CN1541644A - Fluoxetine enteric coated tablet - Google Patents
Fluoxetine enteric coated tablet Download PDFInfo
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- CN1541644A CN1541644A CNA031166660A CN03116666A CN1541644A CN 1541644 A CN1541644 A CN 1541644A CN A031166660 A CNA031166660 A CN A031166660A CN 03116666 A CN03116666 A CN 03116666A CN 1541644 A CN1541644 A CN 1541644A
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Abstract
The present invention relates to medicine preparing technology and provides one kind of enteric Fluoxetine preparation for treating depression. The preparation is one kind of common tablet inside enteric coating. Its isolating layer contains one or several of HPMC, PVP, AEA and HPC; and its enteric coating contains one or several of acrylic resin, HPMC, PVP and CAP. The preparation has its active released in small intestine, and is superior to available Fluoxetine capsule, tablet and oral liquid, which has bad taste and irritation to stomach mucous membrane.
Description
Technical field:
The invention belongs to technical field of medicine.Be specifically related to common enteric coated preparation of hydrochloric fluoxetine and preparation method thereof.
Background technology:
Fluoxetine, promptly N-methyl-3-(right-4-trifluoromethylphenopendant)-3-phenylpropylamine is a kind of antidepressants.This medicine is disclosed in for example United States Patent (USP) 4314081 and 4626549, and the antidepressant effect of described fluoxetine is for suppressing the reuptake of central nervous system to 5-HT.Be applicable to treatment depression and relevant anxiety symptom thereof; Treatment bulimia nervosa and obsessive idea and conduct disorder.
The pharmaceutical dosage form of fluoxetine has both at home and abroad at present: solution, dispersible tablet, ordinary tablet, capsule, slow releasing capsule etc.Eli Lilly company at U. S. application Fluctin slow release capsule patent (US 4847092), this patent is protected matrix type slow release antidepressant capsule; US5985322 has applied for the patent of Fluoxetine enteric micropills; Eli Lilly company China applied for Fluoxetine enteric micropills patent (CN1285189, CN1200924); Eli Lilly company has applied for Fluoxetine pahrmaceutical formulations (dispersible tablet) patent (CN1123142A) in China.
Fluoxetine has intensive bitterness and other tastes beastly, oral common solid preparation influences patient's sense of taste, cause side effect such as nauseating, vomiting at the too high stimulation gastric mucosa of stomach local concentration, therefore, the common drug dosage form of fluoxetine administration comprises capsule, conventional tablet and the solution that just uses recently clinically, all has a series of restrictions and unfavorable factor:
1. oral common solid preparation:
---patient takes the aspect, and limited resource is difficult to swallowable capsule for some patient, and particularly in fact child and old man may can't swallow at all;
---the intensive bitterness of fluoxetine and other tastes beastly, the patient is difficult to accept;
---the too high stimulation gastric mucosa of fluoxetine stomach local concentration causes side effect such as nauseating, vomiting;
---the dosage aspect, it is possible having only single dose.
2. take the fluoxetine Hydrochloride solution unfavorable factor also arranged:
---active component dosage needs to calculate, and is inaccurate usually.
---diabetes patient's medication restriction.
---children is easily out of control, and excessive danger is arranged.
---the dosage complexity, limited operation and transportation.
In addition on the one hand, the depressed constantly administration constantly of fluoxetine (average 2～6 months) that needs effective dose of treatment, therefore when needing long-time the absorption, capsule, tablet or oral liquid administration can produce unhappy phenomenon to patient's special sense feature, produced the problem that can patient accept, can cause finishing treatment, this has greatly reduced curative effect.Therefore, generally speaking, the form of administration of existing fluoxetine can not satisfy the depressed and required ask for something of other relevant disease of treatment fully.
About enteric coated preparation, in the conventional enteric coated preparation of preparation fluoxetine, there are some difficulties at present.Specifically, found that fluoxetine can form the slow even insoluble coating of dissolving with many enteric coating reactions.At other drug such as duloxetine, nortriptyline, desmethylimipramine has also been observed the similar reaction with enteric coating in the Sertraline (sertraline).Antidepressants duloxetine as candidate is (+)-N-methyl-3-(1-naphthoxy)-2-fen thiophene propylamine at present, uses with the form of hydrochlorate usually.In United States Patent (USP) 5508276, required the enteric coating preparation of duloxetine, acid degradation has taken place under one's belt to prevent this chemical compound.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, provides the fluoxetine that needs clinically new enteric dosage form, can make things convenient for patient's administration, reduces the gastrointestinal stimulation symptom.
The invention provides place's Fluoxetine enteric coated tablet, these enteric coatel tablets contain fluoxetine or its optical antipode or its acid-addition salts and pharmaceutically acceptable enteric-coating material, diluent and other excipient.And be suitable for preparing the pharmaceutical composition of enteric coated tablet.Tablet of the present invention contains:
(1) label of forming by fluoxetine and one or more excipient
| Specification 10mg | Specification 20mg | |
| Fluoxetine Hydrochloride | ????11.2mg | ????22.4mg |
| Starch | ????25mg | ????50mg |
| Lactose | ????30mg | ????60mg |
| The L-hydroxypropyl cellulose | ????10mg | ????20mg |
| ??CMS-Na | ????5mg | ????10mg |
| 8% starch slurry | In right amount | In right amount |
| Magnesium stearate | ????0.8mg | ????1.6mg |
(2) one or more and one or more excipient that contains among HPMC, HPC, PVP, the CAP adds the gastric solubleness clothing layer that one or more porogen in PEG, triethyl citrate, triacetin, DEP, the silicone oil are formed.
HPMC??????????????????????3～10mg
PEG???????????????????????0.3～0.6mg
Pulvis Talci (100 order) 0.6～1.5mg
(3) one or more and one or more excipient that contains among acrylic resin, HPMCP, PAP, the CAP adds the enteric coat layer that one or more porogen in PEG, triethyl citrate, triacetin, DEP, the silicone oil are formed.
Acrylic resin 15～45mg
PEG???????????????????????1.5～4.5mg
Pulvis Talci (100 order) 2.5～9.5mg
The present invention relates to principal agent makes graininess and forms the granule that comprises whole active component with binding agent with multiple excipient; The label that is pressed into granule comprises dispensable other excipient such as granule, flavoring agent; The invention still further relates to general thin clothing layer and enteric coating layer.
Specifically describe the most preferred embodiment of the present invention now, also relate to other preferred compositions of the present invention.The various compositions and the coatings of tablet below will be discussed respectively, and discuss simultaneously and add the method that various compositions progressively make up the Fluoxetine enteric tablet.
Another object of the present invention has provided the preparation method of Fluoxetine enteric coated tablet, and this method may further comprise the steps:
(1) principal agent is mixed with multiple excipient, add binding agent or wetting agent system granule, drying, granulate then.
(2) with (1) and mix lubricant.
(3) with (2) tabletting on common tablet machine or high speed tablet press, thus shallow circle or the oval tablet of acquisition hardness 5～8kg.
(4) with HPMC, PEG, Pulvis Talci mixing, become coating solution, to tablet bag sealing coat with water dissolution.
(5) with acrylic resin, PEG and Pulvis Talci mixing, become enteric coating liquid, give (4) enteric coated with water or dissolve with ethanol.
The present invention improves the smoothness and the roundness of clothing layer by plasticizer etc., and plasticizer reduces the defective incidence rate.
The roughness of film-coat increases with the viscosity of used coating solution, and is relevant with the polymer model.The preferred HPMC E6～E15 of the present invention, preferred acrylic resins E30D or L100 or L100-55, preferred PEG is a plasticizer, 30 ℃ of critical temperatures.The polymer coating material can or carry out coatedly at the solution in water or the organic solvent as coating with form of powder, the adding of additive simultaneously increases the thin film internal stress, and film-coat elasticity increases.Pulvis Talci or magnesium carbonate can reduce the incidence rate of film-coat defective.Granule exists with thin slice, is parallel to the surface, and the shrinkage on clothing film surface is restricted.
The present invention can use defoamer, suspending agent, surfactant etc. to improve the fineness of tablet surface, can use tween 80, sodium lauryl sulphate etc. and suspending agent such as CMC etc. usually.
Usually in enteric coating layer, add Powdered excipient such as Pulvis Talci, glyceryl monostearate or hydrated SiO 2 to increase the thickness of layer, make it firm, reduce electrostatic charge to reduce the granule viscous force.About 1% to the about 15% above-mentioned solid that can be end product with content adds in the enteric polymer mixture, and the content of enteric polymer own is generally about 5% to about 30%, preferred 10% to 25%.
The invention provides the enteric coated tablet of 10mg or 20mg fluoxetine, wherein 20mg is administered once every day, and 10mg can adjust dosage or consolidate curative effect according to the state of an illness, is particularly suited for long term administration once a day.Also available 1mg, 5mg, 15mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg or 80mg fluoxetine or its enantiomer or salt preparation unit dosage forms.Described dosage form has low advantage of taking frequency, few side effects, than the known dosage form (capsule, conventional tablet and solution) of fluoxetine series of advantages is arranged, and is as follows:
---be applicable to that treatment is to taking solid dosage forms (capsule) patient that has any problem;
---be applicable to the diabetes patients with depression, reason is not contain the sucrose sweeting agent;
---the special sense of oral administered bitter free, the sense of discomfort of avoiding general formulation to bring, the patient can accept;
---avoid the stomach local concentration excessive, eliminate sticking side effect such as feeling sick of causing, vomiting, the good patient compliance of stimulating of stomach;
---stability is better, and described enteric coating has superior moisture-resisting effect, and its shape, big I be in its cryptomere aluminium-plastic panel of packing into, is easy to carry and takes, and can guarantee that the patient finishes treatment and improves curative effect;
---eliminate the danger of oral solution overdose, made it safer, be particularly suitable for child or gerontal patient.
Following examples have illustrated the embodiment that the present invention is concrete, illustrated embodiment use starch, Lactis Anhydrous, LS-HPC, CMS-Na and HPMC (E6～E15), the high viscosity acrylic acid derivative of German RohmPharm (about 7: 3 copolymer by methacrylic acid and methylmethacrylate is formed) Eudragit series.
Preparation of the present invention can be used for treating the patient who suffers from following disease: depression, depressive sine depression, spirit depressing, inferior syndrome depression (subsyndromal), agitated depression, retarded depression, the depression ill altogether with cancer, the psychosis depression, endogenous cause of ill depression and reactive depression, concurrent depression after diabetes or the myocardial infarction, menopausal depression, the nerve bulimia, obsessive idea and behavior illness or bulimia nerovsa, nervous anorexia, alcoholism, anorexia nervosa, anxiety, Panic disorder, social panic, dysorexia, emotion relevant and/or appetite fluctuation with premenstrual syndrome, relevant with premenstrual syndrome is in a very depressed state and/or the sugar addiction, anxious state of mind, the appetite fluctuation is because of nicotine withdrawal is recommitted the fluctuation that trend causes, circadian rhythm obstacle, the borderline personality disorder, hypochondriasis, after the premenstrual syndrome luteal phase anxiety neurosis, trichotillomania, the symptom of having no progeny in other antidepressants, attack/intermittence irritability disease, compulsive gambling, mandatory cost, mandatory sexual behaviour, neurological disorder due to the application mentation material, sexual intercourse obstacle, psychotic disorder, premature ejaculation or psychiatric symptom such as anxiety, anxiety, indignation is refused sensitivity and lack of wisdom or physical ability.
Contain the tablet of fluoxetine as active component except that above-mentioned, also fluoxetine and other active ingredients can be prepared the administering drug combinations product.
The specific embodiment
Embodiment 1:
| The 10mg enteric coatel tablets | The 20mg enteric coatel tablets | |
| Label | ||
| Fluoxetine hydrochloride | ????11.18mg | ????22.36mg |
| Starch | ????25.12mg | ????50.24mg |
| Lactose | ????28.88mg | ????57.76mg |
| ??LS-HPC | ????10.56mg | ????21.12mg |
| ??CMS-Na | ????8.41mg | ????16.82mg |
| Magnesium stearate | ????0.85mg | ????1.7mg |
| Sealing coat | ||
| ??HPMC | ????4.6mg | ????9.2mg |
| ??PEG | ????0.45mg | ????0.9mg |
| Pulvis Talci (100 order) | ????0.95mg | ????1.9mg |
| Enteric coating layer | ||
| Acrylic resin | ????8.15mg | ????16.3mg |
| ??PEG | ????0.91mg | ????1.82mg |
| Pulvis Talci (100 order) | ????1.94mg | ????3.88mg |
Preparation method:
1. with mixing such as fluoxetine hydrochloride, starch, lactose, LS-HPC, CMS-Na, add 8% starch
Slurry is granulated, dry, granulate.
2. obtaining granule with 1 mixes with magnesium stearate.
3. with the 2 mixture tablettings on tablet machine that obtain, thereby obtain the circular or oval of hardness 5～8kg
The shape tablet.
4. with HPMC, PEG, Pulvis Talci mixing, make the gastric solubleness coating solution as solvent, give 3 gained with water
Tablet bag general thin clothing.
5. acrylic resin, PEG and Pulvis Talci are mixed, make enteric coating liquid as solvent with water or ethanol,
Give the tablet of 4 gained enteric coated.
The described preparation method of this embodiment, mobility of particle, compressibility are satisfactory, and the tabletting process is smooth; Art for coating is feasible, and sealing coat and enteric coating layer are smooth, fine and close, and toughness and intensity all reach requirement.
Gained tablet feature is as follows:
1. the coating anter is heavy: 10mg specification 85mg ± 5%, 20mg specification 170mg ± 5%.Hardness: 5～8kg;
2. label friability:＜0.5%;
3. label disintegration: 5min.
4. the coating rear panel is heavy: 10mg specification 102mg ± 5%, 20mg specification 204mg ± 5%.
5. meet the quality standard requirement of Chinese Pharmacopoeia enteric coating preparation.
Embodiment 2:
| The 10mg enteric coatel tablets | The 20mg enteric coatel tablets | |
| Label | ||
| Fluoxetine hydrochloride | ????11.15mg | ????22.30mg |
| Starch | ????21.25mg | ????42.50mg |
| Lactose | ????29.86mg | ????59.72mg |
| ??LS-HPC | ????12.56mg | ????25.12mg |
| ??CMS-Na | ????7.48mg | ????14.96mg |
| Magnesium stearate | ????0.91mg | ????1.82mg |
| Sealing coat | ||
| ??HPMC | ????5.1mg | ????10.2mg |
| ??PEG | ????0.52mg | ????1.04mg |
| Pulvis Talci (100 order) | ????0.91mg | ????1.82mg |
| Enteric coating layer | ||
| Acrylic resin | ????9.05mg | ????18.10mg |
| ??PEG | ????0.91mg | ????1.82mg |
| Pulvis Talci (100 order) | ????1.75mg | ????3.50mg |
Prepare this product according to embodiment 1 described method.
Embodiment 3:
| The 10mg enteric coatel tablets | The 20mg enteric coatel tablets | |
| Label | ||
| Fluoxetine hydrochloride | ????11.20mg | ????22.40mg |
| Starch | ????25.25mg | ????50.50mg |
| Lactose | ????28.86mg | ????57.72mg |
| ??LS-HPC | ????11.56mg | ????23.12mg |
| ??CMS-Na | ????6.48mg | ????12.96mg |
| Magnesium stearate | ????0.91mg | ????1.82mg |
| Sealing coat | ||
| ??HPMC | ????6.05mg | ????12.10mg |
| ??PEG | ????0.62mg | ????1.24mg |
| Pulvis Talci (100 order) | ????0.95mg | ????1.90mg |
| Enteric coating layer | ||
| Acrylic resin | ????9.15mg | ????18.30mg |
| ??PEG | ????0.91mg | ????1.82mg |
| Pulvis Talci (100 order) | ????1.82mg | ????3.64mg |
Substantially according to used this product of method system of embodiment 1, the scale of this method that different is is amplified, and is prepared with 1000 raw materials.
The invention provides following prescription:
1. label:
1) scale 10mg:
Fluoxetine Hydrochloride 11.18-11.32mg
Starch 20-30mg
Lactose 20-40mg
Hydroxypropyl cellulose 8-15mg
Hydroxymethyl starch 2-8mg
8% starch slurry is an amount of
Magnesium stearate 0.5-1.5mg
2) scale 20mg:
Fluoxetine Hydrochloride 22.36-22.64mg
Starch 40-60mg
Lactose 40-80mg
Hydroxypropyl cellulose 16-30mg
Hydroxymethyl starch 4-16mg
8% starch slurry is an amount of
Magnesium stearate 1-3mg
2. general thin coating sealing coat:
HPMC?????????????????????????3～10mg
PEG??????????????????????????0.3～0.6mg
Pulvis Talci (100 order) 0.6～1.5mg
3. enteric coat layer:
Acrylic resin 15～45mg
PEG1500??????????????????????1.5～4.5mg
Pulvis Talci (100 order) 2.5～9.5mg
According to above-mentioned examples preparation tablet, carry out quality control by 2000 editions described enteric coated tablet quality standards of Chinese Pharmacopoeia, and carry out study on the stability by the stability test principle, the result shows that tablet stability is good.
The experiment also show, described tablet in gastric juice in 2 hours sheet shape intact, when touching the generic condition of small intestinal, can discharge contained fluoxetine rapidly.Press Chinese Pharmacopoeia 2000 editions, the 100 paddle methods of changeing are carried out external dissolution test, 2 hours release≤10% under the condition of 37 ℃ ± 0.5 ℃ and pH=1.2 in 750ml water; The 250mlNa that adds pH=12.5 after 2 hours
3PO
4Aqueous solution is to obtain the buffer of pH=6.8,45min release 〉=75%.
Claims (9)
1, a kind of Fluoxetine enteric coated tablet is characterized in that this pharmaceutical composition contains fluoxetine and optical voidness enantiomer or its pharmaceutically acceptable salt and pharmaceutically acceptable enteric coating coating material diluent and excipient.
2, Fluoxetine enteric coated tablet according to claim 1, its special sheet are that this pharmaceutical composition contains 0.1% to 30% fluoxetine and fluoxetine and optical voidness enantiomer or its pharmaceutically acceptable salt.
3, Fluoxetine enteric coated tablet according to claim 1 is characterized in that wherein said enteric coating material is one or more among acrylic resin, HPMCP, PAP or the CAP.The amount of enteric coating be sheet heavy 5～30%.
4, Fluoxetine enteric coated tablet according to claim 1 is characterized in that wherein said diluent is one or more in low-substituted hydroxypropyl cellulose, lactose, the master stream starch.
5, the described Fluoxetine enteric coated tablet of claim 1 is characterized in that these enteric coatel tablets contain 10mg or two kinds of specifications of 20mg fluoxetine.
The label of forming by fluoxetine and one or more excipient
Label 10mg:
Fluoxetine Hydrochloride 11.18-11.32mg
Starch 20-30mg
Lactose 20-40mg
Hydroxypropyl cellulose 8-15mg
Hydroxymethyl starch 2-8mg
8% starch slurry is an amount of
Magnesium stearate 0.5-1.5mg
Label 20mg:
Fluoxetine Hydrochloride 22.36-22.64mg
Starch 40-60mg
Lactose 40-80mg
Hydroxypropyl cellulose 16-30mg
Hydroxymethyl starch 4-16mg
8% starch slurry is an amount of
Magnesium stearate 1-3mg
6, Fluoxetine enteric coated tablet according to claim 1, its special sheet are that one or more and one or more excipient that wherein said enteric-coating material contains among HPMC, PVP, AEA, the HPC adds the general thin coating sealing coat that porogen is formed.
HPMC?????????????????3～10mg
PEG??????????????????0.3～0.6mg
Pulvis Talci (100 order) 0.6～1.5mg
7, Fluoxetine enteric coated tablet according to claim 1, its special sheet are that one or more and one or more excipient that wherein said enteric-coating material contains among acrylic resin, HPMCP, PAP, the CAP adds the enteric coat layer that one or more porogen in PEG, triethyl citrate, triacetin, DEP, the silicone oil are formed.
Acrylic resin 15～45mg
PEG??????????????????1.5～4.5mg
Pulvis Talci (100 order) 2.5～9.5mg
8, Fluoxetine enteric coated tablet according to claim 1, its special sheet are that wherein said diluent is low-substituted hydroxypropyl cellulose, lactose or master stream starch, accounts for 20～50% of tablet total weight amount; Excipient is defoamer, suspending agent and surfactant.
9, a kind of preparation method of Fluoxetine enteric coated tablet as claimed in claim 6 is characterized in that this method comprises the following steps:
(1) with principal agent and multiple excipient composition, adds binding agent system granule, drying, granulate then;
(2) with the granule and the mix lubricant of (1);
(3) with (2) with common tablet machine or high speed tablet press tabletting, obtain shallow circle or the oval tablet of hardness 5～8kg;
(4) gastric solubleness HPMC, PEG, Pulvis Talci are mixed, behind water dissolution, isolate the gastric solubleness clothing to the tablet bag, its weight accounts for 5～10% of tablet total weight amount;
(5) acrylic resin, PEG and Pulvis Talci being mixed, is enteric coating liquid with water or dissolve with ethanol, gives tablet enteric coated, and its weight accounts for 5～30% of tablet total weight amount.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03116666 CN1250208C (en) | 2003-04-29 | 2003-04-29 | Fluoxetine enteric coated tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03116666 CN1250208C (en) | 2003-04-29 | 2003-04-29 | Fluoxetine enteric coated tablet |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1541644A true CN1541644A (en) | 2004-11-03 |
| CN1250208C CN1250208C (en) | 2006-04-12 |
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ID=34320438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03116666 Expired - Lifetime CN1250208C (en) | 2003-04-29 | 2003-04-29 | Fluoxetine enteric coated tablet |
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| Country | Link |
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| CN (1) | CN1250208C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105168171A (en) * | 2015-10-23 | 2015-12-23 | 成都乾坤动物药业有限公司 | Andrographolide enteric-coated tablet as well as preparation method and application thereof |
| CN106176659A (en) * | 2015-05-05 | 2016-12-07 | 四川科瑞德制药股份有限公司 | A kind of tandospirone enteric coatel tablets and preparation method thereof |
| CN106937945A (en) * | 2017-03-27 | 2017-07-11 | 华益药业科技(安徽)有限公司 | Fluoxetine hydrochloride enteric coatel tablets and preparation method thereof |
| CN108553439A (en) * | 2018-04-20 | 2018-09-21 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of enteric coated tablet of carboxymethyl containing S--L-cysteine |
-
2003
- 2003-04-29 CN CN 03116666 patent/CN1250208C/en not_active Expired - Lifetime
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176659A (en) * | 2015-05-05 | 2016-12-07 | 四川科瑞德制药股份有限公司 | A kind of tandospirone enteric coatel tablets and preparation method thereof |
| CN106176659B (en) * | 2015-05-05 | 2019-07-12 | 四川科瑞德制药股份有限公司 | A kind of Tandospirone enteric coatel tablets and preparation method thereof |
| CN105168171A (en) * | 2015-10-23 | 2015-12-23 | 成都乾坤动物药业有限公司 | Andrographolide enteric-coated tablet as well as preparation method and application thereof |
| CN106937945A (en) * | 2017-03-27 | 2017-07-11 | 华益药业科技(安徽)有限公司 | Fluoxetine hydrochloride enteric coatel tablets and preparation method thereof |
| CN108553439A (en) * | 2018-04-20 | 2018-09-21 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of enteric coated tablet of carboxymethyl containing S--L-cysteine |
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| Publication number | Publication date |
|---|---|
| CN1250208C (en) | 2006-04-12 |
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Application publication date: 20041103 Assignee: CHANGZHOU SIYAO PHARMACY Co.,Ltd. Assignor: CHANGZHOU SIYAO PHARM Co.,Ltd. Contract record no.: 2014320000735 Denomination of invention: Fluoxetine enteric coated tablet Granted publication date: 20060412 License type: Exclusive License Record date: 20141128 |
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Granted publication date: 20060412 |
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