8478r=0.9979
0.60ml oleic acid: Q=1.6561t-4.1319r=0.9970
0.90ml oleic acid: Q=1.3702t-2.6721r=0.9984
T maps to Q with the time, gets the releasing medicine through skin penetration curve, the results are shown in accompanying drawing 2.
By release side and calculating infiltration rate J, see Table 4.
Table 4: contain different proportion oleic acid prescription infiltration rate value
| |
5 |
10 |
15 |
20% oleic acid | No penetration enhancer |
| J(μ g/cm 2h) | 1.11 | 4.40 | 1.66 | 1.37 | 1.44 |
The result shows, contains 10% oleic acid in the prescription, and infiltration rate is the highest, and lag time is short; Oleic acid content is 5% and 20% o'clock, and infiltration rate is lower than the basis prescription on the contrary, and content is to write out a prescription a little more than the basis in 15% o'clock.
Embodiment 4: menthol is to the transdermal enhancing effect research of loratadine
Take by weighing Eudragit E 100, succinic acid, dibutyl sebacate in the prescription ratio, add ethanol, left standstill 24 hours, make Eudragit E 100 abundant swellings, accurately add loratadine in the prescription ratio, add the menthol of different proportion respectively, leave standstill a few hours; Fully mix and make into the pastille glue, ultrasonic degas is coated on the separate paper, and thickness is 0.1mm, adds backing layer, and drying forms.
Paster is cut into the circular shaped patches that diameter is 1.9cm, places on the transdermal diffusion experiment instrument, carry out the Transdermal absorption test, measure different time accumulation transdermal amount Q (μ g), get following release equations:
1％：Q＝3.6529t-5.4468r＝0.9974
2％：Q＝2.4854t-3.9785r＝0.9991
T maps to Q with the time, gets the releasing medicine through skin penetration curve, the results are shown in accompanying drawing 3.
According to release equations, calculate infiltration rate J, the results are shown in Table 5.
Table 5: contain different proportion menthol prescription infiltration rate value
| |
1 |
2% menthol | No penetration enhancer |
| J(μg/cm 2h) | 3.65 | 2.49 | 1.44 |
The result shows, adds menthol, and percutaneous rate increases, and 1% consumption is better than 2%.
Embodiment 5: azone is to the transdermal enhancing effect research of loratadine
Take by weighing Eudragit E 100 in the prescription ratio, succinic acid, dibutyl sebacate adds ethanol, leaves standstill 24 hours, makes Eudragit E 100 abundant swellings, accurately adds loratadine in the prescription ratio, adds the azone of different proportion respectively, leaves standstill a few hours; Fully mix and make into the pastille glue, ultrasonic degas is coated on the separate paper, and thickness is 0.1mm, adds backing layer, and drying forms.
Paster is cut into the circular shaped patches that diameter is 1.9cm, places on the transdermal diffusion experiment instrument, carry out the Transdermal absorption test, measure different time accumulation transdermal amount Q (μ g), get following release equations:
3％：Q＝2.3226t-4.3987r＝0.9958
5％：Q＝3.7101t-0.5709r＝0.9968
10％：Q＝2.5732t-6.6208r＝0.9917
T maps to Q with the time, gets the releasing medicine through skin penetration curve, the results are shown in accompanying drawing 4.
According to release equations, calculate infiltration rate J, the results are shown in Table 6.
Table 6: contain different proportion azone prescription infiltration rate value
| |
3 |
5 |
10% azone | No penetration enhancer |
| J(μ g/cm 2h) | 2.32 | 3.71 | 2.57 | 1.44 |
The result shows that Azone has facilitation to the loratadine percutaneous rate, and is wherein best with the short saturating effect of 5% azone.
Embodiment 6: phospholipid is to the transdermal enhancing effect research of loratadine
Take by weighing Eudragit E 100 in the prescription ratio, succinic acid, dibutyl sebacate adds ethanol, leaves standstill 24 hours, makes Eudragit E 100 abundant swellings, accurately adds loratadine in the prescription ratio, adds the phospholipid of different proportion respectively, leaves standstill a few hours; Fully mix and make into the pastille glue, ultrasonic degas is coated on the separate paper, and thickness is 0.1mm, adds backing layer, and drying forms.
Paster is cut into the circular shaped patches that diameter is 1.9cm, places on the transdermal diffusion experiment instrument, carry out the Transdermal absorption test, measure different time accumulation transdermal amount Q (μ g), get following release equations:
1％：Q＝2.5791t-6.6913r＝0.9981
2％：Q＝3.1285t-7.1914r＝0.9964
T maps to Q with the time, gets the releasing medicine through skin penetration curve, the results are shown in accompanying drawing 5.
According to release equations, calculate infiltration rate J, the results are shown in Table 7.
Table 7: contain different proportion phospholipid prescription infiltration rate value
| |
1 |
2% phospholipid | No penetration enhancer |
| J(μ g/cm 2h) | 2.58 | 3.13 | 1.44 |
The result shows that phospholipid has transdermal enhancing effect to medicine, and is wherein more excellent with 2% effect.
Embodiment 7 in vivo tests
Get male rabbit (4kg), fasting 12 hours carefully scrapes off the fine hair on its ear, notes not injured skin.Get prescription 3 pasters, 5 * 5cm
2The paster of area is attached to ear inboard (pastille 20mg), by per kilogram of body weight 5mg administration, after the administration 1,2,5,7,12,23,30,36, the 48h auricular vein is got blood, puts in the centrifuge tube of heparin sodium processing, centrifugal 20 minutes of 3000rpm gets blood plasma 0.5ml and handles, and measures blood drug level according to the HPLC method, the result is through the 3P87 software processes, calculates pharmacokinetic parameter (table 8), and curve (accompanying drawing 6) when drawing medicine.
Table 8 loratadine paster rabbit body giving drugs into nose is for kinetic parameter
The result shows that blood drug level slowly raises after the administration, reaches the blood drug level peak at about 12 hours, and blood drug level tends to be steady substantially in 36 hours, has controlled-release effect preferably.
The rabbit medication was taken off paster after 48 hours, measured the residual drug in skin surface and the paster, calculated by surface disappearance method and entered intravital medication amount, transmission rates in estimation bioavailability and the animal body.The result shows, contains the paster of 20mg, and residual quantity is 12.1mg, surperficial disappearance amount=20-12.1=7.9mg.Because of skin is thinner, residual quantity can be ignored in the skin, can think that the medicine of 7.9mg all enters the body circulation, estimates that roughly bioavailability is 7.9/20=39.5%.Estimate roughly that by constant speed release medicine vivo transdermal speed is 7.9 (mg) ÷, 25 (cm
2) ÷ 48 (h)=6.58 μ g/cm
2.h.
Claims (1)
1, a kind of percutaneous plaster is characterized in that, contains loratadine, Eudragit E 100, succinic acid, dibutyl sebacate, ethanol; With Eudragit E 100 is benchmark, and every Eudragit E 1001800mg is corresponding to be used
Loratadine: 36mg
Succinic acid: 120mg
Dibutyl sebacate: 0.85ml
Ethanol: 3ml.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031346510A CN100536845C (en) | 2003-09-23 | 2003-09-23 | Loratadine paster of penetrating skin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031346510A CN100536845C (en) | 2003-09-23 | 2003-09-23 | Loratadine paster of penetrating skin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1600297A CN1600297A (en) | 2005-03-30 |
| CN100536845C true CN100536845C (en) | 2009-09-09 |
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|---|---|---|---|
| CNB031346510A Expired - Fee Related CN100536845C (en) | 2003-09-23 | 2003-09-23 | Loratadine paster of penetrating skin |
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Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100444841C (en) * | 2004-11-10 | 2008-12-24 | 鲁南制药集团股份有限公司 | Externally used loratadine formulation |
| NZ565049A (en) | 2005-06-17 | 2012-02-24 | Vital Health Sciences Pty Ltd | A carrier comprising one or more DI and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof |
| US10071030B2 (en) | 2010-02-05 | 2018-09-11 | Phosphagenics Limited | Carrier comprising non-neutralised tocopheryl phosphate |
| ES2829386T3 (en) * | 2010-03-30 | 2021-05-31 | Phosphagenics Ltd | Transdermal administration patch |
| WO2012122586A1 (en) | 2011-03-15 | 2012-09-20 | Phosphagenics Limited | New composition |
| CN105078928A (en) * | 2014-05-08 | 2015-11-25 | 广东省中药研究所 | Nisoldipine ethosome controlled-released patch and preparation method thereof |
| CN104840449B (en) * | 2015-04-22 | 2018-05-18 | 崔建平 | A kind of medicine patch and preparation method thereof |
| CN105147642B (en) * | 2015-07-31 | 2018-02-16 | 大连理工大学 | A kind of transdermal patch containing Formoterol or its fumarate |
| WO2017096427A1 (en) | 2015-12-09 | 2017-06-15 | Phosphagenics Limited | Pharmaceutical formulation |
| EP3558903A4 (en) | 2016-12-21 | 2019-11-27 | Avecho Biotechnology Limited | Process |
| CN115778924A (en) * | 2022-12-22 | 2023-03-14 | 河北三禾实创生物科技有限公司 | Loratadine preparation and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4910205A (en) * | 1988-05-02 | 1990-03-20 | Schering Corporation | Transdermal delivery of loratadine |
| WO2002078736A2 (en) * | 2001-03-30 | 2002-10-10 | Antialis | Antiallergic pharmaceutical composition |
-
2003
- 2003-09-23 CN CNB031346510A patent/CN100536845C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4910205A (en) * | 1988-05-02 | 1990-03-20 | Schering Corporation | Transdermal delivery of loratadine |
| WO2002078736A2 (en) * | 2001-03-30 | 2002-10-10 | Antialis | Antiallergic pharmaceutical composition |
Non-Patent Citations (2)
| Title |
|---|
| 药剂学. 毕殿洲，429-446，人民卫生出版社. 2001 * |
| 透皮吸收制剂基质的研究进展. 刘成，胡晋红，朱全刚.中国新药杂志，第11卷第8期. 2002 * |
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| CN1600297A (en) | 2005-03-30 |
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